Alexander Lesokhin, MD
Memorial Sloan Kettering Cancer Center
Interview Date: May 24, 2019
Immunotherapy is becoming the hottest topic in myeloma treatment. But immunotherapy can mean many different things. Learn more in this overview show with immunotherapy expert Dr. Alexander Lesokhin of Memorial Sloan Kettering as he shares more about every type of immunotherapy being used in myeloma care today. This includes vaccines, antibody drug conjugates, CAR T therapies, bi-specific antibodies, monoclonal antibodies and others. Dr. Lesokhin shares how each of these drug classes work in myeloma and their status in open studies or use in the clinic.
Dr. Lesokhin on Myeloma Crowd Radio
Jenny: Welcome to todays episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. Im your host, Jenny Ahlstrom. Wed like to thank our episode sponsor Celgene for their support of Myeloma Crowd Radio.
Now, before we get started with todays show, wed like to share that were going to begin asking a weekly question in HealthTree, and then well be sharing those results. We believe that patients together can help answer important questions to help researchers understand more about myeloma.
This week, well be asking a simple question, what type of myeloma do you have? This will be a description about the light chain and the heavy chain of myeloma. For example, how many patients might have IgG kappa myeloma or IgM lambda myeloma and lets see what type of myeloma is the most common and if it has anything to do with outcomes.
You can help me answer this question by joining healthtree.org. Youll see a myeloma diagnosis page where you can enter the date of your diagnosis, and youll see a section called the Full Health Profile where you can answer the question about the type of myeloma you have. Next week, we will share the results on the Myeloma Crowd website.
Now, todays show is an important one. Immunotherapy is really exploding in myeloma care and we thought it would be great to do a show explaining the different types of immunotherapy and where the field is headed in myeloma. With us, we have myeloma specialist, Dr. Alexander Lesokhin from Memorial Sloan Kettering. So welcome!
Dr. Lesokhin: Hello. Thank you for having me.
Jenny: Thank you so much. Let me introduce you a little bit before we get started. Dr. Alexander Lesokhin is an Assistant Attending Physician at the Memorial Hospital for Cancer and Allied Diseases and Assistant Member of the Memorial Sloan Kettering Cancer Center. Hes an active member of ASCO and ASH and has oversight of fellows and residents in the transplant, lymphoma and myeloma units.
Dr. Lesokhin performs significant immunotherapy research and is engaged in studies to perform work in the lab that will bridge to the clinic as to why cancer cells can evade the bone marrow derived tumor-infiltrating cells. Hes also performing research on checkpoint inhibitors and why T cells get exhausted, particularly following stem cell transplant.
As an immunotherapist, Dr. Lesokhin, maybe you can explain immunotherapy just in terms of a broad term and the goal of immunotherapy in myeloma care?
Dr. Lesokhin: Sure. I think Ill probably sort of step back a little bit and just sort of say, whats the point of having an immune system in the first place? Because the immune system is like a very broad term for a system of cells, and molecules, and proteins that are all geared at distinguishing our own cells from the other.
Its really this self, non-self distinguishing feature thats critical to what our immune system does in maintaining health. Self being good and non-self being bad. This includes bacteria, viruses, as well as cancer cells. Theres a broad range of these cells and molecules and chemicals and such that are all very kind of tightly regulated to maintain a good health of self and remove non-self.
The goal of immunotherapy is really to harness some of these naturally occurring biological tools or mechanisms for the purpose of controlling cancer. In a sense, cancer can be viewed and myeloma as well as a failure of the immune system in detecting a problem. In this case, the malignant plasma cell.
We have a growing amount of knowledge about how an immune system response is activated, what are the parts of the immune response, and really major advances in engineering and bioengineering can help us make very sophisticated cell-based therapies, molecule-based therapies like antibodies or even in some cases, cytokines-based therapies, those are the chemicals that cells use to sort of talk to one another in our bodies.
In broad range, in broad terms, immunotherapy is really trying to use all of these tools to the clinical benefit of the patient.
Jenny: It seems like our immune systems are very complicated. I mean, youve got your T cells and your natural killer cells, and then what youre talking about the signaling, and theres just a lot that goes into that.
Dr. Lesokhin: Theres a lot that goes on. Absolutely. I think, if I were to break down the different classes of immunotherapeutic tools, as you said, you have the T cells so this is sort of the cellular immune response and actually, the idea of cellular immunotherapy has been applied to blood cancers like myeloma for many years.
Allo transplant is probably the first version of this cellular immunotherapy. It removes the patients immune system kind of in bulk and replaces it with a donors immune system. The goal there is to try to affect a donor immune system versus host tumor cell effect and this seems to work certainly in myeloid leukemia and in a proportion of patients perhaps with myeloma, this also leads to a durable clinical benefit. These are the cellular therapies.
I think, more advanced cellular therapies are those where the patients own cells can be removed and re-engineered. This can be applied to a T cell compartment. This can be applied to the natural killer cell compartment. It could potentially, I guess, be applied to other compartments as well. But for now, these are the natural killer cell and T cell approaches are the ones that are showing, particularly, the T cell approaches are the ones that are showing the greatest degree of immediate benefit in myeloma.
Those are the cellular approaches. There are other antibody-based approaches. Plasma cells actually make antibodies, but we can make plasma cells in the laboratory that will make antibodies of our pre-determined reactivity or structure.
Antibodies can be engineered now. There are several classes of antibodies. There are what I would call the naked antibodies. These have been used now for probably almost 30 years in cancer therapy, a little less than that. Things like rituximab probably have the longest positive track record in myeloma. Daratumumab is a naked antibody. Elotuzumab is another naked antibody. But the antibody has a very clear specificity. It binds to myeloma cells.
In this case, daratumumab and elotuzumab leads to their removal from the system, hopefully, through a variety of other cell-based mechanisms. It bridges this recognition of the myeloma cell to effect a cellular killing mechanism.
