CAR T-Cell Therapy for Multiple Myeloma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase one and sarcoma programs today. I'm happy to be joined by Dr. Faiz Anwer, who leads our transplant and T-cell activities for myeloma at Cleveland Clinic. Dr. Anwer is here today to talk to us about CAR T-cell therapy for multiple myeloma. So welcome, Faiz.

Faiz Anwer, MD: Well, thank you Dr. Shepard for the opportunity and I'm really pleased to be here.

Dale Shepard, MD, PhD: Absolutely. So maybe to start, give us a little bit of an idea of what you do here at Cleveland Clinic.

Faiz Anwer, MD: So I'm a staff physician, work with the multiple myeloma group, and we have a very unique arrangement here where our primary myeloma physician who are well trained in the bone marrow transplant and cellular therapy, they actually function as the bone marrow transplant physicians. So we are a group of six physicians, but three of us can also do bone marrow transplant and cellular therapy. And I find that this is a unique and a better arrangement for patients who come for the treatment, and especially for transplant cellular therapy, because as a myeloma physician, we can assess patients who are truly candidate can benefit from this treatment. We can also assess that whether or not these patients have additional therapies available before they can proceed to these therapies.

And after the treatment, that's where we just do not stop our relationship with the patients. We continue to be available to the referring physicians. We continue to be available to the patients and their families, and we individualize their maintenance therapies. And we also get involved when after certain treatment, if the disease come back and disease relapse, we get involved in identifying what will be the best next line of therapy. If there's a clinical trial available, then we can also facilitate that process.

Dale Shepard, MD, PhD: That's excellent. So we're going to focus primarily on CAR T-cell therapies and actually Dr. Betty Hamilton had a previous episode of the Cancer Advances Podcast, and she talked about CAR T therapies, so people can go back and listen to that, but as an overview, just give us a brief idea what is CAR T-cell therapies and how are those currently being used in things other than myeloma. And we'll talk about myeloma here in a bit.

Faiz Anwer, MD: So CAR T therapy is very different from the usual chemotherapy which we had available before. CAR T therapy is an immunotherapy. It's in a therapy where we collect patients own predominantly infection fighting T-cells, which are immune cells, and in the lab inject a piece of a DNA material. And through that genetic engineering process, convert a predominantly infection fighting cell into a cancer fighting cell. And then these cancer fighting cells can identify a target. And so they can hunt and destroy the cancer cells in the body. And they are a living chemotherapy treatment in your own body, which can persist in your body for a long period for many months, and keep on finding the cancer and keep on killing it. So from that standpoint, it's a very different, unique approach how we can now fight against cancers. And for multiple myeloma, we have now two different products which are FDA approved and commercially available for use.

Dale Shepard, MD, PhD: All right. So let's go ahead and switch gears to multiple myeloma. Now you've certainly been involved in some of the research that led to these therapies, so tell us a little bit about the origins of that and some of the work you've done.

Faiz Anwer, MD: So we are involved in a novel T-cell development through a multi-phase. It's a multi-institute collaboration on a phase one clinical trial, where instead of taking autologous T-cell, which come from the patient, these allogeneic T-cell come from a healthy donor and these T-cells are modified in the lab and they are, so to speak, off the shelf ready T-cells for the treatment of multiple myeloma. So we are involved in this phase one drug development trial on an ongoing basis, and so far 42 patients have been treated. And the latest data was reported and updated in the American Society of Hematology meeting back in 2021.

Dale Shepard, MD, PhD: And so of the initial patients that were studied, any early word on outcomes and how well people are doing?

Faiz Anwer, MD: So based on the updated reports, we reported that patients have now shown good responses to the treatment, more than 60% of the patients are responding to this particular CAR T-cell and they are responding very quickly, within first two weeks of therapy and patients who respond, their responses are lasting for many, many months, up to eight months. And many patients are able to achieve deep responses. Up to 40% of the patients are able to achieve very good partial response and a complete response. And those patients who actually have these deeper responses can achieve what we call a minimal residual disease negative status, which truly indicate that the disease is under very well control.

Dale Shepard, MD, PhD: And remind me, the patients that are being studied, these are pretreated patients, so these are patients who have already had some other therapies. Tell me about that.

Faiz Anwer, MD: Yeah. At this point, these are patients who are refractory to many other therapies. So in this particular study, these patients were heavily treated. Some were between three prior lines therapy, all the way up to 11 prior lines of therapy. So these are truly refractory, heavily pretreated patients. And despite all that, they are responding very nicely to this intervention.

