More than 175,000 new cases of leukemia, lymphoma, and multiple myeloma are expected this year in the United States. Several immunotherapies are already FDA-approved, and ongoing research demonstrates even greater potential for new treatments, especially in adoptive cell therapy. At the 2020 CRI Immunotherapy Patient Summit, we hosted a special breakout session on blood cancer and immunotherapy to educate and empower patients, caregivers, and advocates.
Philip Greenberg, M.D., the head of immunology at the Fred Hutchinson Cancer Research Center, addressed different immunotherapies used in the treatment of blood cancers and new treatments in development to bring the benefits of immunotherapy to more blood cancer patients.
Dr. Greenberg opened the session with a presentation focused on available immunotherapies for blood cancers, including cell-based therapies like CAR T cell therapy, targeted cancer therapy like bispecific antibodies, and checkpoint inhibitors. He provided an overview of future immunotherapy research for blood cancer that includes learning how to best reduce potential side effects for blood cancer patients receiving immunotherapy as well as how these side effects differ from those associated with chemotherapy.
Side effects associated with CAR T cell therapy were a common concern among attendees. Dr. Greenberg explained that the biggest risk after CAR T cell therapy is an overactive immune response, wherein your immune system goes into overdrive. However, significant progress has been made in assessing, managing, and mitigating risks.
He advised patients and caregivers in the audience to try to get second opinions at major cancer centers early in their cancer diagnoses to find out what clinical trials are available to them. “Having the option of knowing what’s the algorithm for treatment, where do I go if and when this no longer works, and what will maximize my options, it’s really important,” Dr. Greenberg explained.
Blood Cancer and Immunotherapy Session Transcript
Tamron Hall: Now it’s my pleasure to introduce Dr. Philip Greenberg, who is here to discuss immunotherapy for blood cancers. Dr. Greenberg is the head of immunology at the Fred Hutchinson Cancer Research Center and a professor of medicine and immunology at the University of Washington. He’s also a member of CRI Scientific Advisory Council. We also have with us Brian Brewer from the Cancer Research Institute, who will be sharing your questions with Dr. Greenberg. So please be sure to put them in the Q and A box. Dr. Greenberg, Brian, let’s learn about immunotherapy for blood cancers.
Dr. Greenberg: Hi. Thanks very much, Tamron. And thank you for all the people who are participating on this call. We appreciate your interest in this field. It’s one that obviously I’ve been involved in for a long time and it’s wonderful to get a chance to talk about it. So thanks very much. And thanks to the CRI for putting this together. I think having forums where we can provide information and have an informed public is actually really important. So thank you.
So I thought we should start out by just making it clear about what are the available immunotherapies for blood cancers. And it’s interesting because really immunotherapy of cancers really began with blood cancers. I came to the Fred Hutchinson Cancer Research Center because it was the place where bone marrow transplantation was developed. The idea was that people with leukemia would get high doses of chemotherapy and radiotherapy to get rid of their leukemia. The doses were so high, it was destroying their normal bone marrow.
‘So the initial idea was that you could replace that with bone marrow from a donor. It turned out that actually it was the bone marrow from the donor that was actually providing the cure, not the high dose chemoradiotherapy, so those have been changed. What it was in the bone marrow that was being infused were the immune cells. They had a graft-versus-leukemia effect, GVL effect. And so this bone marrow transplantation was really the first cellular therapy for any cancer.
And then subsequent to that, targeted antibodies have been developed to treat cancer. These are monoclonal antibodies. You’ve probably heard about things like Herceptin for breast cancer. Well, it turns out the very first targeted antibody that was an antibody that was made to recognize cancer was actually a rituximab for lymphoma. That was the first actually approved antibody and now we’ve found ways to engineer antibodies to be more effective. We’ll talk about some of these things like bispecific T cell engagers a bit later.
