What Happens If Car T-Cell Therapy Fails?

What happens if CAR T-cell therapy fails? – In some cases, the cancer may not respond well to treatment, or the cancer may recur —or come back—later on. There are several reasons why CAR T-cell therapy may fail:

The cancer cells may stop making the antigen targeted by the therapy, which means the T-cells that were engineered for that specific antigen won’t work. This is called antigen loss. The CAR T-cells may stop destroying cancer cells due to a process called T-cell exhaustion. The CAR T-cells may not multiply, which will prevent them from targeting all of the cancer cells. The cancer cells may mutate, which means the T-cells can no longer identify the antigen they were programmed to destroy.

If CAR T-cell therapy is unsuccessful, the patient and his or her care team will work together to evaluate next steps, which varies from patient to patient.

What is the survival rate of CAR T-cell therapy?

What is the success rate of CAR T-cell therapy? – In studies, 9 out of 10 people with acute lymphoblastic leukemia whose cancer didn’t respond to other treatments or whose cancer came back had full remission with CAR T-cell therapy. Remission means the cancer can’t be detected in tests.

What are the options after CAR-T failure?

In this issue of Blood, Di Blasi et al highlight the transformational nature of chimeric antigen receptor (CAR) T cells, as well as the new unmet medical need in diffuse large B-cell lymphoma (DLBCL)—managing patients progressing after CAR T-cell therapy.1 Before the availability of CAR T cells, patients with chemotherapy-refractory DLBCL had an extremely low likelihood of response to conventional therapy and a life expectancy in the range of 6 months. Today, CAR T cells induce complete responses in approximately half of these patients, and long-term cure is approximately 40%.2 Di Blasi and colleagues use the French DESCAR-T (Dispositif d’Enregistrement et de Suivi des CAR-T) registry to assess the “real world” outcomes for 550 patients who received 1 of 2 available CAR T-cell products, axicabtagene cilolecuel or tisagenlecleucel, for multiply relapsed or refractory DLBCL. Among patients included in the registry, most had high-risk age-adjusted international prognostic index scores and had received >3 prior lines of therapy. At a median follow-up of 8 months after CAR T-cell infusion, 57% of patients have not progressed. Although this number is likely to decline somewhat with ongoing follow-up, a significant proportion of patients will clearly achieve durable remission because most CAR T-cell failures occur within 6 months of therapy. Despite this optimistic finding, 238 patients (43%) have progressed, for whom there is no agreed upon standard of care. The most commonly used systemic treatment after CAR T-cell progression in the DESCAR-T registry was lenalidomide (38%), followed by targeted therapies (21%), chemoimmunotherapy (20%), and bispecific antibodies (7%); an additional 11% received radiation therapy for localized progression (see figure). Response to post-CAR treatment was low at 14%, with only 7% complete responders, and was disappointing for all systemic therapies administered. The median progression-free survival (PFS) and overall survival (OS) were short at 3 and 5 months, respectively. On multivariable analysis, elevated lactate dehydrogenase (LDH) and ferritin were associated with inferior PFS, whereas progression within 30 days of CAR T-cell infusion, elevated LDH and C-reactive protein were all adversely associated with OS. No specific therapies were associated with an improved PFS by multivariable analysis, although interestingly lenalidomide was associated with improved OS (hazard ratio, 0.42; P =,01). Overall response rate (ORR), complete response (CR) rate, and median progression-free survival (PFS) after CAR-T relapse, according to treatment type. PR, partial response; SD, stable disease. See Figure 1 in the article by Di Blasi et al that begins on page 2584. Overall response rate (ORR), complete response (CR) rate, and median progression-free survival (PFS) after CAR-T relapse, according to treatment type. PR, partial response; SD, stable disease. See Figure 1 in the article by Di Blasi et al that begins on page 2584.

1. Close modal Among classes of treatments employed, chemoimmunotherapy produced the lowest overall response rate, which is not unexpected in a heavily chemotherapy pretreated population.
2. These patients are also more prone to myelotoxic effects of cytotoxic chemotherapy, which in addition would further impair activity of any persistent CAR T cells.

As such, alternate immunotherapies and targeted therapies hold greater appeal in terms of both efficacy and safety. The small number of complete responses observed with lenalidomide, bispecific antibodies, and targeted therapies, although disappointing, provide a welcome signal that patients can respond if given the optimal treatment.

1. The challenge, of course, is identifying what that treatment is for any given patient.
2. Among 45 patients treated with lenalidomide, 5 responded, including 3 complete responses, suggesting that some tumors are particularly susceptible.
3. This is consistent with recognized activity of lenalidomide in relapsed DLBCL, which appears to be most beneficial in activated B-cell (ABC)-like tumors.3 The OS benefit for lenalidomide in this population, despite generally low rates of response, raises the possibility that lenalidomide may be contributing to immune activation, including potential stimulation of persisting CAR T cells, which could be blunting the rate of progression and thus allowing patients to live longer.

Although this is entirely speculative, it reminds us that patients progressing after CAR T cells are distinct from CAR T-cell naïve patients, and that treatments that overcome CAR T-cell exhaustion and immune escape would offer unique appeal in the post-CAR population.

Targeted therapies accounted for the next most common class of therapy, with the most common agents being immune checkpoint inhibitors and ibrutinib, both of which are typically well tolerated in this heavily pretreated patient population. Immune checkpoint inhibition could be an appealing strategy to reinvigorate exhausted CAR T cells, but responses to programmed death (PD)-1 inhibitors as a class in the post-CAR setting have proven disappointing.4 This may reflect that numerous immune checkpoints other than PD-1 mediate T-cell exhaustion, but selected populations may be enriched for exceptional responders to PD-1 inhibitors.

One such subset is primary mediastinal B-cell lymphoma, which frequently carries amplifications of programmed death ligand (PD-L)1 and PD-L2, and for which PD-1 inhibitors have significant activity in the relapsed/refractory setting. Case reports demonstrate reexpansion of CAR T cells and durable responses to pembrolizumab in primary mediastinal B-cell lymphoma relapsing after CAR T-cell treatment, making this an appealing post-CAR treatment in this large B-cell lymphoma subtype.5 Ibrutinib carries the greatest appeal in treating relapsed/refractory DLBCLs with molecular features associated with response, such as ABC-like cell of origin and mutations of CD79B and MYD88 on next-generation sequencing.6 Bispecific antibodies represent one of the most appealing treatments currently under investigation in relapsed non-Hodgkin lymphomas, and have proven responses in heavily pretreated and previously CAR T-cell exposed patients.7, 8 These agents are presently only available on clinical trials in DLBCL, so protocol participation is encouraged for eligible patients.

Antibody drug conjugates are approved therapies with significant clinical activity in multiply relapsed DLBCL and can induce responses in patients progressing after CAR T cells. Polatuzumab vedotin, 9 targeting CD79B, and loncastuximab tesirine, 10 targeting CD19 (if persistent expression is confirmed at the time of post CAR T-cell progression), were not included in the DESCAR-T registry because of lack of availability at the time, but should be considered in patients without a compelling rationale for an alternative agent based on disease characteristics.

Finally, radiation can be a valuable tool for localized relapse or palliation of discrete sites of symptomatic disease. Ultimately, selecting treatment for patients progressing after CAR T-cell therapy today must be personalized and informed by multiple patient- and disease-specific factors, including histologic and molecular subtypes of disease, types of prior therapy, bone marrow function, and comorbidities.

What are the late effects of CAR T-cell therapy?

CAR T-cell Therapy: The Good, The Bad and The Long-Term

• CAR T-Cell Therapy: The Good, the Bad and the Long Term
• Saturday, April 30, 2022
• Presenter: Michael Tees, MD, MPH, Colorado Blood Cancer Institute, part of the Sarah Cannon Cancer Institute at Presbyterian/St. Luke’s Medical Center
• Presentation is 39 minutes long with 20 minutes of Q & A.
• This presentation was made possible, in part, by Kite, a Gilead Company.

Summary: CAR T-cell therapy is a new treatment option for patients with acute lymphoblastic leukemia, some lymphomas, and multiple myeloma that have not responded to prior therapies. This presentation describes how CAR T-cell therapy works, its risks and side effects, and how these may be effectively managed. Highlights:

• CAR T-cell therapy involves removing some of a patient’s T-cells and engineering them to recognize particular cancer cells. These enhanced T-cells are then returned to the patient’s body where they can attack cancer cells.
• CAR T therapy can cause cytokine release syndrome leading to fever, lower blood pressure, and shortness of breath. The likelihood of this side effect is high, but its severity varies a lot. There are several treatments for this problem.
• CAR T-cell therapy can also cause neurotoxicity or ICANS. The likelihood, severity and symptoms of neurological problems vary with the underlying disease. Neurotoxicity is almost always reversible.

1. Key Points:
2. (07:50): CAR-T cell therapy is currently approved for B-cell acute lymphoblastic leukemia, some lymphomas and multiple myeloma if other treatments have failed.
3. (09:46): Acute myeloid leukemia, myelofibrosis and some solid tumors are not yet good candidates for CAR T therapy.
4. (13:23): The correct T-cells must be selected for conversion to CAR T-cells in order to be effective.
5. (13:42): Viruses are used to insert genetic material into T-cells and convert them to CAR T-cells.
6. (15:38): Patients with aggressive disease may require bridging therapy to control their disease while CAR T-cells are being created.
7. (17:41): The major side effects between Day 0 and 28 are infection, cytokine release syndrome and neurotoxicity.
8. (27:46): After CAR T-cell therapy, “chemo brain” or “brain fog” can affect concentration and short term memory.
9. (29:45): Low blood counts and ongoing risk of infection are possible late effects of CAR T-cell therapy.
10. (32:33): Patients do not respond well to the COVID vaccine after CAR T-cell therapy, so precautions against COVID, like wearing a mask for a year, are important.
11. (33:39): Anti-viral therapy is recommended after CAR T-cell therapy to reduce the risk of shingles.
12. Transcript of Presentation:

(00:01): Introduction. Welcome to the workshop, CAR T-cell Therapy: The Good, the Bad, and the Long Term. I’d like to thank Kite, A Gilead Company whose support helped make this workshop possible. (00:12): It is my extreme pleasure to introduce our speaker, Dr.

Michael Tees. Dr. Tees is an associate member at the Colorado Blood Cancer Institute and a leader in their Lymphoma and Autoimmune Program. He focuses on the treatment and management of aggressive lymphocytic disorders and malignancies. Dr. Tees treats patients with standard approach CAR T-cell therapy as well as CAR-based therapies on clinical trials.

He favors the next phase of lymphoma care being rooted in an individualized and targeted approach and is excited about the rapid pace of development in the field. Please welcome Dr. Tees. (00:58): Overview of Talk. Well, thank you. Hi. My name is Mike Tees.

As Michelle said, I am the lymphoma director at Colorado Blood Cancer Institute in Denver, Colorado. Thank you everybody for tuning in today and learning about CAR T-cell therapy. Today, I just wanted to talk about three major objectives: share what CAR T-cell therapy is and why it’s used; explain the short term side effects and toxicities of CAR T-cell therapy; as well as (01:39): Bone marrow inside bones is home to hematopoietic stem cells that produce the body’s blood cells,

To get a better picture of CAR T-cell therapy, I want to start from the top. I draw this picture out on paper to pretty much every single patient that I meet. If any of my patients are in the audience, perhaps you have a little more of a heads up than everybody else and this is a little bit of a biology education.

Everything in the blood system starts with the bone. The bones hold up the body, but they also contain an environment where stem cells grow. Stem cells that live in the bone marrow are called hematopoietic stem cells. Heme is blood and poetic is Latin for growing; so blood-growing stem cells. Hematopoiesis means blood cell growth.

(02:23): They turn into two major types of cells: myeloid cells and lymphoid cells. For many of you in the audience, you’re probably somewhat familiar with many of the myeloid cells. Platelets. Platelets help form blood clots. Red blood cells. Red blood cells carry hemoglobin and hemoglobin carries oxygen to your body.

• Then neutrophils.
• Neutrophils are very important to fight bacterial infections.
• Neutrophils (02:56): The three major lymphoid cells in the immune system are T-cells, B-cells, and NK cells,
• There are three major types of cells.
• I used to just say two major types of cells, but NK cells are becoming a little bit more prevalent or prominent, I guess you could say, and we’ll talk about that in a little bit.

But the way I describe the lymphoid cells is like a military for better or for worse. T-cells are the front lines of the military. They fight the bad folks by recognizing what looks like you and doesn’t look like you. If it looks like you, it’s a friend.

• If it doesn’t look like you, it’s an enemy and it can kill it.
• 03:29): The B-cells are described as like the generals of the army.
• They have the memory and the strategy, and the understanding of what basically needs to occur.
• A good example in B is if you got an infection like the flu, for example.
• If you got sick and then you got better again, it’s because the B-cells eventually understand that.

Then they tell the T-cells, “Oh, I know what this is,” when you get re-exposed and then you don’t get sick because the body takes care of it, because of that inherent memory that has formed. Part of how they do that is actually turning into plasma cells.

• For those of you who may be on the call with a history of multiple myeloma, it is plasma cells that is the derivation of your disease.
• That actually has a lot more relevance as we move forward because CAR T-cell therapy is being used in multiple myeloma.
• 04:24): Now, the other one at the top or to the side right here is the NK cells; those stand for natural killer cells.

It’s a remnant of an archaic immune system, but it does have some natural infection-fighting and actually some natural tumor-fighting abilities. (04:45): To understand CAR T-cell therapy, I just want to do a brief review of what the two different types of stem cell transplants are and how it fits into CAR T-cell therapy.

04:58): In an autologous stem cell transplant, some stem cells are removed, chemotherapy is administered, and the same stem cells are returned. For autologous stem cell transplant, the treatment is high dose chemotherapy. The two major regimens that are used for most diseases are BEAM or melphalan. As you might be aware, it’s not actually the stem cell transplant that’s doing anything.

It’s really actually just bypassing the major side effect of the chemotherapy, in that it eradicates all your hematopoietic stem cells. For that reason, we have to collect your stem cells before the treatment, do the treatment, and then give you back your stem cells.

The correct term is actually high dose chemotherapy followed by stem cell rescue. That’s really difficult to say, too many words. So we just call it autologous stem cell transplant or stem cell transplant, which is a lot scarier of a word, but it’s really the chemotherapy that’s doing the job. (05:50): If chemotherapy is not effective in treating a cancer, an autologous stem cell transplant may not be the best treatment option,

What if you didn’t respond to chemotherapy to begin with? For example, if you had an aggressive lymphoma like diffuse large B-cell lymphoma. If you got the standard treatment CHOP or R-CHOP, for example, or RICE, if you didn’t respond to that, would you get a stem cell transplant? That’s a good question.

It depends on the person; it depends on the patient. But the example is that if you don’t respond to chemotherapy, you might not be a good person to get a stem cell transplant because the whole reason that we do the treatment is for that higher dose chemotherapy to try to eradicate any residual disease or at least decrease the burden of disease.

(06:31): In an allogeneic transplant, it is the donor cells that fight any remaining leukemia after chemotherapy. The other type of stem cell transplant is allogeneic stem cell transplant. The idea is that we first eradicate the immune system with, what we call, conditioning therapy.

It depends on intensity of conditioning, there actually might be some additional anti-cancer benefit. (06:47): It depends on many different factors on what your regimen would be and how aggressive that would be against the disease, but what we truly want is something called the graft-versus-malignancy effect.

