Transcription:
From Transplants to CAR T-Cell Therapy

Dr John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today on the podcast, we'll be talking about scientific treatment advances in cancer care through cell therapy.

I'm very happy to have our guest for this episode, Dr. Koen Van Besien, who is a hematologist and medical oncologist at Weill Cornell Medicine and New York Presbyterian Hospital. Dr. Van Besien and serves as the Director of the Bone Marrow and Stem Cell Transplant Program, as well as the Cellular Therapy Program at Weill Cornell Medicine and New York Presbyterian Hospital.

His research and clinical care have earned him an international reputation for his novel treatment strategies in bone marrow and stem cell transplant, as well as the use of cellular therapy, such as CAR T. Most recently, Dr. Van Besien's team made headlines with a medical breakthrough using haplo-cord transplant in a way that appears to have cured HIV in a leukemia patient.

Today, I'm looking forward to our conversation, which will be focused on how these advancements in cell therapy play a role in cancer treatment and care for patients. So, Koen, thank you very much for joining us today. It's great to have you here.

Dr Koen Van Besien: Thanks, John.

Dr John Leonard (Host): I want to start by asking you how you ended up working in this fairly specialized, but important area of hematology-oncology. Why did you focus in bone marrow transplant initially and cell therapy over the course of your career?

Dr Koen Van Besien: So I've been in this area ever since I was an intern. And one of my first rotations was on a leukemia/bone marrow transplant service. And I was immediately intrigued by the scientific sophistication of the fields that has never ceased to advance, also by the patient care, by dealing with these very ill patients. It's a very intense clinical field and that's just my personality that fits well. Over the years, it's never ceased to disappoint. Transplant and cellular therapy continues to make big advances and have an impact in a variety of hematologic malignancies. So it continues to be quite interesting.

Dr John Leonard (Host): Well, I want to go through some of the key areas of cell therapy and we're going to focus on some of the new advances and exciting things that are happening to make a difference for patients. But I want to start perhaps with a more established form of cell therapy.

So if you could give us a sense of the traditional bone marrow and, more recently, stem cell transplants, how does that process work?

Dr Koen Van Besien: So again, going back to the past, when I was an intern and a resident, stem cell transplant was like the newest treatment and it was quite exciting. It was also quite toxic and amenable for only limited number of patients. That has continued to be the dream of many to make it more efficacious, to make it less toxic, to make it more tolerable. And on the other hand, it has been the dream of many to invent better or less intensive therapies that are equally efficacious.

Be it as it may, allogeneic transplantation, meaning using a donor for replacing one's own marrow, one's own blood-producing cells, because that's really what our marrow is. It's the site of blood production. And when our blood production is defective, which results typically are the disorders such as leukemia, we need to replace that marrow by somebody else's marrow and that's an allogeneic transplant from somebody else.

You were asking about bone marrow versus stem cells. Really, it's a technical difference. In adults, all the blood-producing cells are residing inside the marrow. They can be collected there by doing multiple bone marrow aspirations, a painful procedure. And we have a healthy donor. We need to put the donor to sleep under the general anesthesia. It's a complicated procedure. And we collect the variable number of cells.

About 20 years ago, it was found that one can mobilize these stem cells, at least transient periods of time, into the bloodstream. So we talk about mobilizing peripheral blood stem cells from the bone marrow into the blood stream. Then, it becomes much easier to collect them. We collect the cells by just accessing a vein, removing blood in a continuous centrifugation process, about a three-hour procedure. The patient just is watching TV. We collect the cells. We return most of the blood to the patients after immediately centrifugating it and removing the stem cells. So it's a much easier procedure for the donor. It turns out also that stem cells collected in this fashion recover faster than bone marrow cells, so most centers have moved to using peripheral blood stem cells rather than bone marrow cells.

The third source is cord blood. Strangely enough, newborns have these stem cells circulating in their blood stream. We can use these cord blood stem cells for the same purpose for transplanting.

