CAR T-Cell Therapy Transforming Science and Cancer Patient Outcomes at CU Anschutz

This episode of CU Anschutz 360 focuses on a promising breakthrough therapy for patients with large B-cell lymphoma, an aggressive subtype of the disease. The clinical trial was led by Manali Kamdar, MD, clinical director of the lymphoma program in the Division of Hematology at the University of Colorado School of Medicine. In the trial for relapsed patients or patients who didn’t respond to treatment initially, CAR T-cell therapy with lisocabtagene maraleucel showed significant improvement in keeping patients in remission when compared to the standard-of-care, which consisted of chemotherapy followed by stem cell transplantation. Thomas Flaig, MD, vice chancellor for research, co-hosts the discussion.

Transcript

Announcer: Welcome to CU Anschutz 360, a podcast about the CU Anschutz Medical Campus.

Today's installment focuses on a promising breakthrough therapy for patients with large B-cell lymphoma, an aggressive subtype of lymphoma. In a clinical trial for relapsed patients, or patients who didn't respond to treatment initially, CAR T-cell therapy with lisocabtagene maraleucel, or liso-cel, showed significant improvement in keeping patients in remission when compared to the standard of care, which consisted of chemotherapy followed by stem-cell transplantation.

Our guest is Dr. Manali Kamdar, associate professor and clinical director of the lymphoma program in the Division of Hematology at the University of Colorado School of Medicine and a member of the CU Cancer Center. Dr. Kamdar led this groundbreaking study, which was a phase III global clinical trial known as TRANSFORM.

Co-hosting our discussion today are Dr. Thomas Flaig, CU Anschutz's vice chancellor of research, and Chris Casey, director of digital storytelling in the Office of Communications.

Manali Kamdar: Hi everyone. My name's Manali Kamdar. I am an associate professor and the clinical director of the lymphoma program within the Division of Hematology. I am a member of the CU Cancer Center. Looking forward to talking to you today.

Chris Casey: Terrific. And thanks for being here – both Dr. Flaig and Dr. Kamdar. Dr. Kamdar, could you start us off by just giving a broad overview of lymphoma?

Manali Kamdar: Sure. So lymphoma is the most common blood cancer. It accounts for the fifth-most common cancer in the United States, so that makes up for about 80,000 patients in the United States. And lymphoma is not really one disease – it's made up of nearly 85 different subtypes. So to really understand how to manage lymphomas, it's really important to understand what subtype of lymphoma because the management is very nuanced.

Just to briefly talk about the subtypes, they're primarily divided into aggressive lymphomas and non-aggressive lymphomas. And then the others, where there is a mix of non-aggressive going into aggressive. The current unmet need within the world of aggressive lymphomas is the fact that whenever we have a patient with aggressive lymphoma the frontline therapy is always intensive chemotherapy.

The good news is that we can actually cure at least 40 to 50% of patients, which basically makes the remainder either respond initially to relapse later, or not respond at all. So, that's an unmet need where we need to do better. And in patients with non-aggressive lymphomas, it's basically living with a chronic disease wherein therapies work but, so far whatever we have, these therapies don't have as much of a durability. So, we want to make sure that in these patients, if we are treating it as a chronic disease, we hope to give them treatments that are efficacious, durable, as well as less toxic. So, these are some of the unmet needs within lymphomas as a whole.

Thomas Flaig: Yeah, so it's great to have you here today, by the way. And I've been looking forward to this conversation since we first started talking about it.

So, I'm an oncologist by training. I treat urologic cancers, but, from my perspective in that realm, lymphomas are incredibly complicated. And the therapies are incredibly difficult at times. Or I would say intense – the therapies we give people. CAR T therapy is something that's been introduced. It's been used in a variety of hematologic tumors. What we're going to talk about today is your work in CAR T therapy in lymphoma. Can you just say a few words though, for the audience, just in general, about CAR T therapies. What is it? How's it being used now?

Manali Kamdar: Absolutely. And may I digress, you are probably one of the best urological oncologists I've seen. I've referred so many patients to you. And we have co-shared a lot of patients.