And then as you just heard Jim Alison talk, at the turn of the millennium actually, the checkpoint inhibitors, the idea of the fact that the immune system has regulations on it and that if you can take the brakes off the immune system, you can make it go. These are checkpoints that we talk about in immune systems. And inhibitors were developed and PD1, anti CTLA-4, PD1, PD-L1 were actually developed and approved in 2014. And that’s probably the only one that wasn’t first developed in a blood cancer. It wasn’t until 2016 that those got approved for Hodgkin’s lymphoma. And then finally cell based therapies. And this is the idea that you can take a cell out of a patient’s body and you can engineer it. You can use all these genetic manipulations now to make it capable of recognizing a leukemia lymphoma and then give it back. And the most well-known of these are Chimeric antigen receptor or CAR T cells. Those were first approved in 2017 for acute lymphocytic leukemia and shortly thereafter for B cell lymphoma.
So what we do with engineered T cell therapies, and this is really the field that I’ve been involved in for several decades now, is we take cells out of the body. We have strategies now where we can introduce genes that either add something to the cell, such as to make it recognize the leukemia, make it function better, or that eliminate a gene that’s causing interference with activity, such as for example, one of the checkpoints and you can now then expand those cells. So now you have essentially a whole army of cells that are capable of recognizing the patient’s leukemia, then we re-infuse it back into the patient.
This is what the two most common approaches are right now. One is to take an antibody that’s been engineered, so it can work in a T cell, and we introduce that into the T cell. So the T cell now essentially has an antibody specificity, but still functions with all the activity that immune cells have, and we infuse that back into the patient. That’s what we call a CAR T cell. Or, we find a T cell that can recognize cancer. We isolate the molecule that’s responsible for recognizing it, the T cell receptor, and now we take cells out of any patient and introduce that T cell receptor into their T cells. And you can now again create an army of those cells, make it the numbers that it’s the most potent cell in the patient’s body, and then infuse it back in.
This is just showing you how that works, is a CAR T cell recognizing a cancer cell. This is an engineered T cell. Again, its normal receptor wouldn’t allow it to recognize it, but the receptors that we’ve put in, allow it to bind to molecules that are on the cancer cell. The T cell actually sees molecules from inside the cell that get brought out onto the cell surface. CAR T cells can only see proteins that are naturally expressed on the cell surface. So engineered TCR T cells have a much broader range of targets that they can recognize.
And this is just showing you what happens when it recognizes that the T cell gets activated and it delivers its lytic machinery to the cancer cell and eliminates it. Next slide.
Then as I mentioned, there are bispecific antibodies. There are two antibodies shown here. That’s the recognition structure they have. They can work by themselves but we can actually, again, engineer antibodies so that they, rather than have just the recognition structure of one, as you can see, we can flip the sides there, so that you have two recognition structures making it bispecific, it sees two things. And what we typically do is engineer it so one sees a cancer cell and the other sees a T cell and it brings them together and it can promote recognition. So that’s shown. Next slide.
And again, there’s the antibody, the bispecific, it recognizes the cancer cell brings the T cell in and activates the T cell. And now you’ve essentially made the T cell cancer cell specific. And again these have been now approved for therapy in lymphoma. Next slide.
This is, I think, where the future of immunotherapy research is going. We’ve come full circle from bone marrow transplantation in which donor T cells are shown to effectively target tumors, but have the toxicity because in a bone marrow transplant, the cells that you’re giving, most of them aren’t cancer specific. And some of them actually recognize normal tissues and can cause toxicity. So we’ve come better than that. We can now engineer, engineered cells that are specific.
So the next generation strategies are broadening the number of cancers that can be effectively targeted to engineer the cells so they’re more effective. We can improve their effector activity. Again, we can manipulate their genomes to do that. We can now sustain immune function and enhance the anti-tumor activity and we can engineer cells so that they’re just much more effective.
Dr. Greenberg: We can, for example, rather than have to give the checkpoint inhibitors, we can engineer the cells so that they themselves actually don’t get those inhibitory signals or we can actually turn those inhibitory signals into activating signals so the cells work better. And of course we need to reduce the potential treatment side effects so we can again, engineer cells so they don’t mediate that kind of toxicity. So with that, I’m going to stop and try to open this up to questions from the audience.