A totally different procedure is the autologous transplant, which is collecting the same peripheral blood stem cells from the patient themselves. And those cells then can be preserved. They can be frozen down, kept viable for a prolonged period of time. And these cells are used to rescue a patient from the toxic effects of very intensive chemotherapy, meaning that particularly in disorders such as myeloma and lymphoma, very intensive chemotherapies are extremely effective and can lead to durable and, in lymphoma, sometimes permanent remissions where other treatments have failed. These treatments, these very intensive chemotherapies damage the bone marrow production of blood cells and would be fatal unless we rescue the patients with their own autologous stem cells. So we collect the stem cells from the patients, we freeze them down, then we give the very intensive chemotherapy and we rescue the patient with his or her own stem cells. Of course, this is for lymphoma and myeloma mostly, whereas allogeneic transplantation is used mostly for leukemia where the bone marrow itself is the site of illness.

Dr John Leonard (Host): As you noted, the autologous stem cell transplant from yourself is really a fancy way of giving more chemotherapy primarily. Whereas the allogeneic from someone else has some pros and cons to that. So maybe you could tell us a little bit about what makes that work better against the tumor, particularly in leukemia, what adds to the risk and about the matching process? Because I think people hear a lot about looking for donor drives and things of that nature and finding a family member or an unrelated person who's a match. So maybe you can give us a little bit of a sense of the importance and the implications of the matching process andall of that.

Dr Koen Van Besien: Before I go there, every day, I meet patients who have read on the internet about the risks of transplant, and there's a general feeling that one has to be very careful about that. The autologous transplants, the rescues with the patient's own stem cells have actually become very safe over the years. And it's very rare for the patients to have problems. The donor transplants indeed remain difficult procedures and there is serious risks for complications, including fatal complications and also chronic disease.

Now, what are those and why do they persist? We've actually improved a lot over the duration of my career and many other people's careers the last 30 years. But as we have improved, we have taken on more difficult patients. So when I started, we rarely used allogeneic transplantation for patients over the age of 50. In the last five years, we've regularly accepted patients over the age of 75. Why do we offer this to these older patients? Because we have figured out ways to offer them the transplant and because it's in older age groups, diseases such as leukemia are more common. And so there are no other curative therapies. So these days, we fairly frequently use the transplants in patients over 70, even over 75 and very routinely in patients over the age of 60.

Now, how does one find a donor and what are the complications to deal with? So finding a donor requires having somebody who has the same HLA type. I typically compare with blood groups. Blood group doesn't matter. We transplant across blood groups, but there are only four blood groups. There are many different white blood cell groups or HLA types. There's thousands of them, millions of them probably. Fortunately, within a family, there's only four types. We get half of our types from our father, half of our types from our mother. Therefore by simple, what we call Mendelian genetics, we share the complete HLA type as we call it with one out of four of our siblings. So our siblings can be completely matched, one out of four; completely mismatched, one out of four; and half-matched, two out of four or half of them. Parents are half-matched with their children, and so forth. With current family size, I would say we find these matched siblings in about a third of our patients. A lot of patients either don't have siblings, they're older, they don't match and so forth. So that addresses one-third of our transplants. And those sibling donors remain the best donors, not by a large margin anymore, but by small percentages superior as to other types of grafts.

The second type of graft is the unrelated donor. Since the complexity of this HLA typing is enormous. Very few of us, even if we have 10,000 neighbors or 10,000 friends, we wouldn't find a donor. Fortunately, the transplant community has been v/ery proactive over the last decades and has built a worldwide registry or every country has developed their own registry, but all the registries are linked and we have up to 20 million volunteer donors in the registries. And I would encourage every listener here to volunteer to be a member of this registry. Donating stem cells for those of the volunteer donors is not reimbursed, it's also not dangerous, and this is a major act of selflessness.

There's a problem there though. The complexity of the HLA type is such that even with the registry of 20 million donors, we find matching donors, completely matching donors, for only about 70% of our patients if they are of Caucasian descent. The HLA types are somewhat genetically linked with ancestry and, for any type, any minority, be they patients of Asian descent, Far East Asian descent or from the Indian subcontinent, patients of mixed race, mixed ethnicity, or in particular patients of African American descent, the chance of finding a perfectly matching donor is anywhere from 40% for somebody of East Asian descent, to approximately 15%, 20% for our patients who have African ancestry, so a major limitation. And the ability to identify a perfectly matching donor really determines a lot of the success of a subsequent transplant.

