Optimizing CAR T-Cell and Stem Cell Transplants

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and 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. Craig Sauter, Director of the Blood and Marrow Transplant Program. He's here to talk to us about the BMT program in optimizing treatments with CAR T cells and stem cell transplants. Welcome, Craig.

Craig Sauter, MD: Thank you, Dale. It's great to be here.

Dale Shepard, MD, PhD: So maybe start out, give us a little idea, what's your overall role here?

Craig Sauter, MD: So, in early 2022, I came on as the new director of blood and marrow transplantation, as well as directing oversight of the burgeoning field of cellular therapy here at Cleveland Clinic. The opportunity came up with a departing previous director, Navneet Majhail. So, I've been here a little over six months in a working capacity.

Dale Shepard, MD, PhD: So, I guess, from a very practical standpoint, you were at Sloan Kettering before. And what drew you to Cleveland Clinic?

Craig Sauter, MD: Yeah, so I completed fellowship training at Memorial Sloan Kettering, stayed on as faculty there, and was there in New York City at MSK for 16 years. What drew me back toward Cleveland Clinic was really, one, the opportunity, and two, I am a Cleveland native. So, looking for opportunity for a promotion and to lead a group, particularly with respect to Cleveland Clinic, I was most attracted to the focus on patient-centered care, really focused on clinical excellence with the burgeoning emphasis on investigational therapies here within Taussig Cancer Institute at Cleveland Clinic.

Dale Shepard, MD, PhD: Very good. So certainly, you mentioned sort of the expansion new therapies and things, but what are some of your goals as you take over the role here?

Craig Sauter, MD: Well, the volume of cases is expected to continue to expand, not just for standard of care indications, particularly around blood and marrow transplantation for hematologic malignancies, but we are in the first wave of excitement around engineered cellular therapies and immune effector cell therapies, of which we're conducting studies here at Cleveland Clinic. So, we anticipate volume to continue to expand, especially with increasing investigational efforts.

Dale Shepard, MD, PhD: Let's just go ahead and think about those sort of newer opportunities. Tell us a little bit about kind of where we are and where you'd like to be.

Craig Sauter, MD: Sure. So, there's been a large leap in terms of proof of principle with chimeric antigen receptor modified T-cells, particularly within B-cell malignancies, and then, later, for multiple myeloma targeting the BCE maturation antigen or BCMA. So, with six commercially available products now, there's a lot of investigational energy and excitement around building upon that proof of principle, that engineered immune effector cell therapy can be effective and it can actually improve standards of care. So, it's really twofold is the increased volume of standard of care patients that are available and indicated for commercially available products, but also, more importantly, efforts here within Taussig Cancer Institute, along with the Center for Immunotherapy and Precision Immuno-Oncology, putting a lot of resource and effort behind really building out a cellular therapy investigational unit.

And that's currently being led on the wet bench side in the early phase investigations by Jos Melenhorst, who was a recruit from University of Pennsylvania and was particularly integral to the development of a now-commercially available product tisagenlecleucel or KYMRIAH, while he was at University of Pennsylvania. So, we really want to leverage the academic power that has been built here to build out unique novel investigational therapies that are homegrown here at Cleveland Clinic.

Dale Shepard, MD, PhD: We had the opportunity to talk to him a little bit about that engineering process on a previous episode of the podcast. So, what else is going to be involved, things like actually manufacturing products and things like that?

Craig Sauter, MD: So, there has been allocated resource to building out a GMP facility here at Cleveland Clinic, to be able to manufacture GMP grade cellular therapy products, which we're very excited about. That will be forthcoming with a new physical plan to be determined. But the resources have been allocated clearly what Dr. Melenhorst is doing in the lab. We do want to translate into unique available products for investigation in humans.

Dale Shepard, MD, PhD: Give us some idea of what the impact of our ability to do that, being able to sort of engineer products, make products, give products in trials, compared to, just say, testing things that are coming along in development from companies.