One can also take these antibodies and modify them. You can add a chemical to the antibody so that when it binds the myeloma cell, that chemical acts directly at the sight of that myeloma cell. Instead of giving sort of a traditional chemotherapy drug in the blood system-wide, you can actually give that chemotherapy drug in a very localized fashion and hopefully limit its side effects.
Jenny: I want to go backwards just a little bit.
Dr. Lesokhin: Yes, sure.
Jenny: Its awesome and were going to talk about it all. I want you to go through the specifics like you are, but I think in broad terms, lets talk about just immunotherapy in general. I guess the goal is just to get your immune system to kill the cancer, right? In general, thats what the hope is, and all these different methods or different ways of doing that. But is that the goal? And then Ive heard people talk about also like allo transplant being the very first immunotherapy. So why would that be the case?
The First Immunotherapy, Allo Transplant
Dr. Lesokhin: Right. I guess, yes. I mean allo transplant was probably the first immunotherapy specifically applied to blood cancers such as myeloma. The reason for that is because the donor immune system is geared to, again, recognize self versus non-self and when that donor immune system is transplanted into another individual, the host individual, the host is non-self.
The idea is that the tumor has the most non-selfness. Thats not a medical term of course. It is the best target for this donor immune system. The concept here is that theres an inherent failure in the hosts immune response which allowed the cancer to grow out. By replacing the host immune response with someone elses immune system, you will break down this self, non-self barrier and allow for cancer control.
The downside, of course, is you are breaking down this self, non-self barrier and the donor immune response can attack the host as well. Thats called graft-versus-host disease. And so its the balance between the graft versus tumor effect and the graft versus host effect that is the main sort of clinical challenge that this therapy faces and that is part of the specialization in managing these kind of treatments.
Jenny: Thats why allo transplant isnt used very commonly in myeloma just because you could get that graft-versus-host disease. Whats the risk/benefit to doing that and are there other approaches that might be safer or better or even more effective?
Dr. Lesokhin: I think the main reason that allo transplant has not really been a majorly used treatment in myeloma is that it has not shown yet the degree of benefit that we would want to see in light of the risks of the therapy. It remains an area of active research though.
Jenny: It seems like people recommend allo transplant for younger high-risk patients in that scenario. Is that what you see too?
Dr. Lesokhin: Correct. In the context of, again, clinical trial approaches, considering allo transplant in the appropriate settings is very appropriate. Those settings are younger, fitter individuals, individuals with high risk disease where we know that our currently available therapies are not as good as we would like.
Is Auto Transplant an Immunotherapy?
Jenny: Well, after we think about transplant, I dont know if you think about auto transplant as an immunotherapy. Is that the case or no? Because its not really a non-self, youre still using your own stem cells?
Dr. Lesokhin: Right. Yes and no. I think of auto transplant as a platform for immunotherapy rather than an immunotherapy in and of itself. Although recently, there have been some studies that have demonstrated that perhaps, some of the durability generated by auto transplant is related to a T cell response against myeloma that occurs in some patients.
I think, in general, auto transplant, we dont consider to be an immunotherapy, but there are clearly immune effects that occur in the context of this treatment. The therapy itself can kind of shift the balance where our natural immune barriers that exist to maintain this self, non-self balance are tilted a little bit to favor recognition of self.
Jenny: Right, because if youre killing everything in the bone marrow and then it regrows, like all your lymphocytes are regrowing, so maybe its like a reset button kind of, in some ways, right?
Dr. Lesokhin: In some ways, yes. In the context of this reset button, we call it homeostatic reconstitution, but in the context of this reset, there is transient sort of imbalance in more the attack reset is faster than that dont attack reset.
Jenny: Oh, interesting. Well, I know a lot of patients are very familiar also with immunomodulators or the IMiDs. Sometimes, they call them the IMiDs (Revlimid, Pomalyst, and thalidomide). Are those considered an immunotherapy? They change the immune system in some way or do you want to explain what they do to the immune system?
Dr. Lesokhin: Theyre commonly called the immunomodulators and I think they really are immunomodulatory, but I think its not very well characterized how specific these immunomodulatory effects are. But bottom line is that the IMiDs lead to the breakdown of specific proteins that are inside cells and in myeloma cells that leads to myeloma cell death.
But in immune cells like natural killer cells and some T cells, it leads to greater activation of those cells whether how specific these effects are in terms of are you activating the cells that are specifically targeting your myeloma or other cells that target other things. Thats not fully understood, but clearly the drugs are immunomodulatory and they do work as theyre good partners for other immune-activating drugs.
Jenny: Right. You talked about elotuzumab before and thats maybe one that it works with – elotuzumab seems to not work by itself, but when you put it together with a Revlimid or something like that, then it seems to have impact.
Dr. Lesokhin: Yes, exactly. Thats probably through the natural killer cell activating properties in the drugs.
Jenny: Interesting. Also on that, there was a recent report that came out last week that talked about how lenalidomide delays smoldering myeloma progression and they were pretty important results. Earlier you said that every persons body is trying at all times to flush out non-self and get rid of the non-self stuff.
Ive heard it said that your immune system is doing this on a regular basis – killing cancer cells as you go and it might keep it at this level where you can actually not progress to active cancer. Is that do you think whats happening when people are using Revlimid in a smoldering myeloma situation? That its activating these NK cells, like you were saying, and then keeping the tumor burden down even though you might have myeloma cells in your body?
Dr. Lesokhin: Thats a great question. I think, clearly, if you use an active anti-myeloma therapy in somebody who has a myeloma precursor condition like smoldering myeloma, youre going to see a positive effect in terms of eliminating the plasma cells and perhaps, delaying the time until someone develops symptomatic myeloma.
That makes sense if you treat myeloma at any phase, you will prevent or delay or alter the natural history of the disease and what aspect of that again is immunologic aspect of that is direct anti-myeloma effect, I think is not very clear whether its in the setting of smoldering myeloma, initial myeloma therapy or maintenance therapy with the use of IMiDs. Theyre very effective drugs and again, its part anti-myeloma effect, part immune effect. How much of what and which is not is always the question.