That’s also called the graft-versus-leukemia or the graft-versus-tumor effect; a lot of different names for the same thing. Maybe even graft-versus-lymphoma effect if you were a patient that got a transplant for follicular lymphoma, for example. Essentially, you want the donor’s immune system to recognize the cancer as foreign.

1. If you recall a couple of slides back, that’s exactly what T-cells do; it recognizes what looks like you and doesn’t look like you.
2. If you are getting someone else’s immune system, the idea is that perhaps it could recognize your cancer as foreign and take care of the disease.
3. 07:35): The corollary to that is graft-versus-host disease.

That’s what we don’t want and that’s when the donor’s immune system recognizes other aspects of your body as foreign. But the source of all that are T-cells. (07:50): CAR-T cell therapy is currently approved for several B-cell acute lymphoblastic leukemia, some lymphomas and multiple myeloma if other treatments have failed,

Who gets CAR T-cell therapy? Right now, there are a couple of indications by the FDA. For those of you that are out of the country, I’m just speaking of what’s approved in the United States. Well, for refractory acute lymphoblastic leukemia. This is B-cell acute lymphoblastic leukemia. And it’s for patients who are not responding to therapy.

That’s refractory disease. It’s currently used to achieve disease control. For most patients, it’s proceeding onto an (08:23): Other approvals are for diffuse large B-cell lymphoma, and that was one of the original approvals, and also other aggressive B-cell lymphomas.

There’s some that are in the same category as that disease. It’s for patients who are refractory to two or more lines of therapy: in follicular lymphoma after failing two or more lines of therapy; mantle cell lymphoma after two or more lines of therapy. And then multiple myeloma after four or more lines of therapy.

(08:49): In all of these diseases, we’re looking at them in other settings as well. For example, what we started investigating several years ago, diffuse large B-cell lymphoma in the second-line setting. It just got approved about four weeks ago that CAR T-cell therapy would be indicated for patients who have relapsed within one year of their initial therapy or that are refractory to their first line of therapy.

1. 09:23): Other lymphomas and solid tumor cancers may soon be treated with CAR T therapy,
2. Where is the CAR driving to next? Well, we’re very close to treatment for CLL and small lymphocytic lymphoma, Hodgkin lymphoma, and also, some of the “solid” tumors: that’s glioblastoma; hepatocellular carcinoma, that’s actually liver cancer; and prostate cancer.

(09:46): Acute myeloid leukemia, myelofibrosis and some solid tumors are not yet good candidates for CAR T therapy. Now the ones that we’re a little bit far away from, unfortunately, those are the myeloid diseases: that’s myelodysplastic syndrome; acute myeloid leukemia; myelofibrosis; and some of the other solid tumors.

1. I’ll explain a little bit more why we’re not there just yet for those, but we’re still working.
2. 10:06): What is it ? I told you a little bit about the T-cells.
3. They basically recognize what’s good and what’s bad.
4. But right now for pretty much all diseases, I guess you could say, if you don’t have a T-cell that could recognize the cancer, then you’re in bad shape.

But more importantly, it’s because your diseases love you. Your disease looks like you. (10:34): CAR T therapy re-engineers T cells to recognize and kill cancer cells, How do your T-cells know what’s good and what’s bad if the cancer itself looks like you? The idea is that, “Let’s re-engineer these T-cells, so they know what they need to do, which is kill the cancer,” and that the current process goes something like this.

(10:52): First step in CAR T-cell therapy is to get insurance to approve the treatment. Step 1 is get insurance approval. That’s a very important aspect of it because this is a very expensive therapy. I gave some ballpark numbers right there. But every program, every, unfortunately, insurance company is a little bit different on this.

Also, a lot of it depends on if you’re also entering a clinical trial. Sometimes, it’s actually a little bit quicker; sometimes a little bit not as quick. But it does take some time to actually get all the pieces together to allow you to proceed to this type of treatment.

(11:27):, Part of that now is also how quickly these T-cells can be created. For the majority of CAR T-cell therapy recipients, this is going to be what we call a “commercial” product. “Commercial” means that these are pharmaceutical products. These are made at an institution or program, or pharmaceutical company and that process on how to manipulate these T-cells is a process that the pharmaceutical industry has created.

It allows these cells to be made under a controlled environment. For that to occur, there needs to be a slew of processes to ensure that when we send these cells away, that their production is going to occur at the right time and that it’s going to be received at the right time.

Are there too many cells that are going to arrive all at once and how can they actually manage that? There’s a lot of moving pieces to, actually, that first step. (12:31): The next step is actually collection of the T-cells and growth. The third step is the giving of low intensity chemotherapy followed by the CAR T-cell infusion.

The fourth step is monitoring for the side effects and toxicities. (12:51): This is outlying the exact process of the collection phase, the step 2, I guess you could say, from the slide before. This woman looks very happy, but I guess she’s happy about the possibility of getting these T-cells.

• But the first step is that she’s going to be getting the T-cells taken out and then they get shipped away.
• For many programs, it’s actually done perhaps in-house if it’s a clinical trial.
• Maybe we’ll say it gets shipped internally, but sometimes it’s also being shipped internationally.
• It depends.
• 13:23): The correct T-cells must be selected for conversion to CAR T-cells in order to be effective.

Then the next step is selecting the correct T-cells. I gave a very broad picture of what T-cells are, but there’s many different types of them. We want to make sure that the correct ones are selected because if the correct ones are not and then they might not actually do the job.

• 13:42): Viruses are used to insert genetic material into T-cells and convert them to CAR T-cells.
• The third step is transferring the genetic material to make the CAR into the T-cells.
• It says viral vector transfer.
• There’s many different viruses in the world.
• Obviously, we’re very familiar with that, but these are viruses that don’t actually infect in a bad way.

They’re just transferring the DNA. That DNA is going to tell the T-cells to grow a certain receptor on the outside of the cell. That’s what CAR stands for, chimeric antigen receptor. Chimeric just means it’s a combination of molecules that physically wouldn’t be made if the code wasn’t there.

The next step, then, is to expand these T-cells followed by returning back to the institution, to then ensure that you’re treating the patient. (14:39) It may take roughly three weeks to create and return CAR T-cells to patient. While you’re waiting for that process to occur, there’s a couple of things that might need to happen.

The standard right now, it’s about 14 to 22 days, we’ll say, for those CAR T-cells to be manufactured. Depending on certain clinical trials, that can actually be up to five to six weeks. Because with newer types of, let’s say, products, the CAR T products or CAR NK products, which we’ll get to in a little bit, there might be longer processes that need to occur.

• There might need to be more checks and balances to ensure that, again, it’s the right cells that are being manipulated, the right cells that are being expanded.
• Very, very complex stuff that’s happening and I very much simplified here on the last slide.
• But for the most part, it is roughly about three weeks from the time of removing your T-cells to the time that it comes back to the program where you can get the treatment.

(15:38): Patients with aggressive disease may require bridging therapy to control their disease while CAR T-cells are being created. For many patients, especially those with aggressive lymphomas, for example, they might need some bridging therapy to keep that disease under control.

• Everyone’s a little bit different on this one because you might still have an aggressive lymphoma, for example, or multiple myeloma that perhaps does not need some bridging therapy, but that’s a conversation with you and your treating physician on that aspect of it.
• 16:08) A few days before infusion of CAR T-cells, patients receive low-dose chemotherapy to suppress their immune system,

Approximately five days prior to the CAR T-cell infusion, you’re going to start some lower dose chemotherapy. The reason for that is because even though these cells are you, they’re not exactly you and your immune system might recognize them as foreign.

The idea is that we give two. Typically, it’s two lower dose chemotherapeutic agents and they’re designed just to somewhat knock down the immune system in order for you to accept these cells back. We call it lymphodepleting chemotherapy. (16:43): CAR T-cells may be re-infused in the hospital or outpatient setting.

On Day 0, you get the CARs infused into you. Some programs are doing this all in the inpatient setting; some are also doing this in the outpatient setting. We’re doing a mix of the two and it depends on a couple of different factors. Well, actually, it’s the next topic, which are the side effects and toxicities.

But you get the cells infused and then it’s watching and waiting. It’s not exactly like a stem cell transplant, where you are waiting for those stem cells to find its home, which is back into the bone marrow, start to grow, and reproduce. The reproduction of these T-cells actually happens relatively quickly.

It starts to expand and ideally starts to do its job, which is to start to kill the cancer. With that process comes some side effects. To be honest with you, some of these side effects can still occur even if these CAR T-cells don’t do what you want it to do, which is to kill the cancer.

(17:41): The major side effects between Day 0 and 28 are infection, cytokine release syndrome and neurotoxicity. For these reasons, if you are not in a hospital setting, if you’re not admitted to the hospital, you would definitely need to be close to that treatment center. (18:03):, On Days 0 to 28, infection; I just brought that up.

It’s primarily for a couple of different reasons. The first one is lymphodepleting chemotherapy. They’re two lower dose chemotherapies that does knock down immune system to a level where you would be, what we call, neutropenic, which is probably familiar terminology to many of you.

1. You will be on some prevention antimicrobials.
2. This typically occurs between Day 0 through Day 14.
3. After the neutrophils recover, you will also be continued on an anti-viral medication to help control the risk, primarily, of shingles.
4. 18:43): But this is the big one.
5. This is the biggest concern and the biggest possibility for why you need it to be treated at a program that really knows what they’re doing.

If you are being talked about CAR T-cell therapy by a provider, you’re probably at a program that knows what they’re doing because it’s actually well-controlled, the programs that are able to do this type of treatment. (19:10): Cytokine release syndrome can cause fever, low blood pressure, and shortness of breath.

But as the T-cells expand in your body, they do release natural chemicals. These are called cytokines and these are the natural chemicals that the immune system uses to communicate with each other. If you have a fever, when you get sick, that’s actually being driven by cytokines. It’s telling the body to basically cook out these bacteria that’s maybe causing you to get sick.

It’s a natural immune phenomenon that occurs that comes from T-cells. (19:43): If you are given T-cells to help fight the cancer and it starts to do its job, starts to grow and reproduce, it’s going to start to throw out these natural chemicals. It’s going to mimic like you’re very sick.

1. There’s a very wide spectrum of how ill you could potentially get.
2. We call it cytokine release syndrome.
3. You could get absolutely nothing, which would be great, to it being very severe.
4. The big three is fever, lower blood pressure, and shortness of breath.
5. Shortness of breath comes from having fluid, basically, in the lungs in this reaction that occurs.

Your oxygen level could go down; you might need oxygen support. (20:25: The risk of developing cytokine release syndrome varies depending on amount of disease one has before CAR T-cell therapy and the type of CAR T product you get. Those with a higher disease burden before CAR T-cell therapy do have an increased risk of CRS.

The risk is also dependent upon the exact product that you get. There’s a couple reasons for that, but primarily it’s because of how the CAR T-cells are “built”. Sometimes, there’s different genetic makeup that, basically, turns on the cells in a different way. It might turn on very quickly or it might turn on a little bit later on but expand out in a different way.

Long short is basically that everyone’s risk cannot be clearly defined. For that reason, we have to watch you very closely no matter what. (21:12): Most patients develop cytokine release syndrome. Oh, I guess that’s the next slide. I’m sorry. But will you get it? It depends, but the short answer would be probably yes.

For ALL patients, it’s about 80 to 90%. For diffuse large B-cell lymphoma, follicular lymphoma, it can range between 40 to 80%. Mantle cell lymphoma is actually up to 80%. In multiple myeloma, fairly high. But the severity might be different amongst all of that. If I said, “Oh, yeah. You have an 80% of getting it, but you might get a fever that’s different than 80% of patients getting it and then needed blood pressure medicines and advanced cardiac support, for example.” But it is something to be aware of going into it, that it tends to start between Days 3 to 5 and lasts about five to 10 days.

It’s a wide variability if and when it does present, how severe it is, and how long it lasts. (22:07): There are several treatments for cytokine release syndrome but they have their own side effects. The treatment is a medicine called tocilizumab or comparable medicines such as one called siltuximab and steroids.

1. It is completely reversible, but there can be secondary effects.
2. That’s where there can be some longer term injuries that can occur.
3. For example, if your blood pressure drops too low and you can’t get the blood and the oxygen to support your kidneys, for example, that could cause kidney injury.
4. Steroids can increase the risk of infection.

If you’re very sick and you’re not able to move out of that hospital bed, you could get deconditioned and lose lots of muscle mass. (22:49): Neurotoxicity, also called ICANS (immune effector cell-associated neurotoxicity syndrome) can occur after CAR T-cell therapy.

• The third major side effect is neurotoxicity.
• You can probably guess what that means, but really the correct term is actually immune effector cell-associated neurotoxicity syndrome; that’s where ICANS comes from.
• But it’s actually a similar process.
• It’s driven by cytokines.
• Those natural chemicals that are released by those T-cells can cross over the blood-brain barrier and basically jumble up the wire.

That’s why I describe it to patients, is that all the neurons in your brain that allow you to remember what day it is, what your children’s names are, allow you to connect your brain, your main computer system to your body to tell you to breathe, those can get jumbled, all those wires by the cytokines.

That can make you very, very sick. It can be something from a simple. Sounds simple, but just forgetfulness to actually not being able to comprehend. Severe is something like seizures; that can actually occur. (23:54): To monitor for this, you’re going to get very frequent, standardized assessments. It’s repetitive.

Patients don’t get offended. You’re going to be asked the same questions. What day it is? Can you write a sentence out? Because if we start to notice some change in your writing, for example, that could be a signal of things to come. The idea is that we’re identifying it sooner rather than later.

(24:25): The likelihood, severity, and symptoms of neurotoxicity depend on the underlying disease, Will you get it? It depends. It’s not easy to predict, but there are certain diseases and certain treatments for those diseases that do have a higher risk. ALL is another one. Again, mantle cell lymphoma is also high on the list.

Now for multiple myeloma, it’s actually. I apologize. This is not probably the correct way to put this in this slide, but there is a lower incidence of the standard neurotoxicity that we tend to see for other types of CAR T-cell therapies. But we do see a unique type of neurotoxicity that’s related to multiple myeloma CAR T.

There can be these Parkinsonian-like symptoms. There’s other unusual tremors and motor neuron-type issues. It tends actually to be perhaps a little bit later than Day 0 through 28. We’re going to understand a little bit more about that one over time, but it is something that your CAR T physician will probably be talking with you about.

(25:34): Neurotoxicity can be treated with steroids and is almost always reversible, Now neurotoxicity tends to begin around Days 6 to 9 and it tends to last about 11 to 20 days. It’s a little bit shorter for those with multiple myeloma. There’s a wide variability of if and when it presents, how severe it is, and how long it lasts.

• The treatment is steroids.
• Neurotoxicity is almost always reversible, but there can be those secondary side effects.
• If you’re on steroids to treat anything, you can oftentimes become deconditioned.
• It’s always important to stay as active as possible if it’s safe.
• 26:09): CAR T-cell therapy is very expensive and it takes time to get insurance approval.

Now is a good time to talk about the financial toxicities. That’s a very real issue. I do need to bring this up because this can come up at the wrong time. Well, there’s never a good time to talk about this. I brought it up earlier, but the cost of this cell therapy itself is absurd.

It’s absurd; I’ll just say that. The cost of the supportive care also somewhat absurd. But if you think about it, you could do great, not have any complications whatsoever, or you could get very, very sick, and be in a critical care unit needing to be on medicines that are helping support your heart or you need to be on a ventilator for a brief period of time.