Craig Sauter, MD: Sure. So, there are commercially available products, and clearly, there's a lot of effort and energy from private pharmaceutical companies to continue to develop and expand these technologies. What we know, despite the excitement in the proof of principle of targeting tumor associated antigens with engineered immune effector cells, such as CAR modified T-cells, is that the excitement needs to be tempered a bit. Because still, the majority of patients have progressive disease following this therapy. So, we are keeping patients alive longer, thus the prevalence of some of these diseases are going up, maybe not necessarily the incidents. And there's still going to be a need for unique therapies. And we know by the recently developed products that the proof of principle again is there. So, we want to build on that leverage, but continue to improve, because clearly, we haven't hit the home run quite yet.

Dale Shepard, MD, PhD: And so, I guess that leads to a number of questions. When can you have better efficacy? Can you have more durability? And then, other targets?

Craig Sauter, MD: Certainly, and less toxicity. These are largely therapies that have to be delivered in the inpatient hospital setting. I think one of the facets of this therapy is that they're autologous derived engineered T-cells, and that requires an apheresis procedure from the patient, a manufacturing step, which typically takes at least weeks. Part of the investigational efforts are really to shorten that to within days, where the product goes through quality control, assurance, cultures, et cetera, so that we know it's a clinical grade product that can go back to the patient. In that interim of time, whether it's three weeks, six weeks, eight weeks, these are high risk patients with advanced disease, and certainly, from a disease and pathophysiologic standpoint, a lot can happen. So, one of the shortcomings thus far, especially with commercially available products, is the availability. It's like the sports pundits say with professional athletes, the best ability is availability.

And with a lot of these products, particularly the newer multiple myeloma products, there are patients waiting, and not just waiting for the autologous T-cells to be sent off and come back produced, but actually, waiting for slots that are available with the company. So again, that substrate would feed an investigational effort if we had unique products here that we believe have some sort of rational or rationalized improvement over previous products towards the access end as well, as many of these efforts are using universal donor off-the-shelf CAR modified T-cells, meaning allogeneic donors donate lymphocytes, they're engineered to target a tumor associated antigen. And then, there's additional engineering steps particularly to take out the T-cell receptor, so as not to introduce potential toxicities, like graft versus host disease. The biggest hurdle to overcome will be endogenous immune rejection of the product. So those would not only need to be tested for response rate efficacy, but really, durability of these responses.

Dale Shepard, MD, PhD: And then, I guess, when we think about barriers, what's the current environment in terms of coverages and insurance? And where does that sort of fall in with these products at this point?

Craig Sauter, MD: So, all of these products are well into the six figures, as a sticker price. As some of the forthcoming engineered products for other diseases, such as hemoglobinopathies, are approaching seven figures. So clearly, there's going to be a reckoning at some point about how this is compensated, how these therapies are going to be administered, particularly to patients who have less means or less robust insurance coverage. Part of this is controlling the pricing that we hope, through avenues like CMS and negotiation with the companies, we can help to remedy at least.

Dale Shepard, MD, PhD: Certainly, a lot going on in the CAR T arena. And so, as you're building a program and you're thinking both clinical use and as you're doing research, what other types of cellular therapies do you find most interesting?

Craig Sauter, MD: Well, we're expecting the FDA approval of a tumor infiltrating lymphocyte product for advanced melanoma. So, we're expecting to become commercially available. Part of the next horizon is that a lot of these successes have been particularly in B-cell non-Hodgkin lymphoma and B-cell malignancies, as well as the plasma cell disorders targeting BCMA. We do believe the next horizon is to understand the biology of solid organ malignancies and be able to hopefully target some of these tumor associated antigens on some of these malignancies with cell therapy modified product. And those are the next wave of studies that we're beginning to entertain and open here at Cleveland Clinic.

Dale Shepard, MD, PhD: Let's shift gears a little bit, more of traditional transplants. What's the?

Craig Sauter, MD: The bread-and-butter transplant?