Jenny: That makes sense. Thats interesting. On the smoldering myeloma scenario, it may just be that it has an anti-myeloma effect and you dont know what percentage is what. Well, so interesting.
Okay, lets go back to the monoclonal antibodies that you were talking about and you said that there had been in development really for 30 years with rituximab and daratumumab and elotuzumab. As you look at myeloma therapy and immunotherapy, everyone was so excited when those two were developed because it really made a big impact on progression-free survival and outcomes.
Where are those now? As weve seen data come out over the last few years on that, as youve been seeing patients in the clinic using those, whats your assessment now of those? How do you use them? You started explaining how they work. So maybe, well just go back to that, too.
Dr. Lesokhin: Sure. These naked antibodies as I call them, daratumumab and elotuzumab. Elotuzumab as you said, on its own, it doesnt lead to a response rate, but when combined with immunomodulatory drugs, it does. We now have data that elotuzumab with lenalidomide and dexamethasone and early relapse is effective and the elotuzumab with pomalidomide and dexamethasone in later lines of relapse in specific patient populations may also be effective.
I think elotuzumab is something that I commonly use in an early asymptomatic relapse because I think it is very well tolerated, relatively easy to administer and can lead to efficacy in that setting. Daratumumab has single agent efficacy although its rarely, I think, these days used as a single agent. Its commonly used in early, also an early maybe less indolent relapse or, I guess, I would say an early formal relapse.
I think, in the current landscape, daratumumab is being pretty aggressively investigated in the first line setting in clinical trials. For example at Memorial, our first-line treatment program has been a combination of carfilzomib, lenalidomide, and dexamethasone induction. We now have an actively accruing clinical trial adding daratumumab to that and were hopeful that this will be very effective and hopefully, that we will soon develop a therapy that includes an antibody – a chemo/immunotherapy approach similar to what has been used in lymphoma with such great success for so many years.
Jenny: Oh, thats so interesting. When youre thinking about putting this quad combination together (dara, carfilzomib, lenalidomide, and dex), are you doing that for all patients? Just high risk patients? Or for everybody? What are you thinking about that?
Dr. Lesokhin: Right now, this is for all newly diagnosed myeloma patients who require therapy. Thats the way the clinical trial has been designed. I think, in our case, we generally use carfilzomib, lenalidomide, and dexamethasone as our standard of care, off-study approaches, first-line therapy for individuals who dont have a contrary indication for carfilzomib or lenalidomide administration.
Jenny: Can I go back also to your elotuzumab comment? You were saying that for patients who, their numbers might be going up, but they dont necessarily have new lesions, so its not like this full clinical relapse. Its what I hear as a biochemical relapse. Youre saying, you use that for those types of patients. Are you using that with Revlimid, or just by itself?
Dr. Lesokhin: Our most common practices to put patients on lenalidomide maintenance after their induction therapy and so the pattern that one sees is that you see a rise in biochemical progression or relapse. In settings exactly as you said with just bad or limited other disease manifestations, I would add elotuzumab to the program and essentially an Elo-Rd (elotuzumab/Revlimid/dex) type regimen.
We know from our own prior studies that just increasing lenalidomide dose and adding dexamethasone doesnt really result in a very meaningful or durable response, at least in my own experience. In discussing with other colleagues and other peoples experience, the use of elotuzumab and lenalidomide and dexamethasone as per the ELOQUENT study dosing does seem to provide some benefit.
Jenny: Thats interesting. Okay, sorry. Im skipping around. But I did want to ask you that before we keep going. You were talking about daratumumab moving up closer to the front-line therapy as a trend basically because youre doing that in clinical trials, early clinical trials. Then, a lot of patients I know are using daratumumab now at relapse and things like that, are there any things that youre learning about that? I know some patients can become resistant to daratumumab. Do you see patterns in who or how or why? Im just curious about that too.
Dr. Lesokhin: Sure, no. Its sort of early days in terms of understanding who are the progressors and who are not. There may be some. One of the ways by which these antibodies work is that through their sort of constant region, their nonspecific constant region, this is the IgG portion.
Your antibodies are typically illustrated as a Y. The stem of the Y is the constant region that interacts with other receptors or other proteins on cells of the immune system such as macrophages or natural killer cells, and these receptors, theyre called Fc receptors, some of them activate responses, some of them inhibit responses and depending on individuals, there may be some effects dependent on the individuals sort of pre-existing genetic background in terms of what kind of these Fc receptors they harbor that may impact on how they respond to these types of therapies. This is similar to something thats been seen with rituximab.
There are some signals around that with these antibodies as well, but probably more complex than that. I think its an area of active study. So just as an aside, from a clinical perspective, one of the things that we have observed and whether its happening more or less often in this scenario of the patient thats on chronic dara pom-dex, or dara Rev-dex therapy, the patterns of progression havent been really fully described or characterized.
But one of the things that we noticed, at least on an anecdotal level is that patients can progress with more isolated sites of disease. Sometimes, we would radiate just an isolated site of disease and continue on the same daratumumab-based treatment approach.
This, in our minds, was something that allowed for an immune-based treatment strategy where in addition to radiation which in and of itself can release tumor substance for the immune system to process and respond to and can be inflammatory in and of its own on its own can we further target that lesion that we are radiating to try to generate a more systemic broad immune response and delay the development of additional localized lesions in these individuals.
Weve actually designed a study to do just that and which were now actively accruing where individuals can continue on their dara-based treatment program but then after the radiation, we would inject a protein into the radiated lesion to try to spread the immune response beyond that lesion and try to limit further progression.
Jenny: Wow. Thats really fascinating. Whats that study?
Dr. Lesokhin: Its a study about a compound, its a kind of immune checkpoint, although its not a T cell checkpoint. Its more of a macrophage checkpoint. Macrophages are sort of like the garbage men or garbage women, garbage people, that go around and engulf debris or engulf dead cells or engulf things that are coated with antibody.