You need to be on antibiotics if you’re having a fever. All of that adds up in the cost of overall care. That makes it very difficult for insurance companies and those who are covering the cost of care to determine what is the best price to pay. (27:14): For that reason, it does take some time before the treatment even begins for your coverage entity, we’ll say, to agree with that program on how to cover the cost of your treatment.

1. More than you ever want to know, but it does sometimes cause some unnecessary delay.
2. I’m hopeful that over a time as the treatment is becoming more and more prevalent and necessary, that this is less of a problem.
3. 27:46): After CAR T-cell therapy, ” chemo brain” or “brain fog” can affect concentration and short term memory.

Now, the longer term. I guess we’ll say the intermediate term. There is a concept of something called brain fog. This is something that I’m going to probably put in the anecdotal-type realm, but it’s something very real that my colleagues across the country also notice.

It’s getting out there a little bit. It’s a little bit of a delay in that maybe neurotoxicity. All right? Essentially, some people could put it in the realm of the chemo brain. There’s two major things of chemo brain. I would say there’s two major things that I’ve noticed with brain fog; it’s concentration and short term memory.

One of also the reasons why it’s not advised to drive about two months after the cell infusion because your reaction time might be a little bit decreased. It’s one of the main reasons that even though people say, “I feel fine.” I say, “You know what? Maybe just take the bus.

• Actually, don’t take the bus.
• Wear a mask if you’re going to take the bus.” But maybe find a different way to get to work.
• Take an Uber type of thing.
• 28:52): But in those patients with this brain fog, it is actually a little bit difficult to get back to work.
• It does resolve.
• I’ve seen it in every single one of my patients, but it’s something just to be thinking of because it’s not something that’s very well reported.

If you have the ability to maybe take some time off of work for a little bit longer to allow your body to heal and recover from a very serious type of treatment like this, please consider that if it’s available to you. Now there is a real thing. It’s likely because of the cytokines that are lingering and some disruption in the communication of the neurons across the body perhaps, but something that’s not to minimize.

(29:45): Low blood counts and ongoing risk of infection are possible late effects of CAR T-cell therapy. The other late effects and something that’s underreported from the initial studies that led to many of the CAR T-cells being approved is blood counts. You actually can have a prolonged cytopenia; basically, low hemoglobin, low platelet count, and of course, low neutrophils, neutropenia.

This can actually last up to, I would say, about six months for some patients. It resolves over time. You could say that some of the bad comes with the good on this one because it is associated with patients who have persistence of their CAR T-cells. That’s important for some diseases because if they’re sticking around, it’s probably because they have some work that they still need to do.

• As long as you’re being supported appropriately and know that that’s going to resolve over time, then you should be okay.
• 30:43): On that note, somewhat related to these late effects is risk of infection.
• I told you about the shorter term risk of infection that’s typically related to the neutropenia; so low neutrophils that fight bacterial infections.

But CAR T-cell therapies target for the most part. Actually, I do a quick lesson on this I guess, but for the B-cell lymphomas, for follicular lymphoma, for mantle cell lymphoma, for diffuse large B-cell lymphoma, for acute lymphoblastic leukemia, it’s CD19.

1. It’s called Clusters of Differentiation 19.
2. It’s something on the outside of the cancer cell that’s unique to that,for the most part, and that’s how the T-cell recognizes the cancer.
3. For myeloma, it’s called BCMA.
4. 31:34): Now both of those targets are actually on healthy immune system cells, healthy B-cells.

It’s not too much of a concern if the CAR T-cells attack healthy B-cells for a brief period of time. But if it’s persistently attacking the healthy B-cells, you’ll have an effect on that memory aspect of your immune system. If you recall on one of the first couple of slides, I said that the B-cells were like the generals of the army.

1. If you knock out the generals of the army or they all quit, then the troops don’t know what to do.
2. The rest of the crew won’t know how to fight something and that’s exactly what we see.
3. This could be actually up to a year or so where patients who have received CAR T-cell therapy have a weakened immune system to the extent that it’s more than likely very much similar to those who get an autologous stem cell transplant.

(32:33): Patients do not respond well to the COVID vaccine after CAR T-cell therapy, so precautions against COVID, like wearing a mask for a year, are important. For those who have received an autologous stem cell transplant or even an allo transplant, more than likely you receive post-transplant vaccinations.

In some programs, it starts at six months and others, it starts at one year. We start ours at one year. That’s just to re-educate the immune system. Also, within the era of COVID, we have been seeing that patients don’t respond as well to the COVID vaccine after CAR T-cell therapy. That’s because we’re knocking down, unfortunately, the good immune aspect of immune system.

It will eventually come back, but it’s important to know this that you do have a prolonged risk of infection. If we wanted to say that there was anything good about COVID, which is nothing, no one looks at you funny if you’re wearing a mask anymore. I would be advising that patients wear masks for at least a year after CAR T-cell therapy in public.

1. 33:39): Anti-viral therapy is recommended after CAR T-cell therapy to reduce the risk of shingles.
2. This is essentially saying the same things.
3. I’m just going to be a little bit briefer on this one.
4. But essentially you do have a risk of shingles, which is why the recommendations that you would continue an anti-viral therapy.

There’s a risk of a certain type of lung infection called Pneumocystis pneumonia. You would want to be on an antibiotic for likely about 12 months after a CAR T-cell therapy; three times a week is not too bad. (34:04): Natural antibodies are called immunoglobulins.

IgG is the most common one and that helps fight mainly sinus and pulmonary infections, respiratory infections. In many patients, it is low for a period of time. For this reason, IV immunoglobulin, IVIg is oftentimes administered on a monthly to every six-week basis for some patients after that CAR T-cell therapy just to simply support the immune system and reduce the risk of viral and sinus, and pulmonary infections.

(34:35): Now if you had a decrease in neutrophil count, then you could also get a medicine called G-CSF. Brand names are called Neupogen or Zarxio or Granix, but they do help support the neutrophils. Many CAR T-cell patients respond beautifully to that medicine.

Again, vaccinations would be advised. (34:57): Late neurological effects after CAR T-cell therapy have been reported. Other late effects, there have been some rare, long term neurologic effects. I am not entirely sure that this is as much as perhaps been reported. It’s definitely less than 1%. It’s not clear if they’re actually associated with the therapy or perhaps it was associated with other therapies in the past.

Or it was something that maybe was undiagnosed and then it’s presented afterwards, and saying, “Okay. Well, maybe it was associated with CAR T-cell therapy.” (35:38): Some patients have developed skin cancer or myelodysplastic syndrome (MDS) after CAR T-cell therapy, but it is unclear whether that’s related to CAR T or prior treatments.

1. Now there is some second malignancy risks.
2. I can probably tell you that a lot of it is not necessarily directly related to the CAR T-cell therapy.
3. It’s probably because many patients had required several lines of other therapies prior.
4. That addition of all those treatments do make patients prone to have an increased risk of skin cancers and an increased risk of something called myelodysplastic syndrome, which is another type of blood cancer.

There are some things in the pipeline that is allowing us to decrease the toxicity and allowing us actually to do more treatments in the outpatient setting. One example is using steroids at Day 0 through 2 after CAR T-cell therapy. It’s shown to reduce the severity of cytokine release syndrome in lymphoma patients.

Many clinical trials are investigating ways of reducing a toxicity. (36:39): Many studies are underway to improve CAR T-cell therapy and expand its use to other cancers. The future, well, when CARs fly, there’s different ways of looking at where we’re going to be going into the future. There’s so many different paths and the field is changing so quickly, but it’s very exciting.

One way is actually instead of having to wait three weeks perhaps for the CAR T-cells to be produced, what about just educating your body to make the T-cells themselves? That’s under investigation right now at several programs across the country. (37:10): What about using those natural killer cells, the remnants of an archaic immune system that can recognize you versus not you? What about just re-engineering them to recognize another aspect of what the cancer is on the outside and use that one-two punch effect? We’re investigating that at CBCI using different immune system cells.

• Monocytes are one cell that turns into something called a macrophage; that’s one example.
• 37:42): What about using T-cells or NK cells that are available and ready to go from donors? That’s another aspect of the future.
• Then re-engineering the drivers of the toxicity, re-engineering and taking out those genes that’s called knockout.

Knocking out those specific genes that could actually drive the toxicity. (38:11): One last thing is that we are actually investigating this type of treatment for the “solid” tumors and those are the ones that are non-blood cancers. If you have a target that’s unique to a cancer, you might be able to create a CAR T-cell to fight that.

1. Now there’s a lot of aspects on why that has some work to do and why we’re a little bit farther behind on that.
2. But we’re getting there and it’s quite exciting.
3. With that, I want to thank you all for your time.
4. Question and Answer Session (38:49): Wow.
5. Thank you, Dr.
6. Tees, for an excellent presentation.
7. Very, very informative.

We will now take questions. We’ve got a lot of questions, Dr. Tees. I hope you’re ready. What is my role as a caregiver for my husband who will go through CAR T-cell therapy? What can I expect and how does my role as a caregiver differ from caring for someone during or after transplant (39:28): Oh, that’s a great question.

Well, I would say big picture, your role would be the same as it would be if you had an allo or an auto transplant as you would for a CAR T caregiver. You are the second set of eyes and ears for that patient. You’re their lifeline. Not in that term, I guess you could say, but you are the one that will be calling or bringing in your loved one if and when he or she gets sick.

You are going to be educated. You should be educated on what are the signs to be looking out for. If your loved one gets a fever, you’re going to be calling the on-call service, where you’re going to be bringing in. You’re going to follow to the T what you’re educated because each program’s a little bit different.

But you’re going to be looking out for a fever, most importantly. (40:25): Then I would also be saying that it’s typically family members that notice the first nuances, the first signs of those neurologic changes. Years ago, when the first patients were being treated for CAR T-cell therapy, it was quickly realized that it’s almost like those wires just aren’t connecting correctly.

Your loved one might say just the wrong thing or just not act who they are for brief periods of times. It’s oftentimes the loved ones that are picking up on that even before we objectively identify that. That is something to share when you’re at the appointments or share with the care team if your loved one’s in the hospital, but your role is to be the eyes and ears when you’re not in that healthcare environment.

Now what you need to do and ask questions on, if you don’t know, how to actually reach out to your care team when you’re not in that office or when you’re not in the hospital. (41:37): Dr. Tees, well, if a patient was exhibiting new signs of weakness, would that be something you’d want a caregiver to report as well? (41:47): Absolutely.100%.

Absolutely. Yeah. Because it could be something normal if your immune system is weaker, but it might not be. It might be a signal of something else. It could be that their blood pressure is a little bit lower or maybe it’s a reaction to one of the medicines, but absolutely.

1. 42:13): Great response.
2. I have multiple myeloma.
3. What do you consider a line of therapy? Your slide said I must have a minimum of four lines of therapy before I can qualify for a CAR T.
4. 42:27): Yeah.
5. That’s a very good question as well.
6. As of right now, the standard of care treatment for multiple myeloma in the United States is induction therapy.

Well, say just Rvd, it’s a very common one, followed by stem cell transplant, followed by maintenance therapy. Many studies look at that as one line of therapy. Then if your disease comes back, you get another line of, let’s say, daratumumab-based treatment.

That’s a second line and so on, and so forth. (43:05): But each study actually has their own unique criteria on what they determine as a line of therapy. For example, if you received radiation to a lesion, for example, some studies might actually consider that a line of therapy. It ends up being the institution that determines if you meet the internal criteria and then they decide if you meet the candidacy of either trial or standard of care for multiple myeloma.

When I say standard of care, I mean that “commercial” products, the ones that are already proved by the FDA. (43:47): The next question is: What is meant by bridging therapy? (43:53): Yeah. Good question. When you get the T-cells removed from you and when they move on to the production of those cells, it typically takes about three weeks for that to occur.

For many diseases, three weeks is a long time. It’s not the case for all cancers, but sometimes, for example, an aggressive diffuse large B-cell lymphoma, if you’re not responding to all the treatment, three weeks is a long period of time for that cancer to keep growing. Let’s suppose it’s in a bad area of your body where, let’s say, it’s pushing upon your kidneys.

Well, I don’t think we can wait three weeks to see if this medicine will work or the CAR T-cell therapy will work. (44:43): Bridging therapy is done between the time of your leukapheresis, or removal of your T-cells, and from the time it takes for it to come back in order for you to get the treatment for CAR T-cell therapy.

• It’s about three weeks roughly.
• You would get treated soon after the cells are removed in order to try to control the disease for a period of time.
• Now some programs actually do that even if your disease maybe isn’t “taking off” or being that aggressive because some evidence suggests that going into CAR T-cell therapy with as little disease as possible have better outcomes.

Your provider might be recommending it even if your disease isn’t very aggressive, I guess you could say. (45:33): Terrific. Our next question is: How long do people stay in remission after CAR T? Is it a cure or a temporary remission? (45:44) Yeah. Tough question.

Well, it depends. It depends. I always tell patients I don’t like to use numbers. Everybody likes numbers, of course. But you’re one person, right? Your response is either it works or it doesn’t work. Your doc and your care team would ideally have a plan of action if it doesn’t work. If it does work, then great.

In general, roughly speaking for diffuse large B-cell lymphoma and the related aggressive lymphomas, it is at roughly 40 to 50% long-term response rate. Response rate, we would call, perhaps a cure. For acute lymphoblastic leukemia, that could be closer to 40%.

For mantle cell lymphoma, that could be about 60%. For follicular lymphoma, it’s looking like it’s about 50 to 60%. It’s tough to say. (46:56): If you think about where we were, I don’t know, let’s say just 10 years ago, where we are now is that we’re using this for many patients that don’t have an option, who didn’t have an option in the past.

Where we’re also going more quickly though, is, well, if this is a treatment that actually works for the longer term for many patients, what if we did it earlier on in their treatment? That’s one thing that I showed a slide, for example, for aggressive lymphomas, diffuse large B-cell lymphoma.

It was approved on April 1st for patients in the second line setting if they’ve had a relapse within one year of their first line therapy or didn’t respond to their first line therapy. (47:43): In many patients, you would be actually replacing a stem cell transplant. It’s actually taking away one of the therapies that we have currently been using for a long time that has shown benefit because perhaps CAR T-cell therapy actually has an additional benefit on top of that.

We have a lot of understanding still to know what a complete response truly means, if it’s actually a cure. We’re starting to see that more with, what we call, real world data following patients for the long term. (48:26): This next question really aligns with what you were just talking about it.

It’s asking more questions about number of lines of therapy and I’m going to assume this one is about lymphoma. It says, “When you say that the treatment has been approved after two lines of therapy, can you give examples of the lines of therapy that are considered?” (48:48): Yeah. For lymphoma, if a patient has received their first line of therapy, we’ll say it’s R-CHOP and they got a complete response, that’s one line of therapy.

If their disease comes back, then they would be getting another line of treatment; that would be a second line of therapy. If that doesn’t work, they would be a candidate for CAR T-cell therapy. If it did work, then they moved on to a stem cell transplant, that’s considered a line of therapy right there.

Then if their disease comes back again, then they’re a candidate for CAR T-cell therapy. That’s the example, I guess, for aggressive lymphoma. (49:38): For other types of lymphoma such as follicular lymphoma, for example, maintenance therapy would not be considered a line of treatment. A standard induction treatment for follicular lymphoma will be bendamustine/obinutuzumab or bendamustine/rituximab followed by maintenance therapy thereafter.

Maintenance therapy would not be considered another line of treatment because it’s basically piggybacking off the success of the first line of treatment. It depends on every single patient and their actual treatment history. I encourage you to talk to your hematologist on this because they would be able to more clearly tell you what lines of treatment means and how that applies to your treatment history.

