More than 175,000 new cases of leukemia, lymphoma, and multiple myeloma are expected this year in the United States. Fortunately, a revolution in blood cancer treatment has arrived with immune checkpoint blockade and CAR T cell therapies providing new options for patients. Several immunotherapies are already FDA-approved, and ongoing research demonstrates even greater potential for new treatments, especially in adoptive cell therapy. Join Dr. Hearn Jay Cho of Mount Sinai Tisch Cancer Institute in a Q&A discussion about different immunotherapies used in the treatment of blood cancers and new treatments in development to bring the benefits of immunotherapy to even more patients.
Tamron Hall: Welcome back. Let’s start with our blood cancer immunotherapy breakout. We’re joined by Dr. Hearn Jay Cho. He’s an associate professor of medicine at the Icahn School of Medicine at Mount Sinai, and is an attending physician with the Multiple Myeloma Service at the Mount Sinai Tisch Cancer Institute in New York City. Dr. Cho Brian, let’s learn about what’s new in immunotherapy for blood cancer.
Dr. Hearn Jay Cho: Thank you for the introduction, Tamron. Good afternoon, everyone. My name is Hearn Jay Cho. I’m here with Brian Brewer from the Cancer Research Institute. Today, we’re going to be talking about immune therapies for blood cancers. So the original immunotherapy for blood cancers, leukemia, lymphoma and multiple myeloma, was allogeneic bone marrow transplantation. So this is when a donor provides bone marrow, which is then transplanted into a recipient who is the cancer patient. What happens is when the bone marrow and grafts and starts to make new blood, this also makes new immune cells and the immune cells from the graft can recognize the cancer cells as being foreign and kill them. This was the first demonstration of immunotherapy against blood cancers, the so-called graft versus leukemia, or GBL effect. This was demonstrated way back in 1979, and it’s been shown to be effective in many different kinds of blood cancers, including leukemia and multiple myeloma. So we have a very strong basis for understanding the ability of the immune system to control blood cancers. However, allogeneic bone marrow transplantation is a very risky procedure, so it is an intensive, hospital-based procedure and there’s many side effects. So the goal of immunotherapies for blood cancers is to reproduce that graft versus cancer effect with, with minimal side effects and without the associated risks of bone marrow transplantation. This is largely taken the form of three strategies which are listed here. The first are targeted antibodies. Now, this actually covers a fairly broad range of strategies, including “naked antibodies” that are aimed at a target on the cancer cell, and it helps the immune system recognize the cancer cells and kill them. Sometimes we attach chemotherapy molecules to these antibodies, so this is like a guided missile that takes chemo directly to the tumor cells. There’s also a new strategy, which I’ll talk about a little bit more called bispecific T-cell engagers. The next category are checkpoint inhibitors. You’ve heard about some of these already quite a bit. These are gaining a lot of traction, particularly in the Hodgkin’s lymphoma field. There is investigation in other blood cancers, some of which are too early to really report results and others which have led to advanced trials, and in some cases, some are not advancing. These are antibodies that block these brakes on the immune systems called immune checkpoints, and PD one and PD-L1 are probably the most well-known, and these were first approved in 2014. Then the most recent breakthrough in blood cancers has been cell-based therapies. In particular, the so-called CAR T cells car stands for chimeric antigen receptor. The first of these was approved for lymphoma in 2017. The first car for multiple myeloma was just approved in 2021 a few months ago.
When we think about these strategies, I’m going to focus on two strategies that are directing T cells to blood cancer cells, and the first of these are the so-called engineered cell therapy. So this is CAR T cells and transgenic T-cell receptor cells. For the purposes of this talk, I’m going to mostly talk about CAR T cells, since those are ones that have been approved now. Engineered cellular therapy is exactly what it sounds like. We have to do some work under the hood on those T cells in order to make them effective anticancer agents. So what this involves is first isolating T cells from patients. So we take the large volume of blood. We isolate T cells from them. Those get sent to a laboratory where we insert receptors into the T cells of the T cell can recognize cancer cells. Then we grow those T cells, so we make millions of copies so that they we have a large force of cells that can go after the tumor, and then these ultimately get re infused into the patient. Now, as you can imagine, this is a very involved process that requires specialized laboratories and it requires time. It typically takes around three to four weeks to make enough T cells to do this therapy. So sometimes patients need other types of chemotherapy between the time that their T cells are isolated and the time that they get their engineered T cells back.