In the context of radiation, theres some cell death that occurs, macrophages would take up things, and this compound is one that blocks a checkpoint that its sort of like a do not eat me molecule thats expressed on myeloma cells and other cancer cells. It would block that molecule and promote the macrophage eating of myeloma cells and perhaps presenting of myeloma cell substances to other parts of the immune system so that in the context of this inflamed radiation type situation, you want to spread the immune response to other parts of the body.
Jenny: That is so fascinating. Okay, Im going to add a link in the show transcripts when we do that, because I know some patients who might want to consider that.
Dr. Lesokhin: Yes, absolutely.
Jenny: Thats great. Awesome. I also noticed that I was reading somewhere that elotuzumab boosts natural killer cells while daratumumab doesnt. Dees that have any impact long-term on patients? Because theyre both using the immune system in different ways, but I dont know enough about the immune system to know what that does.
Dr. Lesokhin: Elotuzumab can activate natural killer cells. It just has to do with the target, the CS1 or the SLAMF7 target that elotuzumab binds inside the natural killer cells, can lead to activation of natural killer cells. Daratumumab actually can deplete natural killer cells. These things are transient when the molecules are around. In terms of long-term effect, I dont think there are sort of long-term effects to individuals. People will replenish their natural killer cells over time.
Jenny: Overtime, whether or not on the drug, right? That makes sense. Okay. Well, maybe we want to move to the bispecific antibodies. Well first, let me ask, there are two approved drugs in this category for monoclonal antibodies, and I know isatuximab is coming out. Are other people developing new monoclonal antibodies for different targets or do we feel like in myeloma, okay, theyve developed these monoclonal antibodies that are doing great and helping a lot but were moving on to different types of strategies? Please give us an assessment of where that class of drugs is going.
Dr. Lesokhin: Of course, isatuximab is still on the map and I think it, in many ways, is similar to daratumumab but not exactly the same. Whether or not there is a non-overlap there from a utilization strategy, Im not sure. There may be. There are other targets that are being pursued.
I think BCMA is a target thats being pursued as an antibody. Its also being, of course, pursued in many different ways as a bispecific target or CAR T cell target and antibody-drug conjugate targets. I think there are more, I certainly hope, there are more naked antibody approaches that will be pursued. I think, BCMA will hopefully be one of them.
Jenny: Okay. Thats so interesting. Okay, lets move to the bispecific antibodies. How do they work and there are quite a few now being developed in myeloma, right?
Dr. Lesokhin: Sure. Antibodies, theyre like this Y structure so they have these two different areas that allow for activation or binding of specific proteins on cells. Bispecifics really are ones that are designed where one side binds one thing, one side binds the other thing. Generally, the kind that have seen the most sort of success are engineered proteins that use the two specificities of antibodies to bind a tumor target and activate a T cell.
Blinatumomab is a bispecific targeting CD19. Its used in B-cell leukemia. In addition to that CD19 target, it also binds and activates this molecule called CD3, which is part of the T cell activation receptor, the T cell receptor.
What happens is that when the molecule binds CD19 and also binds a T cell, you form this immune synapse, its sort of an artificially formed immune synapse, where you activate that T cell in the direction of the tumor cell. The same type of approach can be applied to a number of targets. I mean, it depends. It doesnt have to be CD19, it could be CD20, it could be BCMA, for example, it could be FcRH5, it could be other targets as well.
Theres a variety of these bispecifics that are being developed. I think this year at ASH, we saw some Phase I data reported from an Amgen molecule AMG 420 that binds BCMA and CD3 and at the maximally tolerated dose. There were a number of Individuals that responded, four of them with MRD-negative response, meaning there was no detectable myeloma after treatment.
Thats a very exciting area. These are off-the-shelf therapies. They dont require engineering. They dont require harvesting an individuals immune cells, but they are dependent on the individual having immune cells of course, and on having the right target present on the plasma cells. Fortunately, BCMA is actually a very, very good plasma cell targeted really uniformly. It seems to be relatively uniformly present on plasma cells.
The downside of this AMG model or this Amgen molecule is that its a small molecule, its not quite an antibody and so it has a very short survival time in the blood and as a result, it requires a continuous infusion. But its very exciting and its moving along in its development and we actually will have the Phase II portion of the study open at our center hopefully in the next, I would hope in the next three to four weeks.
Jenny: Right. I heard a lot of people talking about the Amgen-420. Also, the Janssen is working on a different target for the bispecific antibodies?
Dr. Lesokhin: Yes, theyre working on a number of targets. They also, I believe, have a BCMA and then another target, I believe, one called GPRC5D. I think we dont really have any clinical data on that yet, but certainly the fact that the field, as a whole, is working on multiple different targets is very encouraging because these are off-the-shelf therapies.
One can envision a future where if you have one or two or three of these that work against different targets one can combine against multiple targets in sequential ways, but I think itll take quite a bit of time to, not a ton of time, but quite some time. Certainly, it will take some time to figure out how to sequence and combine, et cetera, should these treatments all individually have some efficacy.
Jenny: Right. Thats so important. Will they all be this continuous therapy administration? For patients that dont know what that is, you basically kind of wear a backpack, right?
Dr. Lesokhin: You wear a fanny pack. No, they wont, because there are multiple opportunities for engineering here because if you engineer a small version where youre just using parts of an antibody that has less sort of lifespan in the blood, half-life as we call it, but if it looks more like an antibody than it has more of an antibody half-like, which is generally on the order of about two weeks.
That can be given at a less frequent infusion type therapy similar to how things like daratumumab or elotuzumab are given on a weekly basis or every other week basis or something like that. I think it really depends a lot on the specific structures of the different drugs.
Antibody Drug Conjugates
Jenny: Interesting. Well, lets talk about next antibody-drug conjugates and what they are and how they work.
Dr. Lesokhin: I kind of view these more as chemotherapy but in chemotherapy, the antibody is basically like the truck (UPS) and the address is whatever the antibody targets. You could call it the suicide bomber. I dont know. That’s not so nice. You have this payload and you just basically drop it off when you see your target, and hopefully you killed the target.