50:27): Excellent response. Our next question is: Has CAR T-cell therapy been approved for mantle cell lymphoma? If so, what is the efficacy of the therapy on MCL? (50:41): Yeah. It is approved for mantle cell lymphoma. It was approved, I want to say, in 2020, maybe 2021 for patients who have failed two lines of therapy.

What that means is that the standard treatment for mantle cell lymphoma would be first line treatment followed by stem cell transplant, followed by maintenance. That’s all one treatment. Then if you received another line of treatment such as ibrutinib, for example, or acalabrutinib and then fail that, then you meet the candidacy for a CAR T-cell therapy.

1. It has been investigated actually in the second line setting, too.
2. You would maybe not even get that second line of treatment and just maybe get CAR T-cell therapy, but the response rate is fairly good.
3. It’s a roughly 60-somewhat percent response rate and it drops a little bit down for that long term response, though.

Somewhere between 50 to 60% of patients get a long term response. (51:44): If okay, I’m going to answer this next question. One of the viewers asked if we could list some facilities that offer CAR T-cell therapy. If you go to the bmtinfonet.org site, you will be able to click on find a treatment tab and it will list multiple centers that have CAR T-cell therapy available in your area.

(52:16): The next question is: How far down the road is CAR T treatment for myelofibrosis? One to two years? Five to 10 years? Is it worth waiting for to avoid massive chemo or transplant? (52:31): Yeah. Myelofibrosis, I can tell you, is far down the road. As of right now, we don’t have a very good target that’s specific to myelofibrosis.

Part of the reason is for everything that’s a myeloid disease, myelofibrosis, MDS, myelodysplastic syndrome, acute myeloid leukemia, the issue tends to actually be far higher up towards that stem cell. When you get higher up, when the issues start higher up, if you target those cells, you could actually be injuring the healthy stem cells.

• We have a lot of work to do to what can we target that’s unique to some of these cancers.
• Whereas for the lymphomas and multiple myelomas, we already have an understanding because it’s a little bit of a different mechanism on how that disease evolved to that point.
• 53:39): For myelofibrosis, unfortunately, we are a little bit behind the times and hopeful that we’re moving in that direction.

But I will tell you that the time for identifying that to the time when this treatment would be available to patients, we’re talking years. Many times, diseases can’t wait that long. That’s why if you’re considering not pursuing the treatment that is advised, for example, do your homework first before making that determination.

1. Get that information that you need.
2. Go to clinicaltrials.gov.
3. Use other resources like Leukemia and Lymphoma Society.
4. They have a clinical trial support center where you could ask to see what other clinical trials could be available and see if there’s something out there that you would want to consider.

But I will say, unfortunately, myelofibrosis, we don’t have a good target just yet. (54:37): The next question is: Is there an age group that has the highest success rate with CAR T-cell therapy? (54:51): Yeah. Good question. That’s a tough question to answer because often with age, as patients get older, they often come with other conditions that have developed over time such as heart disease or chronic kidney disease, that type of thing.

1. That still adds some additional risks to the overall treatment itself.
2. But for the most part, I will say that there isn’t an age group that does better or worse than others.
3. In fact, going back to that real world data, we have not seen that.
4. Now some places might not want to treat patients maybe a little bit older because of the risk of that cytokine release syndrome, for example.

If the body isn’t robust enough to be able to get through that, our goal is to not have the treatment cause any compromise to you. It’s person-specific. It’s patient-specific on the recommendation sometimes if CAR T-cell therapy is the best treatment strategy.

56:06): Terrific. We’re down to our last couple of questions. Our session timing is almost up. Which do you suggest, an allogeneic transplant or CAR T? Which one is better for relapsed mantle cell lymphoma patients? (56:23): Yeah. Oh. Ooh. Another tough question to answer. Mantle cell lymphoma, just like all other cancers.

I always tell patients this, is that there’s no one in the world that has your cancer, even though it’s the same name. Because your cancer came from you, of you, and it still continues to evolve over time. For example, patients with mantle cell lymphoma, sometimes there are certain mutations that confer a poor risk, a higher risk.

1. I will say, though, generally speaking, I would be advising that most patients try CAR T-cell therapy first.
2. If that doesn’t work, try to get the disease under control and then proceed to an allogeneic stem cell transplant.
3. Now here’s a problem though, is that CAR T-cell therapy was studied and is used for patients who are refractory to treatments.

Meaning that the treatments aren’t working; that’s why you’re getting that treatment. (57:28): Now allogeneic transplant, you have to proceed when you have as little disease as possible. You have to be in almost a complete response to get that. When you say, “Okay.

1. We’ll do CAR T.
2. We’ll try that first and then we’ll do allo in the future,” there could be a problem with that because you might not respond to treatments after CAR T-cell therapy to get you to a point where an allo transplant provides the benefit.
3. In an allo transplant historic data, it does show it’s just as good as perhaps CAR T-cell therapy, but it’s different patient populations that you’re comparing it to.

That’s a very tough question to answer, but I would say it’s a different scenario for different patients. (58:17): But in general, we’re all thinking that we would try CAR first and then maybe an allo transplant in the future if it doesn’t work. With that understanding, that could be a risk.

Because if we can’t get that disease under control, then we can’t do that allo transplant because that donor’s immune system is not going to be able to recognize what’s good and what’s bad if the disease isn’t under control first. That’s called that graft-versus-malignancy effect. (58:47): Closing, Wow.

This has been an incredible Q&A session and such a great presentation, Dr. Tees. Thank you for sharing your expertise and thank you to our audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way. Enjoy the rest of the symposium.

What is relapse after CAR T-cell?

2. Clinical relevance – Although CD19 CAR-T cell therapy has achieved amazing overall CR rates in patients with R/R B-ALL and B-cell lymphoma ( Larson and Maus, 2021 ), 40%–60% of CR patients eventually experience relapse. At the 2021 American Society of Hematology (ASH) annual meeting, real-world outcomes of tisa-cel treatment of pediatric and young adult patients with R/R B-ALL showed that, after a median follow-up of 21.5 months (11.9‍–‍37.2 months), the median event-free survival (EFS) was 14.0 months (95% confidence interval (CI), 9.8‍–‍24.8) and the median relapse-free survival (RFS) was 23.9 months (13.0‍–‍not estimated (NE)).

1. The 12-month EFS rate was 54.3% and the RFS rate was 62.3% ( John et al., 2021 ).
2. In axi-cel-treated patients with R/R large B-cell lymphoma (LBCL), a 12-month EFS rate of 43% (95% CI, 33%‍–‍52%) and a 24-month EFS rate of 38% (95% CI, 28%‍–‍47%) were reported ( Jacobson et al., 2021 ).
3. The relapse after CAR-T cell therapy in B-cell malignancies is defined as the recurrence of tumor cells after achieving CR by target-specific CAR-T cell infusion, such as CD19 CAR-T.

Generally, the relapse can be categorized as the bone marrow relapse, the extramedullary relapse (such as in the central nervous system (CNS) or testis), or a combined relapse according to anatomical sites ( Tallen et al., 2010 ). More specifically, the relapse can also be classified as antigen-positive or antigen-negative based on the expression profile of initially targeted antigens of tumor cells.

Is CAR T-cell therapy a last resort?

Identifying Good Candidates – Until last year, CAR T-cell therapy was considered a last resort for patients who had previously undergone chemotherapy and a stem cell transplant. That changed in April 2022 when the FDA approved axicabtagene ciloleucel (Yescarta) for use in patients with large B-cell lymphoma after only 1 treatment failure.2 There are now several clinical trials underway to determine whether other CAR T-cell agents can be used safely and effectively and may be offered to patients earlier in their cancer care.

Feleciano noted that a lot of work goes into preparing patients for CAR T-cell therapy, beginning with a wide array of tests that are conducted approximately 30 days before they are scheduled to receive treatment. ” Patients have their overall health, function, and fitness level evaluated through bloodwork, an EKG, echocardiogram, a bone marrow aspiration, and a PET scan to determine if they’re a good candidate for CAR T-cell therapy,” she said, adding that patients also meet with the hospital’s financial services department to ensure their insurance covers a portion of the therapy.

“Since CAR T-cell therapy is only offered at a limited number of cancer centers, many patients incur travel and lodging costs,” Feleciano pointed out. “There are financial assistance programs available that can sometimes help with the costs of lodging for them and their caregivers, since we require them to stay within 60 minutes of UC Davis Health for a month after their procedure.” Because it takes time for the CAR T cells to be reprogrammed in the laboratory, in some cases patients are offered bridging therapy—which can include high-dose steroids, chemotherapy, or radiation— to control disease before CAR T-cell therapy begins.

Does CAR T-cell therapy always work?

Since MD Anderson’s first CAR T cell therapy clinical trial launched in 2015, we’ve cared for hundreds of patients undergoing CAR T cell therapy. Over the years, we’ve gained valuable insight into this game-changing treatment that trains a patient’s immune system to find and kill cancer cells.

With CAR T cell therapy, T cells that defend the body against disease are extracted from a cancer patient’s blood. The cells are then changed in the lab by adding a protein called chimeric antigen receptor, or CAR. This protein acts like a navigation system that helps the T cells track down and kill cancer cells.

These altered T cells – now called CAR T cells – are then multiplied in the lab and reinfused into the patient’s bloodstream. Today, CAR T cell therapy is approved by the Food and Drug Administration (FDA) to treat certain types of leukemia, lymphoma, and most recently, myeloma,

The treatment has produced dramatic results for many patients. In some cases, it has eliminated all evidence of cancer. With each patient we’ve treated, we’ve learned new lessons that have helped us improve how we care for patients today. Here’s what we’ve learned. Lesson 1: Side effects can be serious, but managed Like all cancer treatments, CAR T cell therapy can cause side effects.

One of the most frequent and serious side effects is cytokine release syndrome, also called a cytokine storm. This occurs when the immune system responds to the infused CAR T cells more aggressively than it should. Some patients experience mild, flu-like symptoms such as high fever, fatigue and body aches.

Others may have more severe symptoms, including a drop in blood pressure or a lack of oxygen in the tissues that may lead to organ failure. Cytokine release syndrome was an unexpected side effect in the early days of CAR T cell therapy. But now we know that the drug tocilizumab, originally prescribed for juvenile arthritis, reverses most cases fairly quickly.

Another side effect is ICANS, which stands for “immune effector cell-associated neurotoxicity syndrome.” Patients may become confused and disoriented. They may lose the ability to speak for a short time, which mimics a stroke. We still don’t know exactly why ICANS occurs, but we’ve learned that most patients recover after several days.

Steroids, we’ve discovered, are the most effective treatment for ICANS. Sherry Adkins, an advanced practice nurse who manages CAR T cell clinical trials in MD Anderson’s Lymphoma/Myeloma department, witnessed these side effects firsthand. She realized that the earlier symptoms are treated, the better patients fare.

So she collaborated with MD Anderson’s Informatics department to develop a mobile app that uses a grading system to classify the seriousness of a patient’s side effects. The app then quickly conveys to the patient’s doctors and nurses what treatments to administer, based on national guidelines.

The app has become so successful that we’re now sharing it free of charge with cancer centers and other health care professionals throughout the world. Lesson 2: Earlier CAR T cell therapy produces better results In the past, CAR T cell therapy was approved only for patients who had undergone two unsuccessful treatments – typically chemotherapy and a stem cell transplant,

Their cancer either didn’t respond, or it responded at first, but then worsened. CAR T cell therapy was a last resort when other treatments failed. But now we’re starting to prescribe CAR T cell therapy for some patients who’ve had only one type of treatment that failed to work.

• Early data from clinical trials suggest that CAR T cell therapy is better at treating some cancers than other therapies.
• One such trial is ZUMA-12, led by our Sattva Neelapu, M.D.
• The study found that patients with large B-cell lymphoma who received CAR T cell therapy as part of their initial treatment achieved much higher complete remission rates than patients who did not receive CAR T cell therapy at the start of their treatment.

With ongoing clinical trials producing similar results, we predict CAR T cell therapy will become the first prescribed treatment for some cancers very soon. Lesson 3: CAR T cell therapy can treat more patients than we initially realized When CAR T cell therapy first debuted, patients could obtain it only by enrolling in a clinical trial.

The treatment was experimental, and not yet approved by the FDA. Clinical trials have strict inclusion and exclusion criteria, meaning people can enroll only if they meet certain conditions. Typically, they must fall within a certain age range, have no or very limited chronic health conditions, not take medications that would interfere with the trial drug, not be pregnant, and have good liver and kidney function – those two organs play a crucial role in how drugs are metabolized in the body.

These criteria excluded many cancer patients whose only hope for survival was CAR T cell therapy. Our Loretta Nastoupil, M.D., conducted a clinical study that showed patients who don’t meet eligibility criteria for CAR T cell trials do just as well as patients who do meet the criteria.

Thanks to her research, patients no longer need to enroll in clinical trials to obtain CAR T cell therapy. This has made it possible for us to treat a much larger number of patients with lifesaving CAR T cell therapy. In many of these cases, the cancer has spread. Lesson 4: We must help CAR T cells work harder and last longer Many patients achieve complete remission with CAR T cell therapy that essentially cures their disease.

But for some, the cancer comes back. We don’t know why this happens. Perhaps the CAR T cells become exhausted and stop working. Or maybe they get crowded out by ordinary T cells that weren’t re-engineered with the CAR protein. Or perhaps patients’ other drugs and treatments interfere with CAR T cells.

1. We’re working now to learn how to make CAR T cells work better and last longer.
2. We’re seeking answers to questions such as: Do multiple CAR T cell infusions work better than just one? Can certain drugs improve, or worsen, CAR T cells’ persistence and potency? Can we add genes to CAR T cells to make them stronger, or remove genes that make them weaker? CAR T cell “persistence and potency” is a hot topic in the cancer community, and many studies are underway to increase our knowledge.

Lessen 5: CAR T cells’ ability to treat solid tumors is limited but improving CAR T cell therapy has revolutionized treatment for blood cancers, but its ability to treat solid tumors remains limited for four reasons: The proteins on solid tumors that CAR T cells zero in on are also found at low levels on the surface of normal cells, making it difficult for the CAR T cells to distinguish tumor cells from healthy ones; the proteins targeted by CAR T cells sometimes hide inside tumor cells and escape detection; cancer cells in the blood are easier to access, since CAR T cells are infused directly into the bloodstream, and; CAR T cells became exhausted when trying to penetrate solid tumors.

Researchers are working to overcome these challenges. Progress is being made, especially in lung, breast and brain cancers. Given the large number of ongoing clinical trials, we’ll soon see CAR T cell treatments designed for solid tumors. Lesson 6: The demand for CAR T cells is outpacing the supply There are at least 60,000 patients with blood cancers in the United States each year for whom conventional treatments don’t work.

To provide CAR T cells to this many people, we need to ramp up manufacturing. Companies can’t make CAR T cells fast enough. There simply aren’t enough manufacturers to keep up with the demand. Because the therapy is custom-made for each patient using their own cells, it’s a slow process.

1. Typically, it takes five to six weeks before a patient’s CAR T cells are ready to be infused.
2. Some patients can’t wait that long.
3. So we’re looking at other alternatives, like using T cells from healthy donors to mass-produce an off-the-shelf option.
4. The CAR T cells would be available immediately, waiting in the freezer.