So how does it work? So, as I said, I’m going to mostly focus on chimeric antigen receptor T cells, the way things are made is an artificial receptor. The chimeric antigen receptor is made with an extracellular region that sticks to the tumor cell. It recognizes something on the surface of the tumor cells so that the CAR T-cell has this on the surface. It can find the tumor cell and stick to it. But inside of the receptor has all the activation machinery necessary to turn on the T cell. So it takes the T cell to the tumor cell and it turns it on. The other strategy shown here is the engineered T cell receptor. This is taking a T cell receptor that already recognizes cancer cells, so this is typically cloned from a patient who has a good response against a certain type of tumor, and then we’re inserting that receptor into the patient’s T cells so that they can go after the cancer cells for a variety of reasons. That’s a more restrictive pathway, so the chimeric antigen receptors or cars are much more universally available now.
So what happens is the cancer cells have a particular target on their surface, those are the red triangles and the car or the engineered T cell receptor recognizes those antigens, and so it brings the T cell directly to the cancer cell, and as I said, it has the activation machinery there, so it turns it on so that the cancer cells that the car T cell can then kill the cancer cells.
So bispecific antibodies are another strategy to bring T cells to cancer cells and turn them off. This is a slightly different strategy in which we use the sticky parts, the antigen recognizing sites from two different antibodies and put them together. So in this example, targeted antibody number one, the blue antibody, we take one of those red circle antigen receptor sites and then targeted antibody number two, the green antibody, we take another one of those antigen receptor sites and we graft them together. So we have an artificial antibody that has two ends, one that recognizes one target, another end that recognizes another target. Now, in the case of most of the bispecific that are under investigation now or approve, one end recognizes an antigen on a tumor cell. The other side recognizes something on the T cells. It’s part of the activation machinery, a molecule called CD3. So if something sticks to CD3 three on a T cell, it typically is one of the on switches for the T cell. So these strategies are another strategy to bring T cells to tumor cells and turn them off so that they can kill the tumor cells.
So that’s illustrated in this example. Here again, the red triangle is the target on the surface of the cancer cells. As you can see, the blue end sticks to the target on the cancer cells, the green and sticks to CD3 on the T cells and turns them on. So then those T cells can kill the cancer cell. So these are both powerful strategies to bring T cells to tumor cells and kill them. The difference with a bispecific antibody is there’s no engineering involved here. These are off the shelf reagents so patients can receive the treatment more or less right away, and it does not require three to four weeks to engineer cells and expand them and so forth.
These are both effective strategies, and they’re very powerful in a lot of different blood cancers. So, there’s actually four car T cells that are listed here that have been FDA approved for them. Sorry, five CAR-T cells. Four them are for lymphoma and leukemia, one of them, which just got approved a few months ago, a BCMA or IDA cell, was just approved for multiple myeloma. So these are first car T-cell for myeloma is just to prove there are checkpoint inhibitors that are approved for, as I noted, for Hodgkin’s lymphoma, nivolumab and pembrolizumab. These are targeting the PD-1 pathway and there are bispecific antibodies approved for leukemia that’s Blinatumomab, and there’s a number of them under investigation for myeloma and lymphoma right now.