Dale Shepard, MD, PhD: So it makes that even more impressive that you get 60%. I've pointed out to some of your colleagues that as a solid tumor oncologist, I'm very jealous.

Faiz Anwer, MD: And I think the development in the CAR T for the solid tumor is also progressing, of course, the initial success we're seeing in the hematological cancers, but I anticipate that we'll continue to develop these product further and hopefully one day we'll see similar good outcome for other cancers.

Dale Shepard, MD, PhD: I do get asked frequently about CAR T therapies and solid tumors. And as you mentioned, we're much further behind. Remind us why that's true, why have we had much better success in hematologic malignancies and solid tumors?

Faiz Anwer, MD: I think so far we have a success with two targets. One is CD19, which is predominantly present on the B cell. So there's a host of these B cell related cancers, including diffused large B cell lymphomas, follicular lymphomas, B cell leukemia's, mantle cell lymphomas. And in multiple myeloma, we have a target, which is called BCMA. So far these targets are unique, they are selective, and they are working in a sense that the CAR Ts are highly effective. But we develop additional targets for other diseases, I hope that we'll have similar success in other cancers as well.

Dale Shepard, MD, PhD: So a lot of the lack of benefit in solid tumors, not having a uniform target?

Faiz Anwer, MD: That's correct.

Dale Shepard, MD, PhD: Gotcha. Let's put this back in perspective, the 60% response heavily treated patients, they have failed prior lines of therapy, but oftentimes patients might get a response and then fail. How does that compare? If a patient, instead of going on a trial like this, would've gone to a more traditional therapy, what would you have told a patient would be an expected response?

Faiz Anwer, MD: So somebody who's heavily predated and received five, six or seven therapies typically we expect that they will be responding to any intervention between three to six months. So to expect responses in a large number of patients, and to expect that these responses last for a longer duration, this is actually very exciting and unique for the CAR T therapy. Typically, if a patient responds to a prior therapy and it lasts for one year, the next line of therapy typically gives you 50% of the duration.

Dale Shepard, MD, PhD: The phase one trial you talked about, that's with an allogeneic CAR T-cell, there are a couple of therapies that are available commercially. How do these compare, they're autologous? And then are they in a similar setting in terms of refractory disease?

Faiz Anwer, MD: So currently we have access to two autologous CAR T-cell for the refractory multiple myeloma. The product which got approval first last year was the Abecma, which is a BCMA targeting autologous T-cell for multiple myeloma. These patients need to be refractory, they should have exposure to at least three prior lines of therapy, and they should have exposure to at least three different classes of drugs, which include immunomodulatory drugs, proteasome inhibitors, and an antibody targeting CD38. So most of the patients who got treatment, they were refractory to these three main drugs, which are currently used for the myeloma treatment. The new product called Carvykti is also an autologous T-cell. It targets the same target, which is called BCMA. So the current FDA approval is for the relapse and refractor multiple myeloma. There are trials which are now looking at how we can move these CAR T-cell treatment to the more frontline setting. But those trials are either in the design phase or they are early in the development phase.

Dale Shepard, MD, PhD: Does it seem like this might be something that we can shift a lot of these therapies earlier if these trials are successful and how might things like transplant fall in line with these newer therapies?

Faiz Anwer, MD: So I think if the data continue to support the use of T-cells in the frontline setting, it is possible that in the future we may not be doing transplant at least for a majority of the patients, because transplant relies on old fashioned alkylator heavy dose chemotherapy, which has a lot of regimen related toxicity. And if you can avoid that with the help of a more targeted approach, then that's where the future is.

Dale Shepard, MD, PhD: Certainly when you think about transplants or certain patient factors, it might make patients more or less eligible for transplants. When we think about CAR T-cell therapies, either the allogeneic or the autologous, are there particular patient factors that come into consideration in terms of who might be a candidate?

Faiz Anwer, MD: That is a good question. So on one hand we are very excited about how effective the CAR T therapies are, but we're also aware that these CAR T treatments are costly and they are still toxic. There's a long list of toxicities, which we need to consider before we can make a decision whether or not patient will benefit from CAR T. It is true that there is a possibility a particular patient may not be eligible for high dose chemotherapy and autologous stem cell transplantation, but may be very well eligible to receive a CAR T based treatment.