Other cell therapies similar to CAR T cell therapy are also being studied for potential off-the-shelf options, including CAR NK (natural killer) and TCR (T cell receptor) cell therapies. Katy Rezvani, M.D., Ph.D., and her team are adding CAR to natural killer cells gathered from umbilical cord blood that is donated by parents after a baby’s birth.

A single cord blood donation yields hundreds of doses of CAR NK cell therapy to benefit multiple patients. Her cord blood-derived NK cells have been highly successful in clinical trials of patients who achieved remission with chemotherapy and stem cell transplants only to see their cancer return. She’s now exploring CAR NK cells for the treatment of many types of solid-tumor cancers.

CAR T cell therapy can be a lifesaving treatment It’s been less than a decade since our first patient received CAR T cell therapy. Although there is still work to be done, the treatment has been lifesaving for many. A significant number of patients treated with CAR T cells will be long-term survivors.

What is the mortality with car t?

Purpose: The development of chimeric antigen receptor (CAR) T cells has transformed oncology treatment, with the potential to cure certain cancers. Although shown to be effective in selected populations and studies, CAR T-cell technology requires considerable health care resources, which may lead to additional wait times to access this type of treatment in future.

• The objective of our study was to estimate the potential impact of increasing wait times on CAR T-cell therapy effectiveness compared with standard chemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma.
• Methods: A health system-level discrete event simulation model was developed to project the potential impact of wait times on CAR T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma.

Waiting queues and health states related to treatment and clinical progression were implemented. Using data from the literature, we evaluated nine scenarios of using CAR T-cell therapy with wait times ranging from 1 to 9 months. The outcome of interest was 1-year all-cause mortality.

1. Results: Increasing the wait time of receiving CAR T-cell therapy from 1 to 9 months increased the predicted 1-year mortality rate from 36.1% to 76.3%.
2. Baseline 1-year mortality was 34.0% in patients receiving CAR T-cell therapy with no wait times and 75.1% in patients treated with chemotherapy.
3. This resulted in an increased relative mortality rate of 6.2% to 124.5% over a 1- to 9-month wait time compared with no wait time.

Conclusion: We found that modest delays in CAR T-cell therapy significantly hinder its effectiveness. Because CAR T-cell therapy offers a potential cure, it is expected that the uptake rate will be substantially increased once the therapy is regularly funded by a health care system.

What are the problems with car t?

Dual CAR system – One of the main problems of CAR-T therapy is the identification of an ideal antigen, because most antigens in tumor cells are also present in normal cells of the human body. As a result, in the process of attacking tumor cells, activated T cells can also inflict damage on normal tissues.

To this end, two CARs exist on engineered T cells, and T cell activation depends on the binding of these two CARs to their specific antigens. That is to say, dual tumor antigen binding with CAR-T cells is required to initiate immune response ( 36 ). Therefore, the dual CAR-T strategy renders control over the affinity of the immune response and the prevention of immune-related adverse events.

Caruso et al. attempted to generate CAR-T cells from monoclonal antibodies with different affinities, thereby distinguishing malignant tumors from normal cells based on the different densities of EGFR expression ( 37 ). In a study on liver cancer in mice, Chen et al.

How do you know if car T therapy is working?

What are common side effects of CAR T-cell therapy? – Too much activation of the immune system, which is called cytokine release syndrome (CRS), can be very harmful to the person with cancer. CRS is typically seen within a few days to 2 weeks after CAR T-cell infusion and stops within days to weeks.

CRS affects people receiving CAR T-cell therapy on a wide spectrum. Some people only experience a high-grade fever, some have low blood pressure and/or low oxygen levels, and others need an intensive care unit (ICU) level of care, which may include needing machines to help keep the person alive. However, doctors have become much better at controlling CRS, so being admitted to the ICU after CAR T-cell therapy is not as common.

A drug called tociluzumab, which turns off an important cytokine called IL-6, has improved care for CRS. However, CRS is still a risk of CAR T-cell therapy and can be very serious. Sometimes during CAR T-cell therapy, the cytokines can also affect the brain, causing a symptom called immune effector cell-associated neurotoxicity syndrome (ICANS).

ICANS also has a range of symptoms, including mild to severe confusion, shaking, or more rarely, seizures. It can also create memory loss. ICANS is almost always associated with CRS and typically occurs later than CRS, usually within 1 to 4 weeks after CAR T-cell infusion. ICANS is reversible, though some symptoms may take longer to resolve.

After about 2 to 4 weeks following a CAR T-cell infusion, the person with cancer is typically “out of the woods” for more severe complications. However, they must still stay near the treatment center for close observation for a period of time as required by their doctor.

• After about 3 months, the doctor will check to see if the CAR T cells worked.
• It’s important to note that CAR T cells kill all cells against which they are directed, including normal cells.
• This usually results in a weak immune system for several months following treatment.
• This may lead to rare types of infections usually seen in people with severe immunodeficiencies.

A person receiving CAR T-cell therapy must be particularly cautious in this stage of recovery and report a fever or other symptoms to their doctor.

What are the long term complications of CAR-T?

As long as these CAR-T cells persist and are functional, patients may not be able to make normal B-cells, so may not be able to make normal antibodies. That could put them at higher risk of certain infections, and they may not respond normally to vaccines.

How long does it take to recover from CAR-T therapy?

What is the treatment process for patients? – The treatment process involves:

1. Evaluation : Patients undergo a series of tests and screenings to determine if CAR T-cell therapy is an appropriate option.
2. Collection : T cells are collected from patients via apheresis, a process that withdraws blood from the body and moves through a cell separator to collect the needed blood components, in this case, T cells. The remaining blood is then returned into the body. The procedure is done in one day in the outpatient clinic at the Kraft Family Blood Donor Center at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.
3. Engineering : The T cells are sent to a laboratory where they are genetically engineered to target a specific type of cancer.
4. Multiplication : The genetically modified T cells are “expanded” by growing cells in the laboratory until there are millions of them. This process can take a few weeks. When there are enough CAR T cells, they are frozen and sent to the hospital or center where the patient is being treated. At our center, these cells are returned and processed at Dana-Farber’s Connell and O’Reilly Families Cell Manipulation Core Facility.
5. Conditioning Therapy : Prior to infusion of the CAR T cells, patients may receive chemotherapy for their cancer. This helps to create space in your immune system for the infused CAR T cells to expand and proliferate.
6. Infusion : When the CAR T cells are ready, the cells are infused through a central line, in a process similar to a blood transfusion. Patients may receive medications to prevent and control possible side effects of the newly-engineered cells. Patients may receive their CAR T cells in the hospital or in the outpatient clinic. The patient’s physician will decide which approach is best.
7. Recovery : Patients who receive CAR T-cell therapy have a risk/recovery period of approximately 2-3 months. During this period, patients will be evaluated for side effects and treatment response. It is not uncommon for patients to be admitted to the hospital during this period to manage complications. During the first 30 days after CAR T-cell infusion, patients need to remain close to our center for regular follow-up care. A resource specialist can assist in arranging for a place to stay during this time, if needed.

How long does it take for car T cells to start working?

CAR T cell therapy is a type of immunotherapy used to treat lymphoma, multiple myeloma and some forms of leukemia, The treatment modifies T cells so that they can better recognize and attack cancer, To learn what to expect if you need CAR T cell therapy, we spoke with lymphoma and myeloma specialist Sairah Ahmed, M.D.

1. Your care team will determine if you’re eligible for CAR T cell therapy Before you can consider CAR T cell therapy as a part of your treatment plan, your care team will need to determine if you’re a good candidate for it.
2. They’ll look at many factors, including whether you’re in good overall health and have adequate organ function.

“‘Adequate’ doesn’t necessarily mean ‘normal,'” notes Ahmed. “But CAR T cell therapy can be very stressful to the body. So, there’s a baseline you have to meet for heart, lung, liver and kidney function. You’ll need to be strong enough to get up, move around and participate in your own care.” Doctors will also consider your age, though Ahmed stresses that age alone won’t necessarily disqualify you from receiving CAR T cell therapy.

MD Anderson doctors have infused adults in their 90s and children younger than age 10,” she says. Your care team will consider your living situation, too, as you’ll need a caregiver to stay with you for the entire T cell-extraction period (apheresis). You and your caregiver will also need to remain close to MD Anderson for the first 30 days after the infusion.

“We rarely deny anyone CAR T cell therapy just for caregiver or proximity reasons,” says Ahmed. “Our social work counselors work with patients to make sure they have an appropriate place to stay and adequate support.” Steps in the CAR T cell therapy process: A timeline The entire CAR T cell therapy process takes about three months to complete, from the time your doctor orders an eligibility assessment until you finish the 30-day observation period after the infusion.

Determining eligibility : 5-7 days, depending on the number of tests, scans and consultations ordered by your doctor. Obtaining insurance approval: 10 to 14 days, on average, but sometimes as long as 4 weeks. (Patients may either rest at home during this period or have additional treatments, such as bridging chemotherapy, to keep their disease under control.) Extracting the T cells (apheresis): 2 days. Patients must come to the hospital on both days and expect to stay for several hours. The first day is for placing the apheresis catheter to extract the cells. The second day is for collecting the cells. Enhancing the T cells: 3 weeks. That’s generally how long it takes for T cells to be sent to the lab, altered and returned to MD Anderson, Lympho-depletion chemotherapy : 5 days. This step helps deplete your natural immune system to allow the CAR T cells to expand and proliferate after they are infused. Infusing the CAR T cells : This usually takes no more than an hour, though it could be as quick as 15 minutes. It depends on how many bags of cells are being infused, and if you have a reaction, Recovering from the infusion : 30 days

“The evaluation period can sometimes last all the way up until we’re ready to infuse the CAR T cells,” explains Ahmed. “We use that time not only to determine the full extent of your disease and identify your baseline organ function, but also to assess what other treatments might be needed.

If you have a fixable heart problem, for instance, we may send you to one of our cardiologists. That way, they can recommend a medication change or a procedure to resolve the issue before you start CAR T cell therapy.” You may be prescribed chemotherapy, too Between the time your T cells are collected and the time they’re re-infused, you may be prescribed bridging chemotherapy.

This treatment is not given to all patients, though, so your doctors will only suggest it if it’s necessary to control the cancer. “Lympho-depletion chemotherapy, on the other hand, is done just prior to infusion of the CAR T cells and all patients who are receiving that therapy will need it,'” explains Ahmed.

“Your immune system has to be suppressed so the CAR T cells can do their job properly.” The first 30 days after CAR T cell therapy require close monitoring Patients must be closely monitored for the first 30 days after a CAR T cell infusion, so any potential side effects can be dealt with promptly. The first two weeks may be spent either as an inpatient at the hospital or an outpatient who lives nearby and comes in for daily evaluations.

The remainder are spent as an outpatient. “Ultimately, though, where you spend that time is up to your doctor,” says Ahmed. “It all depends on your general state of health, the type of cancer you have and any potential complications you may encounter.” If you’re released from the hospital before the 30-day observation period is up, you’ll be asked to come back to MD Anderson two or three times a week until you’ve reached that milestone.

You’ll also be asked to stay within 15 to 20 minutes of the hospital. That way, you can get back to MD Anderson quickly if you have any complications. Each checkup will require both lab work and scans, so you should plan to return to MD Anderson for the first 30 days. After that, you may be able to have your bloodwork and scans done locally if you live far away, and just get the results sent to MD Anderson prior to a virtual visit with your doctor.

Restrictions vary by state, so ask your care team if this is a possibility for you. Even after the first 30 days, you’ll still need some follow-up Once you’ve gotten past the 30-day milestone, you’ll only need to come back to MD Anderson every two or three months for a checkup.

• CAR T cell therapy tends to weaken the natural immune system, though, so patients must take medication to prevent infections for a full year after they’ve received it.
• Some patients may also experience low white blood cell counts,” notes Ahmed.
• In those cases, they might need to monitor their blood counts at home or receive injections of drugs called growth factors to boost their white blood cell production.” While the severity of side effects can be related to how advanced someone’s cancer is, having advanced disease does not automatically disqualify you from having CAR T cell therapy.

“Data from both clinical trials and the products already on the market indicate that many patients with advanced disease can still benefit from CAR T cell therapy,” says Ahmed. Request an appointment at MD Anderson online or by calling 1-877-632-6789.

Do you lose all progress if you relapse?

2. Recognize Your Progress – One way to stop a shame spiral is to recognize the progress you’ve made in your recovery. Too often, people who relapse beat themselves up and treat the relapse as a total reset of their sobriety. But by looking at your progress as a whole, you can see that you’re still on an upward trend.

• The fact is that a relapse doesn’t delete your progress.
• If you’ve gone through addiction treatment, you still have the knowledge and tools to help you deal with triggers, cravings, and risky situations.
• You likely still have resources that are available to help.
• And you still have a greater understanding of the nature of addiction and know the steps you need to take to sustain your recovery from here on out.

Recognize that you have been able to stay abstinent for some time. In active addiction, many people use every day for months or even years. Being able to stop for an extended period is progress, and it shows that you can recover. Looking at your progress over time rather than focusing on the relapse episode in isolation can show you how far you’ve come and provide hope that you’ll be able to do even better in the future.

How likely is T-cell all to relapse?

Introduction – T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/-LL) is an aggressive hematological tumor, driven by malignant transformation and expansion of T-cell progenitors. T-ALL and T-LL are distinguished by the presence of more or 1, 2 ). The 2016 revision of WHO classification added a provisional entity called Early T-cell precursor (ETP) ALL,

This subset is characterized by a unique immunophenotypic (reduced expression of T-cell markers, CD1a, CD8, and CD5) and genetic profile, indicating only limited early T-cell differentiation, with retention of some myeloid and stem cell characteristics ( 2 ). Current treatment of T-ALL consists of high intensity combination chemotherapy, resulting in high overall survival, with the best outcomes observed in pediatric patients ( 3 ).

Despite the high response rates after first-line therapy, about 20% of pediatric and 40% of adult patients will relapse ( 4 ). Differently from B-cell precursors ALL, where highly effective monoclonal antibodies as well as CD19 targeting chimeric antigen receptor (CAR) T-cells have been developed, in T-ALL only the purine nucleoside analog nelarabine is licensed for relapsed/refractory patients ( 1, 5 ).

In what stage of change does relapse happen?

Relapse (Stages of Change) Skip to content The Relapse Stage is the sixth stage of change in the and represents the time in a person’s treatment where they have slipped back into old habits and returned to use. Relapse is said to happen when people lose sight of their recovery.

As a result of an inability to cope with current stressors, the person begins use again, instead of reaching out for help. This model is circular in nature with relapse and precontemplation going hand in hand. The Transtheoretical Model (also called the Model) was developed by Prochaska and DiClemente in the late 1970s.

This model focuses on the decision-making of the individual and is a model of intentional change. The Transtheoretical Model operates on the assumption that people do not change behaviors quickly and decisively. Rather, change in behavior, especially habitual behavior, occurs continuously through a cyclical process.

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Which country is best for CAR T-cell therapy?

Geographical distribution of the CAR T-cell therapy – So far, the USA and China are leading in terms of CAR T-cell therapy trials and application, with several countries in Europe being in hot pursuit. The geographical distribution for Europe is not evenly spread out but rather shows a concentration in specific regions.

How successful is CAR-T therapy?

Scott McIntyre: CAR T-cell Therapy for Lymphoma Scott MacIntyre is a busy guy. He works at a company he co-owns called Shamrock Truck Sales. You would never guess by looking at him that he very nearly died because of cancer just two years ago. At the time, basically we had a life expectancy of about six months, but then in the very first part of 2016, we got a call where I was able to harvest my T cells, and it became my turn.