I think the benefit of this type of approach is that it allows a very targeted delivery of chemotherapy so that you can use a molecule that may be toxic systemically or that maybe leads to something that may lead to significant side effects, if its given systemically can now be given in a targeted way and the side effects can be more limited. In that sense, its quite beneficial.
The other potential utility of these antibody-drug conjugates is that they can potentially lead to a local inflammatory response at the side of the tumor depending on what the payload is and that is something that can be manipulated for the benefit of the immune system, again, to allow for localized release of tumor material for the immune system to take up and present and respond against. But perhaps that type of strategy would require additional immune manipulation to help break this self, non-self balance.
Jenny: So fascinating. Which antibody-drug conjugates are now in development? Where are they at? Phase I or Phase II studies or are they further along?
Dr. Lesokhin: I think the one thats furthest along is the BCMA antibody-drug conjugate developed by GSK. This one has gone through its initial Phase I dose finding study, there was a very encouraging 60% response rate. There was also some ocular, some eye toxicity where folks develop this corneal irritation. That has been manageable but noticeable.
Now the compound is going through a variety of registrational approaches, Phase II and Phase III kind of studies to evaluate how best to use the compound. I think its fairly far along probably. I hesitate to give a precise estimate of what I think this is something that may come to market, but I think its encouraging and hopefully, will become available to patients more broadly soon.
Jenny: Right. They have a compassionate use program for this too. It isnt clinical trials. But right now, they do have one for like if a patient has relapsed after many lines of therapy and are looking to clinical trial options that might not qualify, that is something they might consider, correct?
Dr. Lesokhin: Yes. Thats possible. Im generally cautious about compassionate use. I think there has not yet been a sort of a Phase III study that has shown benefits. I think a compassionate use approach, once thats clear that this is a beneficial compound, but yet its not been FDA approved. I think thats a very appropriate utilization of compassionate use.
I say that because weve recently had very encouraging data, early data from venetoclax. We had very encouraging data from pembrolizumab and immunomodulatory drug combinations but yet the Phase III studies were stopped early in both of these cases because of increased fatalities seen in the combinations including pembrolizumab or venetoclax. So one has to approach that with significant caution and sort of compassionate use approach because, well, as I say you know, its hard to know what will happen.
Jenny: Safety is key, right?
Dr. Lesokhin: Yes. Safety is really key – the do no harm approach. One of our founding principles here.
Jenny: Right. Well, lets talk about the checkpoint inhibitors because you mentioned pembrolizumab and that was seen as very exciting and youve done a lot of research on this too. Maybe you want to share what youve learned about the checkpoint inhibitors.
Dr. Lesokhin: Sure. This is a family of molecules that regulate T cell and other immune cell, but Ill just say mostly T cell – immune responses among T cells that have already encountered the thing that they react against. T cells are sort of a specialized kind of cell. They have a T cell receptor that defines their specificity so T cells will react against essentially one protein presented in the right context.
And then once these T cells get the license to activate, then the encounter between a variety of immune secondary signals that are immune checkpoints or immune agonists are what really are the dimmer switch that regulate how bright or how activated these T cells will be. These immune checkpoints can be manipulated.
One can activate an agonist to further enhance an immune response. One can block an immune checkpoint to release and in response that has been blocked or checked through these natural processes of immune regulation through these immune checkpoints
So PD-1 blockade has emerged as a very efficacious immune checkpoint blocking therapy, useful in many cancers. In myeloma by itself, it was not really effective, but early clinical trial data with combinations with immunomodulatory drugs like Pomalyst or lenalidomide and dexamethasone looked encouraging.
Unfortunately, the Phase III studies didnt show that or I should say that the Phase III studies showed that they also unleashed or broke this self, non-self barrier to a significant degree and resulted in toxicity and also that there were increased deaths or mortality signals in the patients that received the anti PD-1 drugs.
There are some mysteries that remain from these studies. Its not exactly clear what occurred to the individuals like there wasnt a uniform pattern of mortalities or fatalities that were seen on the study to clearly pin it on the checkpoints. The other is that as a result of this appropriately so, the studies were stopped. But there really hasnt been long-term follow-up on some of the early phase studies, for example, with the pom-dex and pembrolizumab study.
Patients had to come off of that trial at the time those studies were stopped. But they were followed because this was a single center Phase II study. There were 16 or 17 patients. Half of those patients elected to go off a therapy entirely, half of them stayed on pom-dex, and approximately two years later, many of those patients remains either off therapy or on pom-dex, which is really surprising.
So what that suggests is there is clearly a subset of folks that seem to derive some benefit. Who are they? Not sure. Need to understand that a little bit better. But in a way, this really resembles a little bit the allogeneic transplant approach where theres graft-versus-host disease that is significant. Its the therapy in and of itself doesnt seem to work for a proportion of individuals. But yet there is a subset of folks that seem to derive very durable benefit from allo transplant and perhaps in the context of checkpoint blockade. This is also something that we will see.
Now, there are other immune checkpoints beyond anti PD-1, there are molecules called LAG-3 and TIGIT, and there are clinical trials that are in development that hopefully, well explore these other immune checkpoints in myeloma and these types of combinations. Also, immune checkpoint blockade, even though in the context of immunomodulatory drugs, it seems to not have a clear, favorable risk benefit profile. These immune checkpoints can be utilized in the context of other immune activated therapies.
For example, if one uses CAR T cells, and the CAR T cell durability is not as good as one would like, perhaps, immune checkpoint blockade can enhance that. Same with a vaccine approach, a bispecific approach. So this remains a tool that clinicians and clinical trial investigators can try to think about to manipulate or result in an effective immune response.
Jenny: Have they ever been used with proteasome inhibitors with any impact at all or theyve only been really tested with the IMiDs?