Brian Brewer: Well, thanks Dr. Greenberg for joining us today. It’s a true honor to have you here with us. Just before we get to the Q and A, I just want to remind folks that some of these questions were submitted when you registered for today’s breakout session, but we do have a Q and A box. If you’re listening now live, feel free to drop those questions, and we’ll be sure to pass as many of those as we can along to Dr. Greenberg. Also, as another reminder, if you haven’t scheduled a clinical trial navigator consultation, you’re able to do that at any time. So with that, let’s get into this Dr. Greenberg.
I’d like to start with clinical trials right now. Many people don’t understand what clinical trials are or what role they serve in advancing new cancer treatments. We do have a session that we held in the first part of our immunotherapy patient summit. So folks are able to go back and view that on demand, but let’s get into immunotherapy clinical trials for blood cancers. What are some of the more promising trials that you’re seeing out there right now?
Dr. Greenberg: Well, again, it’s an extraordinarily rich area right now, so it’s very different depending on the disease. So we, for example, have had a trial that’s been active in acute myelogenous leukemia with a TCR engineered T cell. We are, re-engineering another TCR now to go in and we should be reopening that trial. There are CAR T cells again, these are antibody recognition structures put into T cells that are being developed for acute myelogenous leukemia. So these are all going to be quite exciting. And then there are also monoclonal antibodies that are now available to treat acute myelogenous leukemia. And indeed in fact, the first antibody with a drug on it was developed for acute myelogenous leukemia.
So there’s lots of trials that are available. For myeloma, a different blood cancer in particular, there’s an antibody now that’s become standard of care, but the most exciting, there is actually these CAR T cells that are specific for a molecule called BCMA. And some of these trials look very provocative. The complete response rate is quite dramatic. We now need to work on making those more durable. And of course, in acute lymphocytic leukemia and in lymphoma, the CAR T cells that have been targeting CD19 have been very promising, but there have been escapes from that. And there’s now a new trial with what’s called essentially a bispecific CAR that targets two different molecules on lymphoma. This is being run out of Stanford CD19 and CD22. And that’s actually open for patient recruitment right now.
Brian Brewer: That’s wonderful. You mentioned that in one of the trials that the complete response rate was dramatic. Can you explain what is a complete response rate and what makes it dramatic compared to other treatments?
Dr. Greenberg: Well, one thing that of course makes it dramatic is that most experimental trials are started on patients who have failed standard therapy. So people are not put on clinical trials when there is a standard therapy that’s very effective, so that will never happen. In a sense, the only time an experimental therapy is tested, is when there are not good options available. And so the trials with CARS, for example, targeting BCMA and myeloma are given to patients who have failed all standard therapies. And so there isn’t really anything left that’s very effective. And now it turns out you give these CAR T cells and patients who had no options really for therapy, nearly a 100% had been achieving complete responses. To be fair about 80 to 90% have been.
Now about half of those have not been durable, so that gets you down to 40% have more long-lasting responses. So the question is, how do we convert? A complete response means that there is no evidence of your disease anymore. And maintaining a complete response means you remain that way. When we say it’s not durable, it means that at some point you may relapse. And the issue is to make all of these responses durable and complete.
Brian Brewer: We know from experience that a lot of these dramatic responses are more likely to be seen in the leukemias and lymphomas, but not so much in the multiple myelomas. Are there any promising approaches? What immunotherapies seem to be working in multiple myeloma?
Dr. Greenberg: Well, as I said, the BCMA CAR is actually in myeloma itself and it is actually remarkably effective. It turned out that there were a fair number of myelomas that seem to be resistant by decreasing the amount of expression of BCMA and a drug has been found that prevents the myeloma from being able to decrease expression and that’s essentially, dramatically enhanced it. So myeloma is actually one of the targets where there are multiple now immunotherapy trials, all of which are looking remarkably promising.