So the future of immunotherapy for a malignancies, we’ve actually come full circle, so we started in the 70s with the observation that allogeneic bone marrow transplantation, the original immune therapy, can be effective in fighting and controlling blood cancers. Now we have a number of different effective strategies to reproduce this effect safely and reproducibly in the clinic. So next generation strategies are to enhance and sustain that T-cell function. So we’re thinking about different combinations or rationally-designed combinations, not only to kick off that immune response, as we’re seeing with either bispecific or T-cell, but to sustain it. So, can we use things like, for example, checkpoint inhibitors to keep that immune system response rolling against cancers and preventing relapse of disease, or are there different combinations of immune strategies which can increase the response rate, increase the effectiveness of these strategies? Since CAR T cells have been shown to be effective, are there ways to make them more effective because in some cases, for example, multiple myeloma, they’re very effective, but not necessarily curative. So, can we look for better targeting against cancer cells, can we make the car T-cells stronger and more effective against the tumor cells, and can we reduce this potential side effects, as you may have heard in earlier discussions? CAR T cells can have fairly significant side effects that require hospitalization and aggressive management are those ways to deliver that CAR T cell therapy as effectively, but with fewer side effects. So these are the challenges that are facing us in the blood cancer field. I would say that we are incredibly grateful that we’ve turned the corner on immune therapies. We have now been able to bring these strategies into clinical use to FDA-approved therapies and the clinical trials that are ongoing now, I think hold the promise for even better immune therapies in the very near future. So thank you for your attention. I think Brian’s going to come and join us now and we’ll have some questions.
Brian Brewer: Thanks so much, Dr. Cho, for that. I heard a few things in your talk. We talked about cell therapies. We talked about antibody therapies and how we’re on the cutting edge of technology right now, thanks to research on both of those fronts. For the people who are listening for the first time who may not understand, you know, an engineered T cell and what that means, or an engineered antibody that’s going after two targets, and what that means, let’s boil it down to, I’m a blood cancer patient, let’s say, I have myeloma or lymphoma or something, and I go, and now I’m having immunotherapy explained as a potential treatment for me. What’s the difference between the CAR T’s and the antibodies?
Dr. Hearn Jay Cho: That’s a good question. The way I explain it to a lot of my patients are your T cells in many respects are the soldiers that your immune system uses to fight the cancer, so you have to train soldiers to recognize the enemy and kill them. So these are two different ways to train your T-cells to find cancers and kill them. In the car T-cell case, we’re actually modifying the cell itself, so this is the first kind of genetic modification of a cell type that’s been approved by the FDA. We’re using the gene for the artificial receptor of the CAR, and we’re inserting that into the T cell using a vector, basically a way to shuttle that genetic material into the T cell so that it’ll make that receptor and have it on the surface of the cell. It is, as I noted, an involved process that requires obviously special laboratory special reagents and special training technicians and so forth, and it takes time. You have to grow up these cells, you make the cells, you grow them up. So it’s like you’re training your troops, you’re putting them together and then you send them back to the clinic so that they can go into the patient and be infused to fight the cancer cells. So that’s one way to train your soldiers. The other way is with the bispecific. So the bipecifics are kind of like, they’re raising the flag. So the bispecific goes to the tumor cell and identifies that as a bad cell. The other end attracts and sticks to the T cells so that the T cell knows, “OK, this is something bad. We’re going to kill it.” So, it’s a different method, but they both accomplish more or less the same thing. You get the T cells to recognize and kill the tumor cells.
Brian Brewer: What I think is really amazing is all of this stuff sounds very simple now, right? But it took a lot of work, right? A lot of decades of work to understand these basic mechanisms. So before we move on to the next question from one of our viewers, I would love to hear from you: what is the role of science in advancing new cancer treatments?
Dr. Hearn Jay Cho: It’s a constantly evolving process. When I was a student in the 80’s and 90’s, the idea of immunotherapy for cancer was a pipe dream. People believed that the immune system didn’t play an important role in cancer. We now know that that’s not true. Part of part of the immune system’s normal job, in addition to guarding against infections, is to constantly survey the body and make sure that no bad cancer cells are arising. We learned a lot more about basic functions in the immune system in the last 40 years. We’ve also learned how to manipulate that system. So that insight, for example, that came out of the Allison lab that we can block an off signal such as PD-1 was profound because until we got to the point where we could use, for example, antibodies or cytokines to manipulate the immune system, we really had very few options in order to get the immune system to kill cancer or something. This has been an ongoing journey. It was the first real cancer immunology probably happened in the early part of the 20th century, and it’s been a long journey. Science, it was absolutely necessary to understand how does the immune system work? How does it work against cancer? How can we make it work better?