Dr. Lesokhin: The data that Ive seen is mostly with the IMiDs. I think the challenge with the proteasome inhibitors is that one of the ways in which your T cells recognize — or one of the mechanism, the main mechanism by which your T cell recognizes what to attack or not attack is by seeing proteins inside the cell presented on these specialized molecules called MHC. That process of immune presentation is dependent on proteasomal degradation of intracellular proteins.
If you would use a proteasome inhibitor, youre inhibiting that process. Thats actually been shown to alter what is presented by MHC, like carfilzomib alters what myeloma cells present by MHC in relatively specific ways. Its possible that that might negatively impact an immune checkpoint blockade therapy that hasnt really been investigated. I would think, in my personal opinion, thats something that I would not put at the top of the list of things I would investigate. Thats just my own opinion.
CAR T Treatments
Jenny: Interesting. Well, that makes sense because you understand the science behind it. All right. Lets talk about CAR T therapies. Im hoping you can go over time because we still have so much to talk about. We have caller questions already. Lets talk about CAR T therapies and the status because it looks like there are over 26 open clinical trials for CAR T therapy and multiple myeloma. In general, whats the status and it seems like most of them are using BCMA as a target. How is that going? Lets just start there.
Dr. Lesokhin: This is obviously a very exciting and active area of clinical research in myeloma. I think that its clear that BCMA-targeted CAR T cells are very effective. Let me just step back. CAR T cells are basically a therapy where an individuals immune cells are removed from their body through a leukapheresis procedure similar to the stem cell harvest that many myeloma patients undergo.
Those immune cells are then in the laboratory modified to express this chimeric antigen receptor, which basically is a kind of protein thats very much man-made, that uses an antibody immune recognition site, and then fuses it to T cell receptor and also checkpoint immune — actually agonist, immune agonists of that are required for T cell activation. So in short, its like a complete Frankenstein type protein.
This protein is introduced into individuals immune cells, their T cells. There are different ways to introduce these molecules and different constructs, proteins and such that are generated by different folks, and all of them are different. Honestly, nobody knows which one is great or best or whatever, but the bottom line is that there are a variety of these very effective proteins that are placed into immune cells and then those immune cells are given back to the patient.
BCMA directed CAR Ts that have this BCMA-targeted antibody portion on them. They have the CD3-zeta T cell signaling component, and then theres something called 4-1BB which is a further immune activator as part of the construct. These types of CAR Ts lead to really remarkable and rapid responses in patients who, so far, have had very limited other options, kind of have exhausted other options.
So in a very advanced myeloma setting, these are highly effective. I think the furthest advance to these is Bluebird, Celgene (soon to be BMS) compound. Im referring to bb2121. That has demonstrated good response rate and progression-free survival median between 11 and 12 months and among patients that have very deep responses, MRD negative responses, the progression-free survival is even longer.
However, I think, the thing that all folks in myeloma have observed is that in the context of BCMA targeted CAR T cell therapy, these responses have unfortunately not been as durable as, for example, in the context of CD19 CAR in ALL or lymphoma. Some of the patients continued to relapse. I think these therapies are all very encouraging and theyre clearly effective. But there are a lot of questions that remain there about exactly about how to make the effects more durable for patients.
Jenny: Maybe thats using it earlier in the process. I dont know.
Dr. Lesokhin: Maybe, yes to all different strategies. Will using it earlier for patients be better? Thats certainly a valid and very important question. Will changing the construct around in some way to facilitate better immune signaling in the T cell be beneficial or will changing the population of immune cells that is targeted for introduction of the construct be the way that will lead to better activity? All of these questions are relevant.
Also, whats the source of the cells? Is it from the peripheral blood? What about marrow T cells? Are those better T cells to use for CAR T cell therapy? All of these questions remain. And then what about just host factors in terms of response? Our group, for example, has been looking at the components of the microbiome, so this is whats in your intestines. We all live with a lot of bacteria. It turns out that the components of the microbiome also seem to be quite relevant for durability and efficacy of CAR T cell therapy.
Jenny: Thats so interesting because I read that article that talked about the microbiome. Like if youve used a lot of antibiotics, that the checkpoint inhibitors doesnt really work. So that youre saying its kind of similar could be relative to the CAR T therapy too.
Dr. Lesokhin: Absolutely. Theres clearly something about the microbiome that affects immune health in many different ways. I think this is an area ripe for a lot of investigation. We actually are pretty actively investigating the microbiome in the context of our myeloma therapeutic studies to try to understand how it relates to treatment outcomes.
Jenny: Wow. Thats so fascinating. Were excited to hear what you learn about that. Maybe we can do a follow-up show with just that topic because thats a really interesting topic for patients and they feel like they can maybe have some influence on. Sometimes, you dont really know the status of your T cells, but you can control what you eat and if that has any impact on it.
Dr. Lesokhin: Absolutely, absolutely. I think the components of diet and microbiome and immune health and how that all goes together are really quite fascinating. Theres an emerging field there. At this point, theres not enough known to really say, you should do A, B, or C quite yet, but I think thats certainly something that is worthy of investigation.
Jenny: Right. So CAR Ts, it looks like the people are looking now for other targets like CS1, and maybe other targets besides BCMA because CD19 was a great target for leukemia, but its not really on the surface of myeloma cells necessarily. Where do you see that headed?
Dr. Lesokhin: Yes, absolutely.
Dr. Lesokhin: No, I think, additional targets should be investigated. I think CD19 has been investigated to some extent in myeloma. I think there are some folks that may respond in some way. Its a little bit controversial, but the idea that CD19 is expressed on sort of a precursor to the myeloma cell is an interesting one and the combination of BCMA and CD19 CAR T cell targeting is something thats being investigated at other centers, for example, at UPenn.
We have a CAR T cell product targeting GDPRC5D that will hopefully soon be available in a clinical trial, perhaps in a month or so, maybe two months. Its undergoing its final regulatory reviews now. Others have other targets, CS1 is one of them, and others are also using different delivery systems. For example, one can use like a piggyback system that specifically targets a proportion of more stem cell-like T cells.