So how do we get around this lack of donors for many of our patients? We try to develop transplant methods that allow mismatched transplants. And a number of approaches have been utilized. Many centers around the country use children, half-matched children, to transplant their parents or vice versa. That's becoming quite efficacious and it's an excellent approach, not as good as matched siblings, but catching up. We have chosen a different route and have used these cord blood donors combined with an adult donor. But the essence is that we do a cord blood transplant. They can be very mismatched. And the beauty of this approach is that these cord blood donors, the cells of these cord bloods are newborns, and they are extremely adaptable to their environment. They therefore cause very few complications and actually may have superior anti-leukemic effects.

Your question was also how does the transplant work and what are these complications? So the complications are related to the profound impairment of the immune system that is temporary in the first six months after the transplant and also a process called graft-versus-host disease. So after transplant, immune suppression is quite pronounced and patients in the first six months need to be extremely careful and are extremely vulnerable to opportunistic infections, meaning infections that really cause very little problems for the regular person in the street. That improves over time. And we have a number of strategies to prevent infections, but still it is a difficult time.

The second problem is graft-versus-host disease, which is an attack of the graft, meaning the donor cells on the host, the recipient of these cells. And this graft-versus-host manifests itself as skin rashes, gastrointestinal problems, meaning nausea, diarrhea, and liver problems. And it can last a couple of weeks. It can last a couple of months and it can last for years in occasional patients. Again, we have developed over time, many strategies to mitigate that and prevent that, but it continues to be something we have to deal with and a risk for patients.

Closely related to this graft-versus-host disease is its flip side, which is the graft-versus-leukemia effect. And there are longstanding observations that have demonstrated that the donor cells themselves are quite important in eradicating the underlying disease. So in a donor transplant, we cure the patients in part by the high dose chemotherapy that we give before, but to a major extent, just because of the nature of these cells of the donor, recognize characteristics of typically leukemia cell in the patient and eradicate them. So it remains a fascinating and highly effective treatment.

Dr John Leonard (Host): I'd like to go back to the cord blood scenario that you alluded to and you mentioned that the cells come from newborns. So logistically, how does all of that work? Someone might wonder how you and your team access cord blood for a potential patient. And then the concept that you've pioneered of the haplo-cord transplants. Maybe you could tell us a little bit about how that works.

Dr Koen Van Besien: So cord blood as a source of transplantation was developed close to 30 years ago. When researchers found that cord blood contains these blood-producing cells. Banks have been developed where mothers can donate the cord blood of the newborn. So the umbilical cord gets thrown away normally and investigators have set up systems and organizations where mothers in certain hospitals are to donate the blood from the umbilical cord for banks. And there's, I believe, 14 banks in the United States and another 10 in the world, and we can access these banks. They contain umbilical cord that is frozen from mothers and from babies that were born over the past two decades. And these umbilical cord blood grafts are well characterized. We know the number of cells in there, so we can interrogate the banks and find the best matching umbilical cord for our particular patient. And the best matching umbilical cord is one that is as closely matched as available. But usually, it's quite mismatched because we look for it mostly in patients who don't have these matching unrelated donors. So we accept partially matched cord blood donors, and they lead to great transplant success where a similarly partially matched adult donor would have a lot of complications, particularly more pronounced or more severe graft-versus-host disease and also more severe immunosuppression. So this is a well-established strategy for offering transplants to patients who don't have matching donors. And that's up to 40, 50% of my patients here in New York City.

Now, the limitation of these cord blood grafts is also well-established. Namely, they are understandably very small grafts. They have a limited number of cells. And when these cells are transplanted in the patients, and by the way, a transplant is really a transfusion. We transfuse these cells into the bloodstream of the patients, be they from an adult donor or from a cord blood donor. We just give a transfusion of these cells after preceding chemotherapy. And the cells find their way to the marrow and start growing there. Now, an adult graft or a graft from an adult donor has a hundred times more cells than a graft from a cord blood donor. And grafts from an adult donor starts producing white blood cells after about 10 to 14 days. And therefore, the patients regain at least part of their immune system after 10 to 14 days. A cord blood graft can take 30 to 40 days to recover. And that puts the patient at considerable risk of opportunistic infections in these 30, 40 days after transplant. It renders the transplants quite difficult.