Brian Brewer: That’s I think the thing that doesn’t come readily to a person who’s facing a cancer diagnosis, you just want an answer, right? We know science takes time, and I think that’s what’s really exciting about where we are right now, right, where we do know enough about the immune system. We don’t know everything, of course, but we know enough to help some patients, and there’s a lot of potential to help more. You mentioned when you were speaking recently that because of the time it might take to engineer the car T cells, the patient might need to receive chemotherapy. In the meantime, can you say a little bit more about how these therapies work together?
Dr. Hearn Jay Cho: Yeah, so there are, for example, the myeloma field when we take the T cells out to send them to the lab to engineer into car T cells. A lot of times patients may have increasing disease. It’s active, it’s causing problems for the patient. So you need something as a stopgap before the CAR T cells are available, and we often use chemotherapy, but some there’s now a lot of interest into whether that chemotherapy can make the CAR T-cells work better, for example. So we do know that some older style conventional chemotherapy agents actually do have some favorable effects on the immune system. So there is now some interest in doing trials using things like, for example, cytokine as that interim chemotherapy to see if it makes the CAR T-cell therapy work better. So there’s other approaches to try to improve the effectiveness of these car T-cells as well.
Brian Brewer: I just think it’s fascinating because in my role at CRI, as comms director for all these years, I often hear surprise from people who understand the basic idea of mobilizing your immune system to fight cancer and really seizing on that as the answer. I think it is, but I’m not a scientist, but I’ll keep working toward it. But I do hear these questions about, you know, is this replacing chemotherapy? It sounds like that is that’s something patients have to really understand is that this is part of a multifaceted approach.
Dr. Hearn Jay Cho: Absolutely. You know, every cancer is different, and in reality, every cancer patient is different, and what we’ve often found, for example, in the myeloma field, you know, myeloma is a disease of plasma cells. It presents infiltrating the bone marrow. It can damage the bones, cause the blood can affect the kidneys. So that’s the presentation of the disease, but what we actually know now from extensive research is that not every, even though they all have the same sort of common manifestations, there’s actually several different categories of myeloma patients, and these are defined right now by genetic changes in the cancer cells. There is now research into the immune system. This is a disease of the bone marrow. We’re looking very intensively at immune cells and the immune microenvironment and bone marrow. You know, my lab and many others are involved in this research, and what we’ve discovered is there’s also different categories of patients defined by the immune profile in the tumor microenvironment. So there’s a lot of dynamics between the tumor cells, between the immune microenvironment, so every patient is different and unique, and we need to understand that biology better because some patients may work better with a CAR T-cell and some patients may have better responses with the bispecific, and some patients might do better if they get chemotherapy first and then get some sort of immune therapy, and some patients may never need chemotherapy. So that is part of the next step, the combination strategies, how to use our understanding of the biology to then tailor treatment to the individual patient. This is called precision medicine approach and that extends to therapy as well.
Brian Brewer: I am fascinated by what you said that sometimes a round of chemotherapy might make the following immunotherapy more effective, and I can’t get into all of that right now, of course. But it’s interesting again to note that this is about combination approaches and you’re working on two different mechanisms, right? So chemotherapy is talking the cancer, immunotherapy is mobilizing the immune system. These are two different things that come into play together. So I find that interesting. My next question from one of our viewers, is about these tests to know what markers you have. You’ve mentioned you can get screened to see if you are more likely to respond to immunotherapy or not. Is that part of the standard of care, or is that something a patient have to ask for?