These kind of T cells might be longer lived and persist longer and lead to more durable effect. I think theres many, many questions in the CAR T cell field including multiple different antigens as well as multiple different engineering approaches, patient populations, and other host factors. I think theres so many different questions, and were just getting started here.
Jenny: Right. I think so too. What youre talking about when youre developing your own, I think this is a really interesting idea that there are companies that are developing these CAR T cell products, even though theyre personalized for each patient, and theyre manufactured and sent back and things like that.
But facilities like yours are starting to develop your own CAR T products and in some of my reading, it seems like the faster production ends up being more effective over time, so I could see some advantages to doing your own CAR T development at your facility because you may be able to administer it faster. Is that the case?
Dr. Lesokhin: I think that what youre really getting at is one of the challenges of CAR T cell therapy and that theyre relatively complex. Individuals need to be fit enough to undergo the leukapheresis procedure that generally is not a major barrier. Most individuals can sit for several hours and undergo this leukapheresis procedure where the lymphocytes are removed. But then the lymphocyte product needs to undergo processing and where this protein is introduced into the T cells, and then several rounds of expansion and quality control.
All of this takes time and unfortunately, the myeloma doesnt really take a break during that time and so that raises clinical challenges in the delivery of the therapy. I think this is true for all different approaches. Certainly, the faster you can deliver a product, the more likely you will be able to deliver the product because the more likely the patients myeloma will be under control.
I think that if one moves earlier into the natural history of the disease, perhaps this becomes less of a challenge because generally earlier on, disease control is easier to maintain. There are more available, active drugs that the patients have not yet been exposed to.
Jenny: Yes, that makes sense. Hopefully, all the competition with lower cost over time, I would think.
Dr. Lesokhin: Yeah, one can only hope. I think thats the challenge of these treatments. We can make jokes about it, but its actually quite serious. I think, our patients really face a tremendous amount of financial toxicity over their lifetime. The good thing is that we have all these great, treatment tools and our patients are doing better, theyre feeling well during their treatment because theres less toxicity and so on and so on.
But these therapies are very, very expensive. So the question that the CAR T cell space in myeloma will face is, what is a 12-month benefit worth? I dont have any idea. Thats for a higher power than me.
Jenny: Right. Well, we hope that with more availability and more different approaches that that will be beneficial for patients in all sorts of ways, not just for therapy, but also financially because youre right, it is a big issue. Lets talk about the off-the-shelf CAR T approaches because I see those starting to join the landscape.
Dr. Lesokhin: Sure. I think these are early on still. I think, theres a CS1 targeted off-the-shelf product thats being developed, but well see if that turns out to be a viable strategy just on the face of it. One of the challenges that off-the-shelf products face is that the T cells will be non-self and can the elimination of non-self, self be sufficiently slowed down to allow for those CAR T cells to have an effect?
Jenny: Right. And then lastly, we have on our list vaccines, when and how to use them? Do you want to just review how vaccines are being used in myeloma?
Dr. Lesokhin: For now, vaccines are really, and Im not talking about antimicrobial vaccines, I think youre talking about like anti-myeloma vaccines. These are really great in clinical investigation at this point. Theres a variety of vaccine strategies that are undergoing clinical trials. Perhaps the furthest and most sort of informative trial will be a trial of myeloma cell, dendritic cell fusion, cells that are patient-specific, that there was a trial run by the BMT CTN, run by David Avigan and our center and MD Anderson, that randomized individuals who receive the vaccine are not following transplant. So we will see what will happen there.
I think that vaccines are certainly something we shouldnt forget about. Its a way to elicit or expand a T cell response against specific targets. The challenge has been that the targets on myeloma cells have been self-proteins that are perhaps over expressed on myeloma cells that self is recognized as self in our immune systems desire to maintain tolerance and not to attack, self is very strong and it overcomes these vaccines, whether or not this fusion approach where all of the different myeloma cell proteins, including the ones that may be mutated in a particular myeloma cell are being presented to the immune response whether or not that approach turns out to be efficacious, so something that well see hopefully soon. But I think until that time, vaccines are not routinely used in myeloma outside of clinical trials.
Jenny: Right. Okay, that sounds great. Well, this has been an amazing review of immunotherapy and we do have a couple caller questions that I want to allow if youre okay on time. Are you okay? Okay. All right. If you have a question for Dr. Lesokhin, you can call 347-637-2631 and press 1 on your keypad. Go ahead.
Caller: Hi. Yes, I first just wanted to thank you. This has been so great and very informative to learn more about immunotherapy. My question is in regards to the immune system. I am just wondering what patients can do or take to boost their immune system to prevent disease progression if you have any insights on that.
Dr. Lesokhin: Yes. I get this question in the clinic almost every single day. Its such a great question. I wish I had a great answer. A lot of people, especially those with smoldering myeloma really use this curcumin compound to try to modify their immune response and delay smoldering myeloma progression or something like that. Im not for or against this approach.
I think that there isnt a clear data to say that thats beneficial or harmful. Sometimes people think vitamin C is a good approach. I think that that actually can be detrimental particularly when one is being treated with things like proteasome inhibitors particularly bortezomib.
I guess, the short answer is that we dont really know. What we do know from some observational studies is more of a fruit-vegetable based diet may be beneficial in myeloma. This is based on Northern European study that evaluated diet and incidence of MGUS and myeloma, and found that individuals in their adolescence that ate more fruit were less likely to develop MGUS or less likely to progress from MGUS to myeloma.
Now, its hard to go back to your adolescence when youre not an adolescent anymore. But I think that thats a bit of data that suggests more of a plant-based diet may be a healthier approach than an animal-based diet.
Caller: Okay. Well, thank you.
Jenny: Okay. All right. Thank you so much for your question. Go ahead with your question.
Caller: Hi, Jenny. Thanks so much for going overtime, Dr. Lesokhin. I appreciate it so much. So much info covered. My first question is about the BiTEs. Is this a therapy that you must continuously use for them to be effective or is this something that you get once and thats it?