Dale Shepard, MD, PhD: And so when we talk about toxicity, certainly with the early CAR T therapies, the autologous therapies, concerns about cytokine release syndromes and CNS effects, are there differences that we see with the allogeneic in terms of toxicity profiles?

Faiz Anwer, MD: So there are some similarities and there's some differences, because the data is limited and the follow up data is also short at this time for the allogeneic CAR T and we'll continue to monitor for any additional infection risk, because how an allogeneic CAR T is different from an autologous CAR T is these patient receive more immunosuppressive therapy. In addition to receiving the usual lymphoid depleting chemotherapy using cyclophosphamide and fludarabine, they also receive another experimental antibody, which depletes their native T-cells, and that potentially can make them more immunocompromised. So we are continue to observe these patients for any additional risk for infections.

Dale Shepard, MD, PhD: So just from strictly a logistic standpoint, autologous CAR T-cells, you have to send off, have engineered, reintroduce into patients, what's the difference from a logistic standpoint, from a time standpoint, you have someone who shows up in your clinic, they need a treat treatment, how long until you can effectively give a therapy in each situation?

Faiz Anwer, MD: So in the current trial, these patients were able to receive their lymphoid depleting therapy from the enrollment within five days of enrollment. And that means that the product is already available. They just need to do initial screening and eligibility criteria is met, and this patient can be treated. So the allogeneic CAR T overcome lot of challenges of logistic challenges, which currently patient are facing. So the vein to vein time will be less. In this case, the cells are already prepared. There is a possibility that patients can receive multiple infusions, because with the current autologous CAR T, patients have to collect every time the new CAR T is produced. So if these T cells which are allogeneic and available can be infused again, if the CAR T run out from the system and patients need an additional infusion, so that is also possible.

Dale Shepard, MD, PhD: So when we think about these kinds of treatments, where are the biggest gaps? You think it's managing toxicity or targets or efficacy, where are going to be the next big strides?

Faiz Anwer, MD: I think these are all very important factors, so we need to individually look at all these factors. So why a CAR T therapy fail at this time? There are multiple factors for that. One could be that the T-cells are not effective enough so we need to look at the additional targets and possibility of using two target or three target either simultaneously or in a sequential manner, we need to look at that. We also need to look at how long these cells can persist and try to enhance that duration so these cells can stay in the body. We can also work on enhancing the target so they are more visible to the T-cell.

So one approach is the use of a novel small-molecule inhibitor carboxylesterase, which can enhance the BCMA target and hence enhance the efficacy of the T-cells. So all these factors are very important. We are also using CAR T as a single treatment, so there could be a possibility of combining these T-cell with additional therapies such as immunomodulators, such as different antibodies. We can also use additional biologics for the control of myeloma and enhance the anti-myeloma efficacy for these CAR T-cells.

Dale Shepard, MD, PhD: Seems reasonably you realize that in most cases we have a series of treatments for most cancers or we use combinations, whereas here we're talking about a treatment, seems like a very reasonable thing. Logistically, these sound complex. So we have a wide range of people that might be listening in. How easy is it for patients to get access to these treatments?

Faiz Anwer, MD: Well, I will suggest that the first step should be that patient should come and see a physician who can evaluate them whether or not this CAR T therapy is suitable for them. And once the suitability is established, then we have a team of BMT providers which get involved into the care and determine how quickly this patient need to be treated and make arrangement for the T cell treatment.

Dale Shepard, MD, PhD: Makes sense. So we've focused on CAR T therapies, is there any other category of therapies that you find particularly interesting as we move forward in treating this disease?

Faiz Anwer, MD: So, fortunately I practice in myeloma where a lot of new drug development is happening. We are very excited about the possibility of now used by specific antibodies, which can use your native T-cells in your own body and direct them against the cancer. So it is very exciting that we have now drug development happening in that space. In addition, there are third and fourth generation of immunomodulatory drugs which are being developed for the treatment of multiple myeloma. I just want to add heavily possibility that our patients can return to their usual life, enjoy good quality life where they can be active, free of active disease and engage in daily activities like normal individuals. It's personally very exciting and a big motivation to work in myeloma. Thank you.

Dale Shepard, MD, PhD: So lots of exciting things going on.

Faiz Anwer, MD: That's true.

Dale Shepard, MD, PhD: Well, I appreciate all of your insight. Thanks for being with us.

Faiz Anwer, MD: Well, it was a pleasure. Thank you again for the opportunity.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled. This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real updates from Cleveland Clinics cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.