Dale Shepard, MD, PhD: The bread-and-butter kind of transplants, but even though bread and butter transplants, there's things that are happening, like more outpatient utilization, things like that. Tell us a little bit about that.

Craig Sauter, MD: Certainly. So, part of my vision here was to be able to expand some of these therapies to the outpatient arena, because brick and mortar space is a limited resource. And not just a limited physical resource, but also, human resource, in terms of inpatient staffing from a support services nursing on up. Additionally, within transplant, especially within the hematologic malignancy space, a lot of hematologic oncologists say, "Well, transplantation's eventually going to go by the wayside with these smart cellular engineered products, et cetera." But what we know is, with reduced intensity transplant, being able to investigate and abrogate, mitigate, toxicity around transplant, as well as expansion to alternative donors, such as haploidentical donors, mismatched unrelated donors, if anything, we're seeing expansion of the utilization of allogeneic transplant in particular. It should be noted that there have been drugs approved within the space receiving FDA label, such as letermovir for prevention of cytomegalovirus infection, as well as, most contemporarily, in the last few years, three agents that have been approved for steroid refractory or resistant graft versus host disease, which is a first.

Ibrutinib belumosudil, as well as ruxolitinib, with that agent, both for steroid refractory resistant acute and chronic graft versus host disease. So, what we know in data support this through the Center for National Blood and Marrow Transplant Registry is that transplant indications are expanding. We've been able to improve outcomes based on making safer transplants and being able to select patients more wisely for these transplantations. There's still a lot of work to do, because we still deal with the risk of treatment or transplant related mortality, especially in an older more infirm patient population at high risk. And the incidence of progression of the hematologic malignancy following, particularly an allogeneic transplant, is still a relatively low bar that we want to try to address.

Dale Shepard, MD, PhD: So, as a solid tumor guy, that transplant eligibility always seems to be kind of a little fuzzy, and it's kind of like, you know it if you see it kind of deal.

Craig Sauter, MD: A little nebulous. Yeah.

Dale Shepard, MD, PhD: A little bit. And so, then, we're taking it a step further and saying, well, what kind of patients can we even think about doing outpatient? What are some of the factors you think about, in terms of how to select who you might be able to do outpatient transplants?

Craig Sauter, MD: So, in our first outpatient wave, it's really the lowest toxicity autologous transplant, which is just administration of a high-dose chemotherapy followed by reinfusion of their stem cells to reconstitute hematopoiesis. And with that single dose melphalan in the multiple myeloma population is our first pilot of that, and we've had a couple patients since October come in and thus far has been, knock on wood, successful. We've established clear objective criteria. All the patients have to be 65 years of age or younger, they have to have adequate organ function and performance status. And most importantly is that these patients require a non-Cleveland Clinic family friend type caregiver with them 24/7 for at least two weeks to bring them back and forth and to be the ad hoc healthcare provider, while they're at home, with temperature checks, monitoring, fluid intake, and just symptomatology. That is one of the largest barriers. At my previous institution, we actually analyzed those data and demonstrated that the largest barrier is that a lot of people don't have somebody that can mobilize a couple weeks of service. People work, and some people have limited support.

Dale Shepard, MD, PhD: When we think about our ability to move forward bread and butter transplants, you were talking about differences in settings. Is there anything else that's particularly exciting in that area?

Craig Sauter, MD: So particularly, for our largest indication in the allogeneic realm, which is acute myelogenous leukemia and myelodysplastic syndrome, there are often very high-risk biology cases, bad multiply mutated complex karyotype disease that we know is incurable without a transplant, but there are particular high-risk disease biologies that are very high risk for progressing, following allogeneic transplants. So, we take these patients down the road of a high-risk procedure and when the incidents of the disease coming back approaches 30, 40, 50 plus percent, that's really a low bar for investigation. And part of those investigations are including adjusting conditioning programs or at least introducing novel agents within the conditioning prior to the transplant, and then, certain maintenance therapies following the transplantation, whether there's relatively efficacious but low toxicity profile agent that could be administered to a patient following an allogeneic transplant, we feel that that's a ripe platform for investigation.