The way we work around this now for the last decade or so is by complementing that cord blood graft by a partially matched adult donor graft. And that is typically also a relative that is partially matched. And we give these two grafts together. Now, the adult donor graft is manipulated so that it does not contain much of an immune system, but it contains only the cells that produce white blood cells, neutrophils. The adult graft recovers really fast after 10 to 14 days and the patient can leave the hospital. The transplant is safe. And then overtime, the adult graft gets replaced by the umbilical cord blood graft. We use the term it is outcompeted by the umbilical cord blood grafts. So when we look at the graft after 30 days, at the white blood cells 30 days after the transplant, 90% is from the adult donor. When we look after a hundred days, 90% is from the cord blood donors. And typically after half a year, everything comes from the cord blood donor. Therefore, we establish a graft that is really well adapted that does not cause much graft-versus-host disease, but has the advantage thanks to the adult graft of rapid early recovery.

Dr John Leonard (Host): I want to touch on the breakthrough that you and your team had recently in the news where this approach was used in a patient that happened to have leukemia and HIV and how this approach seems to have potentially cured this patient from HIV. How did all of that take place and where do you see that going?

Dr Koen Van Besien: So right now, this type of procedure is applicable only for patients with leukemia and HIV. It's too complex a procedure to offer to the average well-controlled HIV patient who is on medication and not cured. That said, there are a very small percentage of the human population that is completely resistant to HIV. They are practically all Caucasians and mostly their genetic pool, their gene pool is located in Sweden, Russia. And this resistance mutation is not found anywhere else in the world.

So about 10 years ago in Berlin, there was a patient who had HIV and AML and he was Caucasian and they went to extreme lengths to find a donor who was both compatible, HLA-compatible, HLA-identical, and had this HIV resistance mutation. By transplanting this patient with that particular adult donor graft, the patient turned out to be cured of his HIV permanently. Unfortunately, that same patient about a year ago had a very late relapse of his leukemia and died of leukemia. That's highly unusual to have a relapse this late, but unfortunately it happened to him. Now, ever since, a number of centers have been trying to replicate this success. And it's been very difficult to achieve, because if one needs both an HLA-identical donor and a donor that is resistant to HIV. That can be found only in very rare patients who are Caucasian, because that's in that gene pool that the HIV resistance mutation arises.

We had a patient who was not Caucasian, who had leukemia. She was a woman and who needed a transplant and she actually had a perfectly matching unrelated adult donor, but that donor did not have the resistance mutation. We also found partially matched umbilical cord blood. And so again, the advantage of the umbilical cord is that it does not require complete matching. So we found a partially matched umbilical cord blood that had the resistance mutation. So we offered the patient to use that umbilical cord blood using our haplo-cord procedures. So we combined the umbilical cord blood with an adult partially matched donor. And we offered the haplo-cord transplant as I just described, except for using it with a cord blood unit that was HIV-resistant. And we replicated this observation. The patient is now four years out and fortunately seems cured of her leukemia, which after 4 years one would expect. As is typical for cord blood transplant, no graft-versus-host disease. She's in perfect condition, leads a perfectly normal life. And we have not been able to detect any evidence of HIV now for the past four years. And she has been taken off her antiretroviral therapy for about 14 months and continues to do very well without detectable HIV. We are reluctant to use the term cure because we think we need another year or two years follow-up before we can really state that HIV is permanently cured, but we are very optimistic about this.

Dr John Leonard (Host): It sounds like if there are a sufficient number of these cord blood units with a resistant mutation available that this might be a preferred approach for somebody with HIV and leukemia.

Dr Koen Van Besien: Yes. A rough estimate is that we would have such a cord blood unit that is partially matched and HIV-resistant for approximately 50% of our patients who might need it, who have both HIV and leukemia. I think this case will create some enthusiasm. I've talked to a couple of patients who might be interested.

Dr John Leonard (Host): Interesting. Well, in our last several minutes, I wanted to transition to another very hot and innovative area and important area for patients, because it's made a difference for many people. That is the concept of CAR T-cell therapy. So maybe you could briefly explain how CAR T-cells work, what are they and where we tend to use these approaches now and potentially in the future.

Dr Koen Van Besien: So going back to the therapeutic effect of giving cells, this is an observation again from donor transplant, the cells of the patient contribute to cure of leukemia by an immunologic process. They recognize the cancer as something different. That is clearly established now, but also a dangerous and difficult procedure, the donor transplant often lacks efficacy. There are still patients who relapse. A number of investigators have been working on genetically modifying the immune system of the donor and, by genetically modifying them, incorporating receptors into the T-cells that recognize the cancer and destroy it.