So in March of 2016, I was able to receive CAR T treatment. Scott was one of the first people to receive CAR T cell therapy as a trial. He was at a point in his fight with cancer where he had no other options, but CAR T gave him a chance. Michael Bishop is one of the doctors who provided care to Scott.

You pray for that every day as an oncologist, that you can deliver that kind of, give that kind of care, and give that kind of treatment to a patient. So to say that I’m excited would be a major understatement. In the first part of the process, T cells, the workhorse of the immune system, are collected from the patient’s blood.

• Then, scientists insert instructions that enable those T cells to find specific cancer cells.
• While the T cells multiply in the lab, the patient receives chemotherapy to reduce the number of cancer cells.
• And finally, the engineered T cells are returned to the patient’s bloodstream where they seek out and kill remaining cancer cells.

Really, what it does is program the cells to be specific for the cancer, because we know our immune system is capable of eliminating cancer, but sometimes it needs to be more specific and go towards the cancer itself. Next scan, lo and behold, cancer free.

We’ve gone to remission. So I’ve been in remission now for about 15 months. Every month, it gets better and better. My strength has come back, my stamina’s come back. Basically, I’m back living my full life again, enjoying things I like to enjoy. So it’s just absolutely been a miracle, and I owe so much to the team at University of Chicago.

Scott and his wife Cindy have spent a lot of time in hospitals in recent years, and they’re happy to be back at work at their business and back to a normal life with a chance at a happy future ahead. The care at University of Chicago Hospital was absolutely phenomenal.

• Spent a lot of time on the tenth floor, of course, up there at 10th East and everybody was so professional and so, just, compassionate with it.
• That’s what our purpose here is, is we want to bring new and innovative therapies that improve the lives and, particularly, the quality of life for our patients.

You’d never know it by looking at him today, but six years ago, Scott McIntyre was given just a few months to live. He was losing his battle with diffuse large B-cell lymphoma (DLBCL), A few rounds of chemotherapy, a stem cell transplant and even two clinical trials and targeted radiation therapy provided only temporary remission.

1. The cancer kept coming back.
2. When cancer spread to his lungs, McIntyre felt he was out of options.
3. That’s when he decided to participate in a very promising immunotherapy trial being offered at the University of Chicago Medicine.
4. The doctors said to me, ‘We don’t know how this will work, but we hope it will help us learn more about this disease and help patients in the future,” McIntyre said.

“When I heard that, the pressure just eased away. I said, ‘I’m ready. Let’s do it.’ ” He became the first patient to be treated with CAR T-cell therapy in Illinois. CAR T-cell therapy involves extracting a cancer patient’s white blood cells and reprogramming the T cells — the roving warriors of the immune system — with an antibody-like protein called Chimeric Antigen Receptor, or CAR.

The modified cells are returned to the patient’s body, a process that takes less than 10 minutes. These re-engineered T cells bypass healthy cells and latch on to and kill the diseased cells — basically, using a patient’s own immune system to fight cancer. After the procedure, McIntyre had a fever for a few weeks, which doctors expected.

But soon after, he started feeling better. A few weeks after returning home, he got a call from UChicago Medicine oncologist and researcher Sonali Smith, MD, She had the results of his bone marrow biopsy and was ecstatic: The cancer was gone. “You’re my walking miracle,” she told McIntyre.

1. That was in 2016 and the cancer still hasn’t returned.
2. The CAR T-cell therapy success rate is about 30% to 40% for lasting remission, with no additional treatment, according to Michael Bishop, MD, director of UChicago Medicine’s cellular therapy program.
3. My oncologists, they never gave up.
4. The doctors didn’t give up.

My family didn’t give up. And the researchers didn’t give up. While McIntyre still must visit the doctor every few months for a quick infusion of immunoglobulin to help him fight infections, he has no side effects from the therapy. “CAR-T was our ‘hail Mary’ pass.

We threw the ball up in the air, and it ended up being a touchdown,” said McIntyre, a diehard Notre Dame football fan. “My oncologists, they never gave up. The doctors didn’t give up. My family didn’t give up. And the researchers didn’t give up.” At the first Notre Dame football game McIntyre attended after his CAR T-cell therapy, he texted a photo of himself to Smith and wrote: “Because of you, I’m living my dream.” “I will never forget that text,” Smith said.

“It had a gorgeous picture of him, his wife and children at the game, full of life and full of gratitude that something worked. He’d gone through treatment after treatment, clinical trial after clinical trial, always hoping that the next treatment would finally get rid of his cancer.

And now he was the picture of health. Of normalcy. “Having our patients return to a life where they can go to a college football game or spend a day in the sun is the whole reason we are in this field.” Every year since, McIntyre has texted Smith a photo from Notre Dame’s opening day game. Today, McIntyre, 58, is back at work running his truck dealership in South Bend, Indiana, and enjoying life with his wife of 36 years, his three grown children and two grandchildren.

He also provides support to other CAR T-cell therapy patients and their families, sharing his story and helping them learn about the process, including in a private Facebook group, In 2019, McIntyre received the “Inspiration Award” from the American Cancer Society,

Does CAR T-cell therapy work for all cancers?

An error occurred. – Try watching this video on www.youtube.com, or enable JavaScript if it is disabled in your browser. T cells are white blood cells that find and fight illness and infection throughout the body. Each T cell has a receptor that can recognize antigens (proteins or molecules that are recognizable by the immune system).

When the immune system recognizes foreign or abnormal antigens, it can work to destroy them. But cancer cells sometimes have antigens that body doesn’t recognize as abnormal. As a result, the immune system may not send T cells to fight cancer cells. In other cases, the T cells may not be able to clear the cancer cells.

Chimeric antigen receptor T cells are cells that are genetically engineered (changed) in a laboratory. They have a new receptor so they can bind to cancer cells and kill them. Different types of cancer have different antigens. Each kind of CAR T cell therapy is made to fight a specific kind of cancer antigen.

So a CAR T cell therapy made for one type of cancer won’t work against another type of cancer. CAR T cell therapy is a complex process that should be done by experts with extensive experience. Penn Medicine’s Cell Therapy and Transplant Program will help you understand what to expect before, during and after the procedure.

The process may take place in an outpatient infusion center or in the hospital. Several CAR T cell therapies are approved by the U.S. Food and Drug Administration (FDA), and more are being developed. Penn researchers developed the first FDA-approved CAR T cell therapy for cancer, and we continue to lead and participate in several CAR T cell clinical trials,

1. CAR T cell therapy may cause some side effects or complications.
2. Our team will monitor you and educate you so you know what to look for.
3. A serious complication of CAR T cell therapy is cytokine release syndrome (CRS).
4. CAR T cells may release chemicals called cytokines, which causes a reaction from the immune system.

Your care team has specialized treatments to manage this complication. Signs and symptoms may include: CAR T therapy may also cause negative effects on the nervous system. Your care team can manage these complications with specialized treatments. These signs and symptoms may include: If you receive CAR T cell therapy through the Penn Medicine Blood Cancer Program, you’ll find:

Will I lose my hair with CAR T-cell therapy?

– Approximately 40 to 60 percent of patients who undergo CAR T-cell therapy experience side effects. Some of these symptoms can be managed with intravenous fluids and acetaminophen. But CAR T-cell therapy often triggers serious conditions, usually within five days of infusion. These may include:

Flu-like symptoms, such as fever, fatigue, shortness of breath and chills Racing heart beat Drop in blood pressure Neurologic conditions, such as headaches and seizures Short-term memory and cognitive issues

These symptoms are reversible but may require a stay in an intensive care unit. Researchers are actively studying better ways to reduce the side effects of CAR T-cell therapy.

What are alternatives to CAR T-cell therapy?

During a live virtual event, Jakub Svoboda, MD, discussed with participants the choice of therapy for a patient with relapsed/refractory diffuse large B-cell lymphoma who would not receive stem cell transplant or chimeric antigen receptor therapy. Jakub Svoboda, MD (Moderator) Associate Professor of Medicine Hospital of the University of Pennyslvania Philadelphia, PA CASE SUMMARY A 68-year-old man presented with fatigue, back pain, and lymphadenopathy​, and had a prior medical history of medically controlled hypertension. A ​physical exam showed a 1.5-cm left posterior cervical node, a 2.5-cm right anterior cervical node, and a 2.0-cm left supraclavicular node.

• PET-CT scans showed multiple enlarged mesenteric and retroperitoneal nodes, the largest measuring 5.3 x 3.1 cm​.
• A biopsy confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal center (non-GC).
• Immunohistochemistry was positive for CD20, BCL-6, BCL-2 (50% of cells), MYC (greater than 90% of cells), Ki67 85%, MUM1, but was negative for CD10​.

Fluorescence in situ hybridization was negative for translocations involving MYC, BCL2, BCL6​. Laboratory results showed normal complete blood count, elevated lactate hydrogenase. He received a diagnosis of stage III DLBCL with IPI high-intermediate risk and ECOG performance score of 1.

• R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated for 6 cycles and back pain was resolved​.
• Post-treatment PET demonstrated a complete response with Deauville score of 2, and the patient was observed​.
• Eight months after completion of therapy, he complained of fever, night sweats, and back pain.

A palpable lymph node in left groin was discovered on physical examination​. PET and CT scans showed a new left inguinal lymph node, an increase in size of a residual node, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​.

What factors influence your choice of treatment for this patient?What are your goals for treatment?

JAKUB SVOBODA, MD: For patients who you feel would not go through transplant and wouldn’t go through CAR T-cell therapy, the options are GemOx, polatuzumab vedotin with or without bendamustine and rituximab, tafasitamab plus lenalidomide, or probably some other,

1. What would you do in this setting? ARUN BHANDARI, MD: Is polatuzumab approved as second line? Or first line? SVOBODA: Not really,
2. It’s part of the NCCN guidelines—you can usually get polatuzumab in second line.1 But when you look at the label, it would say 2 or more regimens prior.2 None of you would use GemOx.

GemOx was often used as a treatment for the unfit, older patients who didn’t go for transplant. But, I agree, I haven’t used it in a long time. This patient is 68 years old, has hypertension, and relapsed after 8 months. Now what do you discuss with that type of patient; what is the clinical goal? How do you discuss the options? BHANDARI: My goal would be to guess the longest response with a novel agent, such as tafasitamab plus lenalidomide.

You can give treatment to disease progression with tafasitamab plus lenalidomide. My goal is to get the maximum response and duration of response. SVOBODA: I think that that’s a valid point. When I see patients referred to us in our tertiary center, they trust you in the community when they ask “What are my shots? What should I go for?” These discussions are important for them, and your view on this is very important.

So which are the factors that influence your recommendations for a patient with a kind of lymphoma that would relapse within 12 months? HARISH MADALA, MD: I work in a rural part of Virginia, and this sounds like a very common issue I deal with. Patients don’t want to travel for CAR T-cell therapy or stem cell transplant.

We do have an older population, so patient preference or goals would be a very important factor for me, especially in choosing the regimen of tafasitamab plus lenalidomide versus polatuzumab. I would take the number of times they have to come to the cancer center for infusion, especially in this day and age with COVID-19, into consideration.

None of my patients are older, but once healthy 70-year-olds start treatment, their age really shows. With their multiple comorbidities, I try to pick the lesser toxic regimen, but with longer response. SVOBODA: I keep thinking about what I can do to keep the disease under control without necessarily damaging the stem cells, or affecting the immune system as much.

So, for that, I think using something that is like a novel agent, since patients may need other drugs in the future. The subtype of the DLBCL, GC versus non-GC, can really be important in the selection. CASE UPDATE After discussing the treatment options, tafasitamab plus lenalidomide was initiated​. SVOBODA: This regimen has been around for only a short time, and, this is a bit of a unique patient.

Anybody willing to share their experience with the regimen? ANUSHA MADADI, MD: It seems to be better tolerated, similar to rituximab. I admit that I have used it in malignant pancytopenia to watch for some mild reactions in each, but otherwise, pretty well tolerated.

• MATT MCKINNEY, MD: I agree.
• Progressing through CAR T-cell therapy, or transplant, or allogeneic transplant go on tafasitamab plus lenalidomide and come in with disease shrinking or no disease.
• So it is definitely effective.
• SVOBODA: My experience is similar to what you both mentioned.
• I think tafasitamab is like rituximab, but it just attacks different antigen on the B cells.

So, you know, it is very similar to if many of you have had experience with R2, and so this is very similar in terms of that. When you look at the L-MIND study, days 1 and 4, but the first week of tafasitamab, I usually skip day 4 and just do weekly tafasitamab for the first 3 months, and then switch to every other, as per the label.3 DISCUSSION QUESTIONS

What is your reaction to the efficacy data for combination tafasitamab plus lenalidomide? ​What data are most striking to you? ​

DAYA SHARMA, MD: The duration of response is very impressive, much better than the CAR T-cell therapy, if I have to put those data side-by-side. It is very well tolerated, and there are many complete responses, so I think these are the very impressive end points.

• Although it is a phase 2 trial, it is still very impressive.
• SVOBODA: It is a little bit difficult to compare it with CAR T-cell therapy because they didn’t have all of the patients the primary refractory patients.
• I agree, it surprised me that they were able to generate such long term DOR.
• Any other feelings about these data sets from the L-MIND study ? BHANDARI: The data seems quite impressive.

How long can they be given lenalidomide? SVOBODA: For 1 year. BHANDARI: And tafasitamab for 1 year, or longer? SVOBODA: Then tafasitamab is continued as a maintenance. We’ve seen that prior in literature where in mantle cell lymphoma, they use rituximab maintenance until progression.

And so they’ve designed this study the same way, that they used the tafasitamab maintenance until progression. I am not sure how much the tafasitamab maintenance plays a role, but if you want to follow the data, you will follow that. In some of our patients we didn’t continue for the whole duration until progression.

They opted to hold it after some time because they were in remission. BHANDARI: The reason I asked is because I wanted to see which was more cost effective: CAR T-cell therapy, or this regimen. SVOBODA: It’s a good question, and the CAR T cell price tag is huge.

1. Again, I am sure any of these treatments will be very expensive.
2. That is a great question for health care economist, but I can’t answer that well.
3. CHARLES KUZMA, MD: Can you comment on the lenalidomide dose? In my limited experience, I find that the 25 mg dose quite myelosuppressive.
4. SVOBODA: You’re right.

The majority of the patients were at 20 mg or higher. But, surprisingly, they were able to do 20 mg. I agree with you. When I use R2, hematological toxicities were the issue there. Grade 3 to 4 adverse events were definitely seen in those patients: neutropenia, anemia, thrombocytopenia, as expected, and I feel that is very comparable to the R2 data, just from the lenalidomide itself.4 I don’t really feel that the tafasitamab contributes to the cytopenias, personally.

• They did have a 10% rate of febrile neutropenia.
• There was 1 patient with grade 4 agranulocytosis.
• UZMA: How important do you feel that maintaining dose intensity with the lenalidomide is in this regimen? SVOBODA: I don’t think it’s as important, to be honest.
• We did some very early studies with lenalidomide/rituximab at least 10 years ago, and we used 10 mg daily without 3 weeks on and 1 week off, and patients did very well.

I feel that with these immunomodulatory agents, and other agents, the dose is not as critical as conventional chemotherapy. REFERENCES: 1. NCCN. Clinical practice guidelines in Oncology. B-cell lymphomas, version 4.2022. Accessed June 17, 2022. https://bit.ly/3xylMAF 2.