We also believe that the conditioning in the transplant is a unique immunotherapeutic platform for potentially engineered cell therapies, so marrying the two, including donor derived allogeneic transplantation and cellular therapies or even high dose chemotherapy followed by autologous transplant for lymphomas and multiple myelomas, we feel that those are sort of optimized platforms for administration of immunotherapeutics, including potentially cellular therapies as well as other oncologic agents in the space, checkpoint inhibition, et cetera.

Dale Shepard, MD, PhD: When you think about anything in this space, it's a team sport. It takes a lot of people. Tell us a little bit about what you've seen upon arriving, what you'd like to do in terms of further support and getting patients through this entire process.

Craig Sauter, MD: So, I have to give an immediate kudos to the support staff here. It's impressive at a multidisciplinary level, particularly within the blood and marrow transplant program. We have fantastic nursing, nurse practitioners, physician assistants, particularly on the inpatient side, that can be quite high volume. They're professional and experts in the care that they administer. On the inpatient side, we have very strong pharmacists that are dedicated to our program and are a huge resource with many pharmacologic agents and drug interactions. The depth and quality of the social work program here is really second to none and is internationally recognized as a phenomenal social work program. And then, all the other nursing staff, administrative staff, it really is a large program, and I've really felt like a family. There have been a lot of people that have been here a long time with deep institutional knowledge and true commitment to the blood and marrow transplant program.

The basic need is going to be, we're going to need more of them. If you look six years ago, we're going to double the infusions. If you just look at cellular therapy infusions, now, six years ago, those are all basically all autologous or allogeneic transplants. So, part of this expansion is immune effector cell therapy, including CAR modified T-cell therapy. But just over the past three years, there has been incremental 10 to 12 percent increase in volume, and this year, it's going to approach 20 percent annualized at the end of 2022 compared to 2021. So, we are growing. And so, we're just going to need more people and we know that there's a real workforce issue in healthcare in general, with competing interests, particularly industry, pharmaceutical companies, which are able to pull people away with certain incentives, and we hope to be able to retain good quality people that remained extremely committed, which we have in place. We just are going to need more in the future.

Dale Shepard, MD, PhD: What are your biggest wins? What are you most happy about?

Craig Sauter, MD: I think getting the outpatient transplant program off the ground and getting buy-in from the stakeholders, as we would say. They're our champions. Laura Bernhardt, who's our nurse manager on the outpatient side, has been a fantastic champion and really organized it. We really got a program project around this and we want to see expand, because our immediate first or front burner issue is being able to treat more patients without reliance on an inpatient service. The second is building out a cell therapy research team within the blood and marrow transplant program. Paolo Caimi is the associate director of that, and of course, we're working collaboratively with Jos Melenhorst.

There's been a lot of excitement around that. We kicked off a PRG meeting at the end of September. We are entertaining studies. We have a biorepository protocol, so we're trying to build out internal correlative science through the CITI and the Immuno Cell Engineering program with Jos, as well as opening prospective investigational studies. Those have been two of the larger things, but really, it's going to be how do we deal with the growth? And we know that there are patient populations that don't do well, and we have to offer something novel for them going forward.

Dale Shepard, MD, PhD: Well, you have an impressive program going and sounds like you have big plans for the future.

Craig Sauter, MD: It's exciting. It's really exciting. New challenges every day, but I think the biggest plus to coming here that I suspected was that the people are just fantastic, from top down.

Dale Shepard, MD, PhD: Well, we certainly appreciate you being with us and sharing some insight.

Craig Sauter, MD: Thanks, Dale.

Dale Shepard, MD, PhD: That was great. 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 time updates from Cleveland Clinic's Cancer Center experts on our consult QD website, at consultqd.clevelandclinic.org/cancer.

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