Dr. Greenberg: And so certainly, if you’ve got myeloma, I think people should be going to some of the cancer centers and finding out what trials are available, because there’s lots of options. What we would call the algorithm, the treatment algorithm of where you go from one treatment to the next, the list is actually extensive in things that all look really promising.
Brian Brewer: Well, we have a lot of patients in our audience today with multiple myeloma, so I’m sure that’s good news for them. I’m sure many of them now are curious, of course, Fred Hutch is a leader in blood cancer immunotherapy, where else are these trials available?
Dr. Greenberg: The BCMA trials, after the academic centers showed that these work, some of the commercial companies have picked us up and are supporting national trials. So the reality is, is that almost any major cancer center, particularly any academic cancer center in a large city would have these available. So you can check with those cancer centers. But I would think that these are available nationally now, not just at the centers that were responsible for initially developing them.
Brian Brewer: I see. Let’s say someone is recently diagnosed with blood cancer, you mentioned earlier that if a standard therapy is available, that works, they should receive that first and then go on.
Brian Brewer: Is it only at that point when that therapy doesn’t seem to no longer work that they should consider a clinical trial?
Dr. Greenberg: I think that, well, yes and no. Even for standard therapies, there are wrinkles to it that can be very informative. So it really is useful, I think, when people get diagnosed with cancer that they at least get a second opinion at a major cancer center and find out what’s available, whether what they’re going to get is so standard and there’s no other option that nothing that should be added or subtracted that would make sense and whether... So can often return to their community and to their community physician and get treated.
Dr. Greenberg: But having the option of knowing what’s the algorithm for treatment, where do I go if and when this no longer works, and what will maximize my options, it’s really important, I think, to be in link with a major cancer center. It will not only improve your care, but it will be a legacy. It will mean that your care has contributed to the development of increasingly effective therapies for others. So I would, obviously I’m at major cancer center, so that’s somewhat self-serving, but this isn’t just about patients coming into those cancer centers. It’s about making sure that every patient gets the best care that’s out there.
Dr. Greenberg: Sometimes some of these things take a while to trickle down to community physicians. So at least getting a second opinion and hearing it. Then of course, the decision is always yours. Even if you enroll in a clinical trial, you’re not obligated to finish it. The patient always has the right to say no. Don’t ever be confused that anybody would suggest otherwise.
Brian Brewer: Okay. In light of, that’s a good segue, the thought of going to a city right now with everything going on with COVID might be off-putting for a lot of people. What are the considerations there? We now have this vaccine, a couple of vaccines and several other good candidates as well. Let’s talk a little bit about COVID and what are particular considerations for cancer patients? We’ve gotten a lot of questions coming in right now about this. So it’s top of mind.
Dr. Greenberg: Yeah. Well, I can understand why. Yeah. I mean, this is a peak now that nobody had wanted to ever see. So cancer centers, unfortunately, in a sense, had to go through figuring out how to deal with this during the initial peak. So for a while, patients were not being enrolled on new trials because of that, until we could figure it out how to do this safely. So what you can feel comfortable with is that at all of the cancer centers now, everybody who’s essentially based there is going through very routine testing to make sure that they’re incapable of transmitting it. But they’re also wearing protective gear, which makes it virtually impossible, not absolutely impossible, but even if the tests fail, that essentially they couldn’t really transmit it.
Dr. Greenberg: But nobody with any evidence of disease or exposure is being allowed in in terms of the physicians and the caregivers. Now, some patients with the disease do have to come in because if a patient with cancer develops it, it doesn’t mean they can stop getting cancer care. So we’ve developed ways of isolating those patients so that they don’t put other patients at risk. All the caregivers are wearing protective gear and that they then have to change so that they can’t transmit it to the next patient who comes in.
Dr. Greenberg: But I can assure you that all of these centers have now had unfortunately all too much time now to figure out how to effectively deliver care in a way that doesn’t put patients at risk. That allows patients who are at risk to feel safe. It allows those patients who actually, unfortunately, who have contracted the infection to still be able to receive care.