Dr. Hearn Jay Cho: So that’s a very good question, so I think the best example of blood cancers is Hodgkin’s lymphoma. So there’s a there’s a mountain of data now that shows that high PD-L1 expression in Hodgkin’s lymphoma predicts response to checkpoint inhibitor therapy. So this is a standard test because if a patient who presents with Hodgkin’s lymphoma, either newly diagnosed or relapsed, has PD-L1 expression, then you treat them with checkpoint inhibitors, and there’s a very high response rate over 70 percent. So that’s like standard for Hodgkin’s lymphoma. Now in the myeloma space, we don’t have a similar so-called marker for checkpoint inhibitors, for example, but there’s a lot of interest in the expression of certain targets for new therapy on myeloma cells. So many of the CAR T’s, most of the CAR T cells that are under investigation now in myeloma, target something called BCMA, and there’s other bispecifics and that target BCMA and also to other targets received NF CRI 5. So now when we’re seeing new or relapsed patients in at least in our clinic, we are asking our pathology department to look for expression of BCMA and syringe. This isn’t standard yet, but as these agents get approved by the FDA, my suspicion is that that’s going to become part of the regular workup for myeloma as well. So our screening is going to be guided by the science, you know, like the Hodgkin’s lymphoma finding the one was very important and this grew out of clinical trials, and so that now informs regular clinical practice, and I think similarly what we’re learning about other types of immune therapies, for example, in myeloma, that that’s going to affect how we assess each patient as they come in.
Brian Brewer: Well, Mount Sinai, is obviously on the cutting edge of the science around immunotherapy. You’re one of the best treatment centers in the country. What about someone who’s not, you know, can’t travel to New York City or to one of the other excellent centers in the country? Is this something that someone should ask their doctor just to say, “Are you testing me for these three biomarkers?”
Dr. Hearn Jay Cho: I would actually phrase it a little bit differently. So if you’re a myeloma patient and you don’t live near a major metropolitan center or one of the big myeloma centers, you can still benefit from a consultation with one of these institutions. I always encourage myeloma patients wherever they are, if it is at all possible, for them to see in myeloma specialists, even if it’s just as a consultation, because this is something we do, for example. I have patients from as far away as like Florida and Maine and Vermont, even though we’re based in New York, and if I see them once or twice in New York, I will often collaborate with a local physician wherever the patient might live to help manage their disease. So obviously we can’t do clinical trials like that, but we can deliver standard therapies to patients in the community, and now that things like car T cells, and bispecifics are going to be approved for myeloma, we’re going to collaborate with our colleagues who live in the community in order to deliver this kind of care effectively and safely to myeloma patients everywhere.
Brian Brewer: I think that’s amazing advice. I actually didn’t know that I could just log in and get a consultation at one of the top cancer centers around the country, even though I don’t live next to them.
Dr. Hearn Jay Cho: That’s a lot of them will do this. You know, we’re living in an era where we’re discovering all sorts of capabilities about remote work and that that includes medicine. Typically, what I would advise to people is the initial consultation is best done in person. So even if it’s a two or three hour drive that first visit, it’s worthwhile to do it in person, and then maybe subsequent to that, it can be remote, but instead of having to go there every week, if you just have to go there once, it’s much less of a burden, right?
Brian Brewer: I think that’s really practical advice. That’s one of the top questions that we often find in our summit series. If you don’t live next door, but it sounds good that you want to get that initial in-person consultation and then the rest could be more manageable in the age of COVID, I guess. I have another question from our audience here: “If it involves age, difference between adolescents and adults and responses to immunotherapy, do you see any correlation around age or is this not something that really needs to come top of mind when a new patient, maybe an adolescent, is facing one of these blood cancers?”