But coming back to the topic of CAR T-cell therapy. It has been, in my opinion, the most promising breakthrough in the world of hematologic malignancies, particularly lymphomas. Historically, we have had patients who would have succumbed to their disease. And I would say within the subtype of aggressive lymphomas, about 40 to 50% of patients, would've succumbed to their cancer. So, as you can imagine, there is certainly a lot of promise within this treatment.

So, to really cut it down into non-medical terms, what is CAR T? So, as a way of background, we all have what we call fighter cells within our immunity, or our immune system, which have the ability to recognize foreign antigens, such as cancer, as an enemy. And we can identify certain proteins on these cancer cells as foreign, and basically kill it. In patients with lymphoma, the issue is that the ability to recognize these proteins on the cancer cells as foreign is lost by the patient's own fighter cells.

There are many fighter cells such as T cells, NK cells, macrophages. CAR T-cell therapy is basically a therapy which typically manipulates this inability to fight off cancer. So, what CAR T-cell therapy is, is that we take patients' own cells, we take them to the lab. And we isolate their fighter cells, which are T-cells. Now, we know that these T cells have lost the ability to fight off cancer, which is lymphoma. So, we genetically engineer them in such a way that we make them super-fighter cells. Basically, fighter cells will unleash on them, which can now recognize lymphoma cells as foreign.

This manufacturing takes about 3 to 4 weeks with the existing FDA approved constructs. Once we get the cell product back, we then give patients low-dose chemotherapy for 3 days, not to kill cancer, but basically to make space in the marrow so that these CARs can hone in on the marrow. The product is then infused and then, subsequently, the idea is that these T-cell or CAR T-cell, which are your super-fighter cells unleash upon the enemy here, the lymphoma cell, and destroy it. And that is the mechanism of how CAR T-cell therapy works.

Thomas Flaig: Yeah, I think one of the really striking things about this as I've kind of watched this, and it's not used in solid organs like prostate cancer, and colon cancer, has been this idea that it's an individual product. We talk about manufacturing, but it's essentially taking their cells, making these changes and re-infusing them in.

Manali Kamdar: Absolutely. I think it's one of the most phenomenal advances in science. And, I will have to say, some of the early work happened nearly three decades ago, but those CAR T constructs were preliminary because we could make them efficacious, but we couldn't make them last in the system. The idea is when we infuse these CARs they give memory to the existing T cells of the patients as well, and make them fighter cells and thus, wait off cancer forever. Over the last 4 1/2 years, there has been a lot of work with CAR T-cell therapy constructs. And I will have to say the leadership at the CU Cancer Center within the University of Colorado has been exceptionally supportive in helping us open some of the key clinical trials within patients for aggressive, large B-cell lymphoma, as well as for non-aggressive B-cell lymphoma. And I will have to say that I'm very proud that most of these clinical trials have been positive studies, thus leading to FDA approval.

What does it mean to really get on a clinical trial with CAR T? That basically means that our patients who enrolled on the trial had the ability to get this product at least 4 1/2 years before the FDA approved it. So, that is where we got an edge for our patients to be able to first tackle cancer. Number two, be in remission. And most of our patients are still in remission. Thus, basically, getting the advantage of the therapies through the clinical trials.

Thomas Flaig: So, maybe we could just shift gears a little bit with that great background on this complex topic and, frankly, a complex disease. And so, when the CAR T therapy, or any new therapies come into practice, they're typically integrated in the later stages of the disease, where there's fewer therapeutic options. And then, as we gain experience and learn about efficacy, we move things forward, and care for patients. So, there's recently an article in which you were the lead author looking at the use of CAR T therapy in specific lymphomas, which had, I think, a major impact. We'd like to hear more about that, if you could tell us?

Manali Kamdar: Absolutely. We are so pumped about the positive results from this trial. That again, as way of background, as Dr. Flaig just mentioned, CAR T-cell therapy previously has been FDA approved for patients with aggressive, large-cell lymphoma who have failed two lines of treatment. What that means is patients who have failed chemotherapy after chemotherapy, or patients who have failed an autotransplant. An autotransplant is basically chemo times seven. That's the intensity of the autotransplant.