Brian Brewer: So this is top of mind for a lot of people. We’re getting questions about COVID. Are there any special considerations for cancer patients in terms of vulnerability of infection, as well as should they get the vaccine?
Dr. Greenberg: We’ve had the wonderful advantage here that all of the trials which have been run out of the NIH have been run actually by somebody, Larry Corey based here at the Fred Hutch. He became the academic director for the national trials. So we’ve really gotten to see this. What I can assure you is, is that all of these vaccines are looking incredibly effective. I mean, I think many people may have heard Tony Fauci talk about this yesterday. The gold standard has been measles, which has been 98% effective. These are looking every bit as effective, which is really quite remarkable. It just tells us that this is actually an easy, it’s turned out to be a remarkably easy target to develop an effective immune response to.
Dr. Greenberg: We have the two vaccines that are about to be rolled out. There’s every evidence that all of these other vaccines behind it are going to be very effective. Whether they’ll be as effective, I don’t think we can say right now. But what I can assure you is that if you can get a vaccine, I don’t think it’s worth worrying about waiting for any particular one of them. You get the vaccine you can get right now because they are going to be in short supply for the first six to eight months. If it turns out that one of them gives a better, more durable, long lasting response, you can always get boosted a different vaccine later. So I think this is really incredibly promising. This is going to be a really effective vaccine rollout.
Brian Brewer: Well, you’ve given me a bit of optimism there because we certainly need this as soon as possible. So thanks for that. We have another question coming in about CAR T. Is it possible to get CAR T cell therapy after having had a bone marrow transplant and, or are the side effects risks higher?
Dr. Greenberg: So there are potentially higher risks. So the studies have been done to mitigate this. In fact, many of them have been done in New York, out of Sloan Kettering by Michelle Sadelain’s group. So there are ways to minimize the risk. The biggest risk is that the cells you give will cause essentially the same kind of what we talked about, graft versus host disease, where they can essentially reinstill one of the toxicity of bone marrow transplantation. We now have ways of engineering the cells to remove the receptor that causes that. So that’s one way. If you can get the cells out of the patient themselves, then you essentially have largely mitigated that risk.
Dr. Greenberg: So there are ways to make it much less risky. I would say that, ultimately, there is a bit more risk in bone marrow transplantation, much as there is for patients with autoimmune disease of potentially activating those kinds of events. But the reality is that those can generally be quite well controlled now. So yes, CAR T cells can be given and are being given to patients post-transplant.
Brian Brewer: Good to hear. That’s a great segue to another question we have coming in from our audience. I have blood cancer and I also have an auto-immune disease. Most trials list autoimmune disease as an exclusion. Is there a way around this?
Dr. Greenberg: So yes. In fact, it’s typically not an absolute exclusion. So, most of the therapies, in particular, these are the checkpoint therapies that are being given. These are the ones that, again, Jim Allison talked about at the very top of the hour that are being given to essentially take the brakes off the immune system, so it’s more effective at treating cancer, but of course it’s taking the brakes off of every immune response. And so, there have been flares of autoimmune disease, more autoimmune diseases that occur. Occurs in, oh, probably about 30% of patients who get checkpoint blockade. Unfortunately, that experience became evident, but fortunately, we’ve learned how to address that now. So, in the vast majority of those patients, that recrudescence of their autoimmune disease can be controlled. Unfortunately, as some of the patients may be alluding to, in some patients, it does require stopping the therapy, but it is no longer an absolute indication for not getting immunotherapies.
Brian Brewer: If someone is having an autoimmune related response after receiving immunotherapy, which is seen with checkpoint blockade, and it’s, as you’ve mentioned, manageable, is that an indication that the therapy is working?