So the way this currently works as FDA approved for now four products is that we collect cells of the immune system, T-cells, from the patient. We send the cells to a company that genetically modifies them, puts in a chimeric antigen receptor, meaning a foreign receptor, but a receptor with exquisite recognition of the cancer, many times it's lymphoma and myeloma. So therefore, the term CAR T-cells, it's a chimeric antigen receptor T-cell. The cells are grown up over about two or three weeks and then, given back to the patient after a course of minimal chemotherapy. It turns out that T-cells are extremely effective in eradicating certain tumors. Right now, mostly B-cell lymphoma and multiple myeloma where these cells can induce responses and remissions and, particularly in lymphoma, cures in patients who otherwise would be incurable.

The treatment right now is limited to academic centers with extensive support systems because the cells, as they are effective, they cause fever, they cause a number of side effects, something called cytokine release syndrome. Patients can get quite ill, can need very close observation. They can have some transient neurologic side effects. For now, it's a very complicated procedure that is restricted to large academic centers, but it's moving into the preferred treatment for patients with relapsed aggressive lymphomas. It's used in patients with low-grade lymphomas, in patients with mantle cell lymphomas, is soon to be widely used in multiple myeloma that has relapsed. And there's also an enormous investment from the biotech industry and from researchers worldwide, and the general expectation is that these products will continue to rapidly evolve. And for example, we now are already having trials where instead of taking the cells from the patients, an autologous CAR T, we have donor CAR Ts that are available off the shelf. They're still in clinical trials, but these soon will become available. We are addressing the limited efficacy of the CAR T cells in lymphoma. It's about 40%, 50%. I think that these response rates will increase with newer products. And there's major efforts of using these CAR T-cells in other tumors, for example, in solid tumors. And we here have, for example, a trial ongoing for use of these CAR T-cells in aggressive thyroid cancer.

Dr John Leonard (Host): Well, thank you. This has been a great summary. Any kind of last messages for a patient who's dealing with say a blood cancer, leukemia, lymphoma, myeloma. Perhaps they're getting their therapy in the community or needing cell therapy, what would you suggest that patients do to learn about these areas and to decide what scenarios or what options might be available to them for their individual situation?

Dr Koen Van Besien: So John, you'll know this actually better than I do, how lymphoma, myeloma, leukemia are very complex diseases. And probably more than any other cancers, we have many treatment options and they have improved. I think it's very important that particularly for patients who are not doing perfectly, who need further treatment, that they seek expert opinions and multidisciplinary teams that really have access to all types of treatment, because there's much more than cellular therapies. There are a number of innovations in medical therapy as well. So multidisciplinary approach, excellent pathologist, excellent radiologists, lymphoma specialists, leukemia specialists are important for the complicated patients. Access to trials and participation in trials is extremely important and often benefits the patients.

And lastly, particularly for allogeneic transplantation, there's a misconception out there that it's only for the young and that it's way too complicated and way too difficult. There's plenty of patients in their 60s and 70s who look back at this and have done very well and benefited from it. So, patients should not leave any doors closed and look for the best option and not exclude any of them.

Dr John Leonard (Host): Well, thank you for your work and thank you for really a great discussion and summary of a broad and complicated topic. I'd like to invite our audience to download subscribe, rate, and review CancerCast on Apple Podcasts, Google Podcasts, Spotify or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see us cover more in-depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care and research. I'm Dr. John Leonard. Thanks for tuning in.  

Disclaimer: All information contained in this podcast is intended for informational and educational purposes. The information is not intended nor suited to be a replacement or substitute for professional medical treatment or for professional medical advice relative to a specific medical question or condition. We urge you to always seek the advice of your physician or medical professional with respect to your medical condition or questions. Weill Cornell Medicine makes no warranty guarantee or representation as to the accuracy or sufficiency of the information featured in this pod. And any reliance on such information is done at your own risk.

Participants may have consulting equity, board membership, or other relationships with pharmaceutical, biotech or device companies unrelated to their role in this podcast. No payments have been made by any company to endorse any treatments, devices, or procedures. And Weill Cornell Medicine does not endorse, approve or recommend any product, service or entity mentioned in this podcast.

Opinions expressed in this podcast are those of the speaker and do not represent the perspectives of Weill Cornell Medicine as an institution.