So, clearly, if a product works for patients who have failed an autotransplant, intuitively within the world of science, we'd like to move it forward. As a result, the next advance was to really test the current standard of care for relapsed aggressive, large B-cell lymphoma is that we give patients more chemotherapy. And, if they respond, then we take them to an autotransplant. Unfortunately, patients with high-risk, large B-cell lymphoma who have relapsed, although the intention is to take them to an autotransplant, only about a quarter are able to successfully go through the procedure. As a result, most of these patients will succumb to their disease. Or get CAR T in the third-line setting.

So clearly, the next advance was to prove and find out if CAR T can take over autotransplant in the second-line setting. And this is where I will have to say, again, thanks to the leadership within University of Colorado and the Division of Hematology, we opened a clinical trial here, which was called the TRANSFORM study. The TRANSFORM study uses a CAR T construct called lisocabtagene maraleucel. And this construct was compared head-to-head with an autotransplant in patients with high-risk, relapsed, large B-cell lymphoma in the second-line setting.

They enrolled a total of 232 patients over 47 global sites. And I'm, again, very proud to say that we ended up being the largest site in terms of patient enrollment. And our patients, we enrolled a total of about 11 patients on this study. And these patients were high-risk, large B-cell lymphoma, which had come back very quickly after getting initial chemotherapy. And most of our patients, although it was a randomized phase III study, our patients were randomized to CAR T. And these patients ended up getting CAR T in the second-line setting.

The primary endpoint of this study was what we call event-free survival. And at a median follow up of six months, the study was positive. The primary endpoint was met. And the event-free survival was statistically significant and superior on the CAR T arm versus patients who got an autotransplant. Event-free survival was 10 months on the CAR T arm versus only two months on the autotransplant arm. There were many other endpoints within this study that were also positive: meaning complete response rate was higher. Patients were able to remain progression free for a longer period of time. And most impressive, and striking here was the side-effect profile.

As you can imagine, with patients who get an autotransplant because they get high-dose chemotherapy, they do encounter infections, low blood counts, need for blood transfusion. And they're just very, very tired. On the CAR T study, they found that the incidence of the side-effect profile of the toxicities were actually comparable to patients who went through an autotransplant. But there are certain unique toxicities that patients who go through CAR T can actually experience. And these unique toxicities are not chemo-like toxicities. They really happen because these immune cells unleash on the cancer cells, they kill the cancer cells, and that releases substances called cytokines.

So, there is a syndrome called cytokine-release syndrome, which constitutes low blood pressure, shortness of breath, fevers. Patient could also have neurological toxicities. And I will have to say, as compared to the other FDA approved molecule, the molecule here that was tested within this clinical trial, which is lisocabtagene maraleucel, was exceptionally well tolerated. Some of our patients could actually get this therapy outpatient. And we look at side effects in terms of grade. And whenever we look at a clinical trial experimental product, we look at how many patients had high-grade toxicities. And I'm, again, super pumped to say that they absolutely had no high-grade toxicities with regards to cytokine-release syndrome and neurological toxicity. So grade 4 or grade 5 side effects were zero on this clinical trial which is, again, exceptional and impressive.

At the end of the day, this trial was presented at one of our premier meetings called the American Society of Hematology meeting last year. And I got the opportunity to represent these 47 global sites on behalf of the University of Colorado. And it was just fantastic – very well received. And on the 24th of June, we finally found that the FDA reviewed the data, and accepted this as the new standard over autotransplant in patients with second-line relapse, large B-cell lymphoma. So for patients who now have a high-risk relapse, DLBCL, or large B-cell lymphoma, autotransplant is no longer the standard of care. Thanks to all the effort here of the team, as well as all the exceptional resources that were available at the University of Colorado, we led this trial, we championed it. And, at this point, the FDA has approved it.

Chris Casey: That's fantastic. Dr. Kamdar, and you mentioned the resources that are available here. Can you expound on that as far as what resources you took advantage of on the CU Anschutz campus to enable the research, for example, the CAR T cells reprogrammed here on the campus.