Polivy. Prescribing information. Genentech, Inc; 2019. Accessed June 17, 2022. https://bit.ly/39wfGsy 3. Monjuvi. Prescribing information. Morphosys US Inc; 2020. Accessed June 17, 2022. https://bit.ly/3A1wumn 4. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study.

Lancet Oncol,2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

How many patients have been treated with CAR-T?

Hospitals are saving lives with CAR-T. Getting paid is another story W ASHINGTON — Penny Trentham’s hospital is missing more than a million bucks. For about seven months, doctors at Virginia Commonwealth University Massey Cancer Center in Richmond have been treating patients with, a cutting-edge medical procedure that uses a person’s to fight against their cancer.

It’s a last-ditch effort that can cure patients who have run out of any other options, but it’s pricey — the medicines themselves cost hundreds of thousands of dollars, and the extended hospital stay can bring the total bill much higher. For every patient Massey Cancer Center has treated so far, Trentham is still waiting for insurers to pay the bills.

She isn’t even sure if the hospital is breaking even. “We’ve not been paid on those, and it’s been several months,” said Trentham, vice president of managed care and payer relations for VCU Health, whose job is it to set up agreements between the hospital and insurers to make sure procedures like this get paid for.

“It doesn’t mean there’s a problem, necessarily. These are very complex claims. But we have not been paid.” And Trentham isn’t the only one — hospitals around the country, jumping at the opportunity to offer lifesaving treatment to cancer patients, are grappling with a situation full of financial uncertainty.

While CAR-T therapy has been on the market for about a year and a half, how to pay for the therapy, and private insurers, many of whom follow Medicare’s lead to set their own rates, are setting up one-off arrangements in the meantime — each of which can take months to settle.

Whether hospitals will recoup enough money to cover their costs is still an open question. The ad-hoc payment landscape threatens to significantly delay the promise of the therapies. Right now, about 130 medical centers in the U.S. are even set up to offer the treatments, and it’s likely that less than 2,000 patients have been treated, based on data provided by the companies that manufacture the two CAR-T therapies approved by the Food and Drug Administration.

Massey Cancer Center is one of the two medical centers in the entire state of Virginia that offers FDA-approved CAR-T treatments. “It’s dealing with the uncertainty of all the contracting, exactly how much am I going to get paid, and am I going to have to provide a discount for some parts and not others, and how much is it going to be — that can take a really long time, especially when the insurers are contracting on a per-person basis,” said Rena Conti, a professor at Boston University’s business school, who is studying different ways of paying for expensive therapies like CAR-T.

Hospitals like Massey Cancer Center just don’t have the experience they need to guess at the average cost, Trentham said. The only specific dollar figure available is the list price of the medicines, which start at $373,000 apiece. The costs for the procedures and doctors can vary widely. “It’s just really hard right now, and I think everybody’s asking for specific answers, but until we get more experience with this treatment protocol, it’s hard to say that we would be willing to accept as a defined payment term,” she told STAT.

“Literally, you should do hundreds of cases before you draw a conclusion.” “We’ve done four.” From left, members of the Massey Cancer Center team: nurse practitioner Melissa Oldham, nurse clinician Kristen Oliver, nurse Teri Thompson, and Dr. John McCarty, who directs the center’s cellular immunotherapeutics and transplantation program.

John Wallace/VCU Massey Cancer Center D espite being poster children for the high cost of drugs, CAR-T therapies aren’t like any other prescription medicines. Each dose is custom-made — a cancer patient’s cells are shipped to one of the pharmaceutical companies, which spends two to three weeks, The engineered cells are then sent back to the hospital where they are infused into the patient.

So far, there are two FDA-approved CAR-T therapies on the market — Gilead’s Yescarta, a lymphoma treatment for adults, and Novartis’s Kymriah, which also treats adult lymphoma as well as leukemia for children. Spokespeople for both companies declined to say exactly how many doses of the commercial products they have produced.

In order to treat patients with the therapy, hospitals need to be certified by the drug’s manufacturer — and they need to figure out for themselves how they are going to pay for all of the costs, or how they are going to deal with the potential financial losses. Massey Cancer Center began that process shortly after Yescarta was approved in October 2017.

Dr. John McCarty, director of Massey’s cellular immunotherapeutics and transplantation program, which includes CAR-T, said that during the 10-month-long journey, the hospital developed a business plan for how to keep the program sustainable. Senior physicians and nurses trained over 500 hospital staffers from all corners of the facility so they would know how to properly carry out CAR-T treatment.

McCarty said he wasn’t sure how much it cost the hospital to conduct the training. As part of the preparation, the hospital even went through a dry run of the procedure — on May 7, hospital staff packed a bag of colored water into a medium-sized cooler and shipped it off, as if they were sending a patient’s cells to Gilead’s California plant where it manufactures Yescarta.

Later that month, Massey received a cryogenically frozen, fake packet of CAR-T cells, and let it defrost in the hospital, as if it were the real thing. At the same time, the business plan presented its own set of challenges — while the hospital can anticipate some expenses, like the cost of routine tests or procedures that are part of CAR-T treatment, they don’t know in advance if a patient will respond well to the therapy or if the patient will spend weeks in the hospital because of dangerous side effects.

That makes it difficult for the hospital to estimate how much it will cost. “We don’t want to be underpaid if it ends up being complex, which is why we’re longing for more experience, so we can more accurately price this, and that will come with time,” Trentham said. Massey doctors treated their first CAR-T patient with the product Yescarta in August 2018.

They’ve treated three more patients since then. As the hospital gains that experience, Trentham said, it’s working on a case-by-case basis with insurers, setting up individualized agreements for each patient depending on the specifics of his or her case.

1. McCarty said that once the hospital sets up an agreement with one insurance company for a particular patient, it’s easier to work with that same insurance company for different patients in the future.
2. And each time insurers approve a new patient for treatment, the process gets a little faster, he added.

The single-case arrangements aren’t unique to CAR-T — Trentham said that the hospital sometimes uses them in other situations, like if it’s treating patients whose insurance classifies the hospital as out of network. And so far, insurance companies have been going along — a hospital spokesperson said that every insurance company Massey has worked with so far has agreed to cover the therapy.

1. Joanna Hiatt Kim, vice president of payment policy and analysis for the American Hospital Association, said that other hospitals are also setting up arrangements in which the insurers pay for the full cost of the drug.
2. That doesn’t necessarily mean the hospitals will be fully reimbursed for all of their costs, however.

These are two separate decisions that insurance companies make — whether they will cover any of the costs of a therapy for the patient, and how much money they will actually pay to the hospital. Even when an insurer covers a procedure, that doesn’t mean it actually pays the hospital the full amount it costs to treat the patient.

1. Hospitals and insurers negotiate back and forth to set these rates.
2. Trentham said she didn’t have information about how much money insurers have decided to pay the hospital under the custom arrangements for CAR-T.
3. No two cases are identical,” said John Wallace, a Massey spokesperson.
4. Based on the potential complexities of caring for these patients, we cannot accurately estimate how much care will cost and we have not treated enough patients to provide an average cost.” Making it even harder to calculate that average: Massey still has not been reimbursed by the participating insurers for any of the four patients it has treated.

“I don’t know these claims have even been adjudicated,” Trentham said. She added, “The way we structured the single-case agreement, that was our hope, was that we would break even. Given the complexity of health care reimbursement, I would anticipate that there are going to be a lot of questions from the payer.

They’re going to want additional records. It’s not going to be a simple claim that flies through.” But Trentham said she isn’t worried. “It’s not uncommon for a complex claim to be slower to pay,” Trentham said. “I would not conclude that there’s any problem.” F or patients covered by Medicare, there may be more cause for concern.

Right now, Medicare might not pay hospitals enough to cover the full costs associated with the therapy, medical professionals told STAT, which could discourage hospitals from offering the treatment, especially if they’re not affiliated with large academic medical centers that have access to other source of funds.

In a recent speech, CMS Administrator Seema Verma acknowledged that Medicare’s payment system for CAR-T isn’t working.”The CAR-T story is an example of how government programs often fail to keep pace with innovation,” Verma said on March 4.And that failure is threatening the ability of hospitals to offer the treatment, because they have to take a huge loss on each Medicare patient.

“Each case, hypothetically, lose a quarter million dollars to half a million dollars,” said Dr. Henry Fung, who runs the CAR-T program at Fox Chase Cancer Center in Philadelphia. “How can you have this sustainable? And then all the community hospitals will never open a CAR-T program.

• Never.” The losses will only be magnified over time.
• The CAR-T treatments that are commercially available aren’t actually useful for that many Medicare patients — CMS estimated that 373 patients will have been or will be treated inpatient with CAR-T products between October 2018 and September 2019.
• But companies are working on developing CAR-T therapies that could help more people with different cancers, which will increase the number of patients who can benefit from the drugs — and the amount of money hospitals might need to spend overall.

“One of our biggest concerns is not necessarily this CAR-T, it’s all the ones coming down the pike that we see, because sustaining a loss on 10 patients a year is doable, sustaining a massive loss on thousands of patients a year is not, quite frankly,” Hiatt Kim said.

What’s more, private insurers often take guidance from Medicare, so whatever decision the government comes to will have ripple effects across the entire health care system. The federal government is still working through two decisions in parallel. First, it must determine under what circumstances Medicare plans will cover CAR-T; second, it will have to decide how much the plans will actually pay hospitals for the treatment.

In the interim, for patients who receive the therapy at a hospital, which is more common because of the dangerous side effects, Medicare is paying hospitals based on the average cost of care for a similar cancer therapy, a bone-marrow transplant. Medicare is also paying up to $186,500 to offset the cost of the drug, and hospitals can be eligible for some other additional payments.

1. But that might not fully cover the cost of the drugs, which start at $373,000, and the entirety of the treatment, which can run much higher.
2. How can a program stay afloat financially for any length of time if they’re having that kind of deficit for any Medicare patient?” Trentham said.
3. In response to the concerns raised by the doctors, a CMS spokesperson said that the agency “is working within our statutory authority on payment approaches for CAR-T therapy to ensure access to care.” It’s still an open question whether, in the future, Medicare will pay hospitals based on the average cost of CAR-T therapy.

That would involve creating a new billing code, something Medicare has so far declined to do. It’s unclear exactly how much money Medicare is paying hospitals, now, in total. A CMS spokesperson told STAT the data will be released this spring. For patients who receive CAR-T as an outpatient procedure — perhaps at an infusion center that might provide other treatments like chemotherapy — Medicare’s payments are more generous.

1. They fully cover the cost of the drug and pay an extra 6 percent on top of that. Dr.
2. David Porter, director of cell therapy and transplant at the University of Pennsylvania’s Abramson Cancer Center, said that nearly all of the patients treated at his hospital with Kymriah, a lymphoma CAR-T treatment manufactured by Novartis, are done on an outpatient basis.

But he’s in a unique place — Porter helped develop Kymriah, so his hospital has a wealth of experience treating patients with it. “Not lots of people are doing it that way, but again, we have years of experience with this,” Porter said. D espite the complicated payment landscape, patients and their family members are largely insulated from the back and forth between hospitals and insurers over the details of how their therapy will be paid for.

Multiple patients and families told STAT that they didn’t have in-depth conversations with their doctors about the payment details, though they did have to get prior approval from their insurance companies. Two families said that once they did so, their insurer picked up most of the tab. Spokespeople for Aetna, Anthem, Cigna, and UnitedHealthcare told STAT they do cover the procedure and declined to say how how much money they paid hospitals and how many courses of treatment they have covered.

For Caitlin Buchanan, a 32-year-old Californian, it all went smoothly. She was diagnosed with primary mediastinal diffuse large B-cell non-Hodgkin’s lymphoma in January 2017. The doctors tried chemotherapy and other drugs, but they weren’t enough. “The chemotherapy had done nothing to the mass,” Buchanan recalled.

1. She added, “The only thing I had available to me was the CAR-T treatment.” Her insurer, Anthem, approved the therapy in two or three weeks, only slightly longer than it had taken to get some imaging scans approved.
2. It was almost unbelievable,” Buchanan said.
3. We thought it was going to take a lot longer.” Buchanan said that her insurance covered all of the costs beyond her deductible, which was about $4,500.

I n Virginia, the CAR-T program is off to a slow but steady start. McCarty is building the program from the ground up, training hospital staff, and also traveling around the state to give more than a dozen talks to doctors about the therapy so they can refer their patients to him.

1. But he didn’t want to be flooded with patients at the beginning before the hospital was able to treat them properly.
2. We didn’t want to get five patients all at once and get completely overwhelmed and inadvertently deliver care that was less optimal than we wanted to give,” McCarty said.
3. McCarty said that he anticipates a ramp-up and aims to treat one or two patients a month with CAR-T therapies over the coming year.

He’s hoping to soon get certification to offer Kymriah, and maybe participate in other clinical trials. In the meantime, he’s taking a conservative approach. “It’s not like I have a billboard out on I-95 or saying, ‘Come get your CAR-T at Massey,'” McCarty said.

Is CAR-T therapy risky?

T Cells Get a New CAR – CAR T-cell therapy involves arming a patient’s own T cells (a type of ) with a specialized protein called a CAR, or, This receptor helps the T cells find and kill the person’s cancer. The NCI team’s remodeled CAR is different from the original in a few ways.

For instance, two sections (called the hinge and transmembrane domains) of the original CAR were replaced. And another section that originally consisted of a protein fragment found in mice was swapped for a similar fragment found in humans. But, like the original, the new CAR also targets CD19, a molecule that studs the surface of lymphoma cells.

In earlier lab studies, the researchers found that T cells armed with the new CAR, And compared with the original CAR T cells, the new CAR T cells produced lower levels of substances called, Scientists don’t fully understand how CAR T cells cause neurologic side effects, but cytokines may be partially to blame.

How many patients have been treated with CAR-T?

Hospitals are saving lives with CAR-T. Getting paid is another story W ASHINGTON — Penny Trentham’s hospital is missing more than a million bucks. For about seven months, doctors at Virginia Commonwealth University Massey Cancer Center in Richmond have been treating patients with, a cutting-edge medical procedure that uses a person’s to fight against their cancer.

1. It’s a last-ditch effort that can cure patients who have run out of any other options, but it’s pricey — the medicines themselves cost hundreds of thousands of dollars, and the extended hospital stay can bring the total bill much higher.
2. For every patient Massey Cancer Center has treated so far, Trentham is still waiting for insurers to pay the bills.

She isn’t even sure if the hospital is breaking even. “We’ve not been paid on those, and it’s been several months,” said Trentham, vice president of managed care and payer relations for VCU Health, whose job is it to set up agreements between the hospital and insurers to make sure procedures like this get paid for.

• It doesn’t mean there’s a problem, necessarily.
• These are very complex claims.
• But we have not been paid.” And Trentham isn’t the only one — hospitals around the country, jumping at the opportunity to offer lifesaving treatment to cancer patients, are grappling with a situation full of financial uncertainty.

While CAR-T therapy has been on the market for about a year and a half, how to pay for the therapy, and private insurers, many of whom follow Medicare’s lead to set their own rates, are setting up one-off arrangements in the meantime — each of which can take months to settle.

1. Whether hospitals will recoup enough money to cover their costs is still an open question.
2. The ad-hoc payment landscape threatens to significantly delay the promise of the therapies.
3. Right now, about 130 medical centers in the U.S.
4. Are even set up to offer the treatments, and it’s likely that less than 2,000 patients have been treated, based on data provided by the companies that manufacture the two CAR-T therapies approved by the Food and Drug Administration.