Dr. Greenberg: It’s an indication that this is taking the brakes off the response, and it is boosting immunity. So, it is essentially part of what is necessary for the anti-tumor response to work. It still means that there has to be an anti-tumor response in your body that can get activated. And so, it depends in many respects in what tumor is actually being targeted. In tumors that are highly responsive to checkpoint blockade, such as melanoma and lung cancers, almost certainly. In some of the other diseases where the natural immune response has not been typically as potent, it may not necessarily tell us that it’s working. It is in those diseases where cellular therapies are becoming increasingly important, because if you don’t have a natural immune response to a cancer, the question is, “Can we engineer one and give it to you so that you can in fact benefit from immunotherapies?”
Brian Brewer: I want to go back to the eligibility exclusion criteria question, because we just got another question in from one of our audience members. “I’m 78, how does age affect trial eligibility? I have no other underlying issues, but my doctor thinks I’m too old for CAR T or other immunotherapy trials.”
Dr. Greenberg: Yeah. I would disagree with that recommendation. And again, I’m going to guess that, that may be a community physician who’s not treated as many patients and appropriately has that concern. It was a concern certainly all of us had when we started doing all these therapies. But there is right now I believe absolutely no age exclusion for any of these therapies, certainly not for CAR T cells and not for most of the checkpoint therapies. Now, some of these regimens are modified for patients who are older, but in general, they’re tolerated quite well. So, I would think being 78 is by no means an exclusion. And I don’t consider that so old anymore, by the way.
Brian Brewer: As a follow-up, what about the other end of the spectrum with very young patients? What is the youngest patient to be treated with these types of therapies and how successful are they?
Dr. Greenberg: Oh, infants are being treated now with some of the therapies, particularly with some of the pediatric cancers, such as neuroblastoma, where now these are experimental therapies, but experimental therapies that have been shown to have a substantial amount of efficacy. There is an antibody that was developed actually at Sloan Kettering that’s recently been approved, but some of the CAR T cells that target the same molecule are all in development and being given. So, there’s again no absolute limitation. I think with small infants, the difficulty is getting enough cells from them to be able to generate the CAR T cells to treat, but again when we started doing some of these trials, we had an initial concern about limiting it to adults.
Dr. Greenberg: And very interestingly, the pediatric community... And so, when we wrote the protocol and submitted to the FDA, the FDA said... And we said we were only going to treat adults, because we were concerned about toxicity. And the FDA came back and said, “No, you can’t do that. If you think that this can potentially benefit children, you need to include them. It needs to be the parents and the child who get to make the decision that they don’t want to take that risk, but you can’t make that decision for them.” So, virtually all of these experimental therapies are available in very young children.
Brian Brewer: That’s fantastic. We have a follow-up question from several members of our audience. Again, I think the multiple myeloma crowd is very interested in the BCMA, and they’d like you to explain what does BCMA mean?
Dr. Greenberg: Oh, so it’s a B cell antigen. So, it’s just an acronym for a molecule that’s expressed... It’s actually a growth receptor that’s expressed on myeloma cells. And so, essentially, it’s a molecule that’s on the surface of the myeloma cell, and as a consequence, you can make an antibody that recognizes it on the cell surface. And that’s now engineered into a receptor that’s put into these CAR T cells. And now the T cells, when they bind to it, get activated and kill the myeloma cells. Now, the problem is, is that molecule get cleaved off the cell’s surface of the myeloma cell, and therefore it can no longer get recognized. And so, one of the things that’s, as I told you, a drug has been developed that prevents that cleavage. It’s made the BCMA CAR T cells much more effective.
Brian Brewer: Well, that’s all the time we have. I want to thank everyone today for submitting your questions to Dr. Greenberg. And of course, I’d like to thank Dr. Greenberg for joining us and Fred Hutch for letting him join us today, spend your valuable [inaudible] and thank you so much again. I know this was very informative. Thanks, Dr. Greenberg.
Dr. Greenberg: Thanks very much and good luck to everybody. Thank you.
Brian Brewer: Stay safe.
Dr. Greenberg: You too. Thanks.
Tamron Hall: Thank you, Dr. Greenberg, for your informative discussion about blood cancer immunotherapy. And thank you all for joining us and participating in the Q&A.
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