Manali Kamdar: So, within the context of a company-sponsored trial, like the TRANSFORM study, I will say it takes a village. And the village here will constitute my team, my clinical trials team. And it's just so many people, including transfusion medicine doctors, nurses, nurse practitioners, physician assistants, data coordinators. The list just goes on and on, besides just the medical providers like MDs, and DOs, who take care of patients. So, it just is impossible without this large team.

CAR T-cell therapy is resource intensive. And that's why most of the times CAR T-cell therapy gets offered at an academic site like ours, which is experienced and has dealt with many, many trials like this in the past as well. To piggyback on what resources here are currently available, I will have to say that within this world of CAR T everything's looking great. But we are still not at 100% cure. And that's what we aim for. As a result, with that one, single-minded focus, the University of Colorado, the Gates Biomanufacturing Facility, GBF, here has championed the idea of making CARs that are even more efficacious than the existing product. 

The first instance of this was what we call the UCD19 trial. And the UCD19 trial has so far enrolled about 10 to 11 patients. 

We're actually now moving a step further because we now also know that cancers can outsmart us and what can we do to outsmart them. So at this point, we develop CARs against one antigen called CD-19, and the cancers develop resistance against them by becoming CD-19 negative. As a result, the CAR can no longer recognize cancer as foreign. So how do we trick them? We basically now are trying to make products with two antigens on it, and the GBF as well as the University of Colorado campus have been exceptionally helpful. And the team that they have put in place is just so astute that we are now making what we call Bicistronic CARs, which attack two antigens, naming UCD 19/22.

So we have now opened this clinical trial called UCD 19/22 and we have so far enrolled two patients on it. We await their responses, but the hope is that if we do find good efficacy, as well as excellent toxicity profile, the hope is that patients who go through the routine FDA CARs, if they were to fail, which can happen in 40% of patients, we are also going to be now enrolling them on the 19/22 CARs as well.

And this is just the beginning. I think, the idea of cell therapy continues to evolve. And, at this point, we have some excellent scientists, clinicians on campus, not to mention Dr. Terry Fry. Under his leadership, the idea is to really continue to develop more novel products. Like I said, there are just simply three goals here: a cure, make sure that the novel therapy is durable, and make sure that it is not toxic to our patients. I think our patients have had chemotherapy far too long enough that it's time to move on beyond chemo.

Thomas Flaig: So often in oncology, we see therapeutic advances with better efficacy. So, it works better against the cancer. And the downside is there's a lot more toxicity for our patients. That's been the traditional paradigm. You can talk to a patient say, "I can do better and try to control your cancer, but there's been more side effects."

One of the things I just want to bring out about the article we're talking about. And the thing here is that you did not see terrible toxicity with this. You actually saw, compared to the standard, really acceptable toxicity. And so, to me, someone that's been in oncology for 15 or 20 years, that's been a big change. And just I think a very welcome change.

Manali Kamdar: Absolutely. And I think it's really important. Like I do believe that what's the point in killing cancer if the end result is making a patient wheelchair bound? If I can give that patient a good quality of life along with curing the cancer, that's where the true impact lies. 

And I will have to say, within the world of cell therapy, that's exactly what we are shooting for. In fact, within the TRANSFORM study, there was what we call a quality-of-life analysis, or a patient-reported outcome analysis. And it did show that lisocabtagene maraleucel was way superior to an autotransplant from a quality-of-life or patient-reported outcome standpoint. So, absolutely, I agree with you that it's important to now start focusing on treatments that are not just efficacious, but also less toxic.

Chris Casey: And I can tell just by the way you talk about patients, Dr. Kamdar, that you probably develop quite a rapport with your patients. The fact that you enroll patients in clinical trials where potentially a novel therapy can emerge, could you just speak to what you think of your patients? Or how that conversation goes with your patients? And what you think of patients when they volunteer to go into this?