Dr. Hearn Jay Cho: That’s a good question, and it’s one that we typically don’t face in myeloma because myeloma is a disease of aging. So the majority of myeloma patients are diagnosed in their fifties or later. There are rare cases of adolescent and young adult myeloma, but it’s pretty rare. This is a different story for lymphomas and leukemia, as there is sort of two peaks in the distribution of these diseases that a gross generalization is there’s a young peak, and then there’s the older pain. So I think that the question is not so much about effectiveness, but I think about tolerability because immune therapy is very powerful in many cases that are very safe. But you have to recognize that when you’re manipulating the immune system, it can be very, have very profound effects. So the two that we’re most concerned about and things like, for example, CAR-T cell therapy is what it’s called cytokine release syndrome, which can happen within hours of getting that CAR-T infusion, and this is basically an overactivation of the immune system where patients develop high fevers. They can develop low blood pressure, all the signs of a very bad infection, and sometimes this requires ICU level care to support. So this is now the hospitalization after the CAR-T infusion has become a standard practice, at least for the currently approved car teams. So the question, I think, is. It’s not that we’re not going to see less effective treatment or more effective based on age, but whether patients can tolerate those treatments and have repercussions from the side effects of these treatments. So it grows at a very general level. Young patients tolerate those types of burgers much better than older patients, and it’s true. So that does figure into the equation when you’re considering what types of any type of therapy for cancer and certainly for immune therapies, that should be a consideration.
Brian Brewer: I think we heard Dr. Odunsi say, or it might have been Dr. Puré, I don’t recall, say that predicting a patient response to immunotherapy is often tied to the general health of the patient, which is good to know and good things to think about. Another question we have coming in from our viewers is around, how do I say this when your immune system is compromised, they have seen a number of clinical trials have that has an excluding factor. So perhaps you have HIV, or perhaps you are already immunocompromised from receiving some other form of treatment? It’s a big question that we get a lot around how effective can immunotherapy be for patients who might fall into that category, and then, what recourse do they have for enrolling in trials?
Dr. Hearn Jay Cho: It’s a good question. Obviously, for immune therapy, clinical trials, you want to have healthy immune cells to fight the cancer, and unfortunately for a clinical trial, you want to increase the probability of success, so you want to minimize variables such as immune suppression from drugs or for an underlying illness, certainly. I think it’s important to consider then, how can we make people who have immune compromised healthy enough to then benefit from a gene therapy? That’s the question, and there’s certainly strategies that are under investigation to do this, but once an agent is approved, for example, a bispecific T-cell is approved, that gives the option to do whatever a clinician feels is necessary to improve the front end, or improve the immune system so the patient needs treatment for an immune suppressive infection or if you need to change treatments to remove immunosuppressive drugs prior to starting that immune therapy, I think that is an option that remains available. This is, as always, a collaboration between patients and their treating physicians, so there should be discussions about these questions and hopefully we’ll be seeing immune therapy clinical trials in the near future to try to address these issues more formally.
Brian Brewer: I think you’ve underscored that point very well during the discussion, Dr. Cho, that every patient is unique and every patient’s treatment decisions are unique, and that’s part of a discussion with the treatment team. So thank you for saying that. We’re out of time, but I just wanted to ask you in your time in the field, how do you perceive the advances that we’re seeing in treatment with immunotherapy, and where do you think it’s going to lead?
Dr. Hearn Jay Cho: Well, the last 10 years has been the story of big steps, we’ve had approvals for the first vaccines and then checkpoint inhibitors and cellular therapies and specifics. So we’re seeing big steps in new technology and new strategies for treatment. I think the next big step is understanding how to put them together and how to give the right treatments to the right patients, and I think ultimately that is a road to curative therapy for many of these diseases. Certainly, that’s how we’re operating in myeloma, and I have hope for my patients now because when I started treating this disease in the in the late nineties, the median survival is about three years and we only had conventional chemotherapy, and now over the last 10 years, median survival has improved several fold, and for the patients who are diagnosed today, there’s, I think, real optimism that they’re going to benefit from curative therapy. So I’m optimistic and hopeful. There’s a lot of hard work that still needs to be done, but I think we made a lot of progress and we just need to keep going.
Brian Brewer: Well, I wish we can get into more about how much your clinical practice intersects with your research. But we can’t do that here, but I do know that it is a lot of work and kudos to you for doing this and kudos to all the cancer researchers out there who are testing these therapies and learning as much as we can from treating patients. So with that, we’re going to have to conclude our myeloma session and blood cancer session. So Dr. Hearn Cho, thank you so much for being with us today, and let’s move on to the next breakout.
Dr. Hearn Jay Cho: Thanks, Brian. Thanks for having me.