Massey Cancer Center is one of the two medical centers in the entire state of Virginia that offers FDA-approved CAR-T treatments. “It’s dealing with the uncertainty of all the contracting, exactly how much am I going to get paid, and am I going to have to provide a discount for some parts and not others, and how much is it going to be — that can take a really long time, especially when the insurers are contracting on a per-person basis,” said Rena Conti, a professor at Boston University’s business school, who is studying different ways of paying for expensive therapies like CAR-T.

Hospitals like Massey Cancer Center just don’t have the experience they need to guess at the average cost, Trentham said. The only specific dollar figure available is the list price of the medicines, which start at $373,000 apiece. The costs for the procedures and doctors can vary widely. “It’s just really hard right now, and I think everybody’s asking for specific answers, but until we get more experience with this treatment protocol, it’s hard to say that we would be willing to accept as a defined payment term,” she told STAT.

“Literally, you should do hundreds of cases before you draw a conclusion.” “We’ve done four.” From left, members of the Massey Cancer Center team: nurse practitioner Melissa Oldham, nurse clinician Kristen Oliver, nurse Teri Thompson, and Dr. John McCarty, who directs the center’s cellular immunotherapeutics and transplantation program.

1. John Wallace/VCU Massey Cancer Center D espite being poster children for the high cost of drugs, CAR-T therapies aren’t like any other prescription medicines.
2. Each dose is custom-made — a cancer patient’s cells are shipped to one of the pharmaceutical companies, which spends two to three weeks,
3. The engineered cells are then sent back to the hospital where they are infused into the patient.

So far, there are two FDA-approved CAR-T therapies on the market — Gilead’s Yescarta, a lymphoma treatment for adults, and Novartis’s Kymriah, which also treats adult lymphoma as well as leukemia for children. Spokespeople for both companies declined to say exactly how many doses of the commercial products they have produced.

In order to treat patients with the therapy, hospitals need to be certified by the drug’s manufacturer — and they need to figure out for themselves how they are going to pay for all of the costs, or how they are going to deal with the potential financial losses. Massey Cancer Center began that process shortly after Yescarta was approved in October 2017.

Dr. John McCarty, director of Massey’s cellular immunotherapeutics and transplantation program, which includes CAR-T, said that during the 10-month-long journey, the hospital developed a business plan for how to keep the program sustainable. Senior physicians and nurses trained over 500 hospital staffers from all corners of the facility so they would know how to properly carry out CAR-T treatment.

McCarty said he wasn’t sure how much it cost the hospital to conduct the training. As part of the preparation, the hospital even went through a dry run of the procedure — on May 7, hospital staff packed a bag of colored water into a medium-sized cooler and shipped it off, as if they were sending a patient’s cells to Gilead’s California plant where it manufactures Yescarta.

Later that month, Massey received a cryogenically frozen, fake packet of CAR-T cells, and let it defrost in the hospital, as if it were the real thing. At the same time, the business plan presented its own set of challenges — while the hospital can anticipate some expenses, like the cost of routine tests or procedures that are part of CAR-T treatment, they don’t know in advance if a patient will respond well to the therapy or if the patient will spend weeks in the hospital because of dangerous side effects.

• That makes it difficult for the hospital to estimate how much it will cost.
• We don’t want to be underpaid if it ends up being complex, which is why we’re longing for more experience, so we can more accurately price this, and that will come with time,” Trentham said.
• Massey doctors treated their first CAR-T patient with the product Yescarta in August 2018.

They’ve treated three more patients since then. As the hospital gains that experience, Trentham said, it’s working on a case-by-case basis with insurers, setting up individualized agreements for each patient depending on the specifics of his or her case.

• McCarty said that once the hospital sets up an agreement with one insurance company for a particular patient, it’s easier to work with that same insurance company for different patients in the future.
• And each time insurers approve a new patient for treatment, the process gets a little faster, he added.

The single-case arrangements aren’t unique to CAR-T — Trentham said that the hospital sometimes uses them in other situations, like if it’s treating patients whose insurance classifies the hospital as out of network. And so far, insurance companies have been going along — a hospital spokesperson said that every insurance company Massey has worked with so far has agreed to cover the therapy.

• Joanna Hiatt Kim, vice president of payment policy and analysis for the American Hospital Association, said that other hospitals are also setting up arrangements in which the insurers pay for the full cost of the drug.
• That doesn’t necessarily mean the hospitals will be fully reimbursed for all of their costs, however.

These are two separate decisions that insurance companies make — whether they will cover any of the costs of a therapy for the patient, and how much money they will actually pay to the hospital. Even when an insurer covers a procedure, that doesn’t mean it actually pays the hospital the full amount it costs to treat the patient.

• Hospitals and insurers negotiate back and forth to set these rates.
• Trentham said she didn’t have information about how much money insurers have decided to pay the hospital under the custom arrangements for CAR-T.
• No two cases are identical,” said John Wallace, a Massey spokesperson.
• Based on the potential complexities of caring for these patients, we cannot accurately estimate how much care will cost and we have not treated enough patients to provide an average cost.” Making it even harder to calculate that average: Massey still has not been reimbursed by the participating insurers for any of the four patients it has treated.

“I don’t know these claims have even been adjudicated,” Trentham said. She added, “The way we structured the single-case agreement, that was our hope, was that we would break even. Given the complexity of health care reimbursement, I would anticipate that there are going to be a lot of questions from the payer.

They’re going to want additional records. It’s not going to be a simple claim that flies through.” But Trentham said she isn’t worried. “It’s not uncommon for a complex claim to be slower to pay,” Trentham said. “I would not conclude that there’s any problem.” F or patients covered by Medicare, there may be more cause for concern.

Right now, Medicare might not pay hospitals enough to cover the full costs associated with the therapy, medical professionals told STAT, which could discourage hospitals from offering the treatment, especially if they’re not affiliated with large academic medical centers that have access to other source of funds.

In a recent speech, CMS Administrator Seema Verma acknowledged that Medicare’s payment system for CAR-T isn’t working.”The CAR-T story is an example of how government programs often fail to keep pace with innovation,” Verma said on March 4.And that failure is threatening the ability of hospitals to offer the treatment, because they have to take a huge loss on each Medicare patient.

“Each case, hypothetically, lose a quarter million dollars to half a million dollars,” said Dr. Henry Fung, who runs the CAR-T program at Fox Chase Cancer Center in Philadelphia. “How can you have this sustainable? And then all the community hospitals will never open a CAR-T program.

• Never.” The losses will only be magnified over time.
• The CAR-T treatments that are commercially available aren’t actually useful for that many Medicare patients — CMS estimated that 373 patients will have been or will be treated inpatient with CAR-T products between October 2018 and September 2019.
• But companies are working on developing CAR-T therapies that could help more people with different cancers, which will increase the number of patients who can benefit from the drugs — and the amount of money hospitals might need to spend overall.

“One of our biggest concerns is not necessarily this CAR-T, it’s all the ones coming down the pike that we see, because sustaining a loss on 10 patients a year is doable, sustaining a massive loss on thousands of patients a year is not, quite frankly,” Hiatt Kim said.

1. What’s more, private insurers often take guidance from Medicare, so whatever decision the government comes to will have ripple effects across the entire health care system.
2. The federal government is still working through two decisions in parallel.
3. First, it must determine under what circumstances Medicare plans will cover CAR-T; second, it will have to decide how much the plans will actually pay hospitals for the treatment.

In the interim, for patients who receive the therapy at a hospital, which is more common because of the dangerous side effects, Medicare is paying hospitals based on the average cost of care for a similar cancer therapy, a bone-marrow transplant. Medicare is also paying up to $186,500 to offset the cost of the drug, and hospitals can be eligible for some other additional payments.

1. But that might not fully cover the cost of the drugs, which start at $373,000, and the entirety of the treatment, which can run much higher.
2. How can a program stay afloat financially for any length of time if they’re having that kind of deficit for any Medicare patient?” Trentham said.
3. In response to the concerns raised by the doctors, a CMS spokesperson said that the agency “is working within our statutory authority on payment approaches for CAR-T therapy to ensure access to care.” It’s still an open question whether, in the future, Medicare will pay hospitals based on the average cost of CAR-T therapy.

That would involve creating a new billing code, something Medicare has so far declined to do. It’s unclear exactly how much money Medicare is paying hospitals, now, in total. A CMS spokesperson told STAT the data will be released this spring. For patients who receive CAR-T as an outpatient procedure — perhaps at an infusion center that might provide other treatments like chemotherapy — Medicare’s payments are more generous.

1. They fully cover the cost of the drug and pay an extra 6 percent on top of that. Dr.
2. David Porter, director of cell therapy and transplant at the University of Pennsylvania’s Abramson Cancer Center, said that nearly all of the patients treated at his hospital with Kymriah, a lymphoma CAR-T treatment manufactured by Novartis, are done on an outpatient basis.

But he’s in a unique place — Porter helped develop Kymriah, so his hospital has a wealth of experience treating patients with it. “Not lots of people are doing it that way, but again, we have years of experience with this,” Porter said. D espite the complicated payment landscape, patients and their family members are largely insulated from the back and forth between hospitals and insurers over the details of how their therapy will be paid for.

1. Multiple patients and families told STAT that they didn’t have in-depth conversations with their doctors about the payment details, though they did have to get prior approval from their insurance companies.
2. Two families said that once they did so, their insurer picked up most of the tab.
3. Spokespeople for Aetna, Anthem, Cigna, and UnitedHealthcare told STAT they do cover the procedure and declined to say how how much money they paid hospitals and how many courses of treatment they have covered.

For Caitlin Buchanan, a 32-year-old Californian, it all went smoothly. She was diagnosed with primary mediastinal diffuse large B-cell non-Hodgkin’s lymphoma in January 2017. The doctors tried chemotherapy and other drugs, but they weren’t enough. “The chemotherapy had done nothing to the mass,” Buchanan recalled.

She added, “The only thing I had available to me was the CAR-T treatment.” Her insurer, Anthem, approved the therapy in two or three weeks, only slightly longer than it had taken to get some imaging scans approved. “It was almost unbelievable,” Buchanan said. “We thought it was going to take a lot longer.” Buchanan said that her insurance covered all of the costs beyond her deductible, which was about $4,500.

I n Virginia, the CAR-T program is off to a slow but steady start. McCarty is building the program from the ground up, training hospital staff, and also traveling around the state to give more than a dozen talks to doctors about the therapy so they can refer their patients to him.

• But he didn’t want to be flooded with patients at the beginning before the hospital was able to treat them properly.
• We didn’t want to get five patients all at once and get completely overwhelmed and inadvertently deliver care that was less optimal than we wanted to give,” McCarty said.
• McCarty said that he anticipates a ramp-up and aims to treat one or two patients a month with CAR-T therapies over the coming year.

He’s hoping to soon get certification to offer Kymriah, and maybe participate in other clinical trials. In the meantime, he’s taking a conservative approach. “It’s not like I have a billboard out on I-95 or saying, ‘Come get your CAR-T at Massey,'” McCarty said.

What is the recovery time for CAR-T therapy?

What is the treatment process for patients? – The treatment process involves:

1. Evaluation : Patients undergo a series of tests and screenings to determine if CAR T-cell therapy is an appropriate option.
2. Collection : T cells are collected from patients via apheresis, a process that withdraws blood from the body and moves through a cell separator to collect the needed blood components, in this case, T cells. The remaining blood is then returned into the body. The procedure is done in one day in the outpatient clinic at the Kraft Family Blood Donor Center at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.
3. Engineering : The T cells are sent to a laboratory where they are genetically engineered to target a specific type of cancer.
4. Multiplication : The genetically modified T cells are “expanded” by growing cells in the laboratory until there are millions of them. This process can take a few weeks. When there are enough CAR T cells, they are frozen and sent to the hospital or center where the patient is being treated. At our center, these cells are returned and processed at Dana-Farber’s Connell and O’Reilly Families Cell Manipulation Core Facility.
5. Conditioning Therapy : Prior to infusion of the CAR T cells, patients may receive chemotherapy for their cancer. This helps to create space in your immune system for the infused CAR T cells to expand and proliferate.
6. Infusion : When the CAR T cells are ready, the cells are infused through a central line, in a process similar to a blood transfusion. Patients may receive medications to prevent and control possible side effects of the newly-engineered cells. Patients may receive their CAR T cells in the hospital or in the outpatient clinic. The patient’s physician will decide which approach is best.
7. Recovery : Patients who receive CAR T-cell therapy have a risk/recovery period of approximately 2-3 months. During this period, patients will be evaluated for side effects and treatment response. It is not uncommon for patients to be admitted to the hospital during this period to manage complications. During the first 30 days after CAR T-cell infusion, patients need to remain close to our center for regular follow-up care. A resource specialist can assist in arranging for a place to stay during this time, if needed.

How many patients have been treated with CAR T-cell therapy?

The current situation – The majority of clinical trials using CAR-T cells are early phase studies in B cell malignancies. Trial activity increased dramatically in 2016 and continues at a rate of nearly 100 new trial registrations each year. The most common target is CD19, mostly alone, but increasingly in combination with other antigen targets (Fig. An analysis of CAR-T trials registered at clinicaltrials.gov, (A) Distribution of trials by condition targeted. (Note that the majority of trials target more than 1 condition; therefore, the sum does not add up to total number of trials.) (B) Distribution of trials by target antigen. The geographical distribution of chimeric antigen receptor-T trials registered at clinicaltrials.gov, Map created with mapchart.net ©. Data continue to accumulate supporting the efficacy and durability of responses to anti-CD19 CAR-T cell therapy in B cell malignancies.

Response rates in acute lymphoblastic leukemia (ALL) are reported between 68% and 93%, in chronic lymphocytic leukemia between 57% and 71%, and in B cell lymphoma between 64% and 86%.3 Longer-term follow-up data from the ZUMA1 study indicate durable responses for the minority of patients who achieved a complete remission.4 Future work to better identify predictors of response will improve the risk–benefit balance and minimize unnecessary financial outlay for individual patients and healthcare systems.

This could eventually result in those predicted to respond poorly to chemotherapy but well to CAR-T cells receiving them upfront. Despite promising response rates in trials, applying this data to real-world patients is currently very challenging, partly as inclusion criteria favor better prognosis groups.

Owing in part to concerns about increased rates of cytokine release syndrome (CRS) in more unwell patients with more inflammatory physiologies, combined with the risks of disease progression during the 2 to 3 weeks required for product manufacture, trials have largely excluded patients with rapidly progressive or symptomatic disease, those with poor performance status, raised inflammatory markers, fevers, cytopenias, or derangements in renal and hepatic biochemistry.

Less than half of a historical cohort of chemorefractory patients with diffuse large B cell lymphoma (DLBCL) studied at 1 center would have fulfilled eligibility criteria for the ZUMA1 study. Those eligible patients had a significantly better survival with standard of care immunochemotherapy than the ineligible ones.5 This skewed trial subject population has created a false denominator issue, potentially overstating the efficacy and downplaying the toxicity of current products.

• As such, the relative magnitude of the benefit of CAR-T remains undetermined even in CD19 expressing malignancies.
• With future improvements in manufacture and product turnaround time, as well as refinement of CAR-T design and management of CRS, clinical trials should be better able to include more representative subjects.

Randomized studies, of which so far only 1 has opened, will better establish the place for CAR-T cells in relation to existing potentially curative therapies in B cell malignancies. The situation for other hematological malignancies and solid tumors remains a long way behind, although recent advances in myeloma and an increasing range of potential antigen targets in solid cancers have led to a large number of trials opening to address this gap.