Manali Kamdar: At the cost of sounding sappy, I truly believe that my patients are my extended family. And I would do everything to give them the best product. Then, whether it's on a trial, whether it's FDA approved, it's always going to be a conversation. It's never a one-way street. And I think it's a relationship that develops over time. And because we are doing so well in lymphomas, the relationship with our patients is actually long-lasting. I see so many patients. I joined the University of Colorado in 2015, and I'm seeing a lot of patients since 2015, doing absolutely well. This is, of course, thanks to novel therapeutics and clinical trials, which, at the campus level, have worked. And therefore, our patients have gotten the benefit.

But to really talk about patients and their ability to trust in a clinical trial, I want to reiterate that I am in awe of the fact that they have the courage to participate in a clinical trial – that's number one. The reason they have that courage is because we, as physicians, as providers, definitely want to help them understand where they are in their patient journey. Where is their cancer? What are their options? And what is the possibility of a response? Or even better with the clinical trial enrollment?

I want to also underscore that we do not do clinical trials, wherein patients get a placebo, or a sugar pill. That is unethical within the world of lymphoma, especially if patients have relapsed lymphoma. Also, there are many, many patients who initially could be averse to getting on a clinical trial because they feel like they're a guinea pig. But I do want to let you know that clinical trials are very robustly taken care of. We have eyes from the FDA every time we open a clinical trial.

And there are different phases of a clinical trial. Phase I is when it's never been tested in human beings. It's the first time that we are actually testing the molecule that's looking exceptionally promising in a lab. Phase II is when we actually find that it's not that toxic, we now want to see if it's efficacious. That's when it's been tested in human beings, but now we want to enroll a larger cohort and see if it's efficacious. And then phase III, like the TRANSFORM study which was positive, finally, compares it to the existing standard. 

So, of course, this is something that takes time, that takes a lot of energy, both from the standpoint of a patient, as well as the provider. But that is what really keeps us going on campus here. And I, again, have to say hats off to the patients that they are so open to understanding where they are in their patient journey. And then, very open to also accepting of this possible new therapeutic that eventually has led to FDA approval.

Chris Casey: This is pretty amazing work that's been done. And Dr. Kamdar, like you say, a big team effort. And as you say, Dr. Flaig, very complex. Do you have any final thoughts about Dr. Kamdar's work into this lymphoma?

Thomas Flaig: Well, I'd just like to personally say that the work you've been doing here, the leadership you've shown in this trial, I think, is just really outstanding. And at the center of all this, as you've said, and I've watched you as you put in your practice, are the patients – the patients in the trial, the future patients that will benefit from those who have volunteered to be in a trial.

I think it's a great conversation. It's such an exciting topic. I don't know if there's anything that we didn't touch on today in terms of the future of where CAR Ts are going, or next steps that you'd like to add to the conversation?

Manali Kamdar: I think the future is bursting with just so many new things that are coming down the pike. We hope to continue the winning streak. And we hope to offer exceptional treatments to our patients. Like you said, and I completely second that, the center or the core of our aim is just improving patient outcomes. And that is where the entire focus of the campus is. All these thousands of providers at whatever level they are working, that is the focus of care. So, I couldn't be more proud to be associated with this campus, with my team. And I really, really hope that we continue our journey with finding many, many more novel treatments.

Chris Casey: Well, thank you, Dr. Kamdar for sharing your story into this area of research, and the fantastic success you've had, and where you see things going. Thank you for your time. And also thank you, Dr. Flaig.

Manali Kamdar: Thank you so much for having us.

Outro: CU Anschutz 360 is produced by the University of Colorado CU Anschutz Medical Campus. Story editing and production by Chris Casey, Matt Hastings and Kelsey Peters. Digital design by Sarah Adams and Jenny Merchant.

Special thanks to the rest of the Office of Communications team for support and edits. Special thanks to Denver band Splitstep for our theme music featuring School of Medicine student Matt Golub, class of '22, Daniel Carillo and Kevin McKinnon. 

We'd also like to thank our guests this week, Manali Kamdar and Tom Flaig, for co-hosting. You can read about the latest stories on our campus at news.cuanschutz.edu. 

This is CU Anschutz 360.