Dr. Lesokhin: At this time, these are all therapies that are being evaluated in a continuous fashion or at least for a prolonged period of time. Its not a one and done treatment like CAR T cells.
Caller: Okay. Jenny brought up the high-risk smoldering myeloma trial using Revlimid ECOG study. I just had some thoughts about it, wanted to run it past you. Its more things that I just think about when I read the stories about this study and the outcomes by the criteria and definition used back in 2012 when I was first diagnosed with smoldering myeloma.
I was actually eligible to enroll in that trial, but I didnt, and I have not had any treatment to date. Your colleague, Dr. Landgren has actually said to me that my disease is yet to really declare itself yet by todays definition, I fit neatly into the intermediate risk to progression box and obviously dont meet the criteria of the new high-risk smoldering trials. So Im left to wonder if some of the smoldering trial patients who received or who were in the Revlimid arm were potentially like me and would not have progressed anyway.
At this point, Im cautiously trying to interpret those results, keeping my own experience in mind because I continue to think about using what I would consider potentially suboptimal therapy, which may eradicate some of the less aggressive clones and leave the most aggressive ones behind, leading to perhaps a really aggressive relapse or progression in some of these smoldering patients. What are your thoughts of something along those lines?
Dr. Lesokhin: I think youve asked a very thoughtful question and I think actually, perhaps partially answered it in your question. I think there are of course in any population of individuals that we treat, especially those that may not progress for a long period of time, patients that will not progress whether we treat them or not, I think thats one of the challenges of designing smoldering myeloma clinical trials.
Although, I think its very important to do those kind of trials. I think interpretation of this study, the way youve interpreted sounds very reasonable. Theoretically speaking, your concern about eliminating a Revlimid sensitive clone by somehow affecting the clonal balance of myeloma to allow for a more aggressive or a different kind of relapse is a plausible hypothesis, something that may occur whether it will or not is not known.
Caller: Okay. Right. I guess theyre still trying to really determine that across the board in all of these smoldering trials if that would be the eventual outcome. You touched upon the vaccine trials in myeloma, and I know there are some vaccine trials in smoldering patients. Theres one actually opened at MDA and I believe another one is going to be opening at Dana-Farber. Theyre called neoantigen vaccines. Im not really quite sure what that means.
But Im thinking that its tumor precision, so to speak, like they were actually taking whatever antigens are expressed on your cells and targeting each and every one of them with these vaccines. Is that correct? If yes, what are your thoughts about those types of vaccines being used in a smoldering myeloma population?
Dr. Lesokhin: I think those are very interesting approaches. Well see whether or not they work.
Caller: Will Sloan Kettering be engaging in such a trial, do you think? Because I know you guys are all doing all these immunotherapies and Dr. Chung is looking at the immune system and it seems to be a really well-rounded approach to this disease because its so super complex.
Dr. Lesokhin: I think these are all things that we keep on our horizons and think about. We, as far as Im aware, dont currently have a trial like this, but it doesnt mean we dont talk about it or think about it, and wont eventually do something like that.
Caller: Okay. Now, my last question is really related to, I guess, CAR T cells. Would more heavily pre-treated patients have T cells that are of poor quality, so to speak, when theyre extracted and used as the cell to become these fighting T cells? Does treatment beat these cells down to the degree where theyre not really as viable as they potentially could be earlier in the disease?
Dr. Lesokhin: I cant answer the question the way you ask it, but what I can say is that individuals that have more T cells in their product that have features of early stem cell like T cell or stem cell memory T cell properties tend to respond better.
Caller: Oh, the memory T cells. Ive heard that expression. Okay, very good.
Jenny: Go ahead. Whats your question?
Caller: Yes. Hi. Regarding personalized medicine. Do any genomic tests such as next generation sequencing as such inform us a priori about how effective some of these treatments could be so that we dont have to do trial and error?
Dr. Lesokhin: Are you talking about immunotherapy approaches? Are you talking about more precision medicine like a mutationally targeted treatment approaches?
Sounds like we lost the caller. From a myeloma immunotherapy approach at the moment, next generation sequencing approaches targeted on the tumor cell dont necessarily inform who may or may not respond. Of course, you might identify a targetable mutation and there are some clinical studies out there directed at specific mutational subsets to individuals. But thats I think outside the realm of what we know today.
Caller: Im more referring to in terms of screening for candidates for a successful CAR T therapy or other immunotherapies – is there anything we can do before the treatment by sequencing the tumor that can tell us beforehand whether it be immunotherapy might or might not be more successful?
Dr. Lesokhin: Yes. Thats in the realm of research these days. I dont think theres something that we can, real-time, do to answer that question.
Caller: Its clinical considerations and trial and error basically.
Dr. Lesokhin: At this point, yes. Although the question is valid and one thats probably being investigated.
Jenny: Great. Thank you for your question. Great question. Last question and then were finished.
Caller: Hey there, Dr. Lesokhin. Im going to go from highly theoretical or highly practice. You have mentioned BCMA antibody. How many people have you enrolled over at Sloan Kettering?
Dr. Lesokhin: That trial here is not yet opened, but it will hopefully open in the next, Im hopeful, in the next month or so. Its about a hundred patient study so I dont know that well enroll a hundreds patient, probably not. But well certainly have availability relatively soon.
Caller: Well, thats a very good news. So contact Sloan Kettering oncologist?
Jenny: Yes, just stay up-to-date with your doctor at Memorial. That would be great.
Caller: Okay, thanks.
Jenny: Okay, great. Thank you so much.
Well, Dr. Lesokhin, thank you so much for the extra time. We really, really appreciate it. We thank all our callers. Well, thank you just for so much. Were so grateful for your research, for the work that youre doing, for what youre teaching us and just for dedicating your life to helping myeloma patients.
Dr. Lesokhin: Its an honor. Thank you for having me.
Jenny: Thank you so much.
Thank you to our listeners for listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest on myeloma research and what it means for you.