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    • Myeloma Crowd Radio Episodes
    • May 14, 2019

    Full Show: Off-the Shelf CAR T Cell Therapy Targeting CS1 by Cellectis with David Siegel, MD, PhD, Hackensack University

David Siegel, MD, PhD
John Theurer Cancer Center / Hackensack University
Interview Date: May 3, 2019

Thanks to our episode sponsor

Summary

CAR T cell therapy is making its way into the myeloma clinic. Most of of the early CAR T therapies have been personalized for each patient using a target of BCMA. In this new Phase I study, the CAR T treatment is an off-the-shelf treatment from a donor. The target for this Cellectis treatment is CS1. This study will open this year at several locations and will include patients who have relapsed most of the myeloma drugs, including another CS1 targeted therapy called elotuzumab. Learn more about this fascinating new approach to CAR T therapy from Dr. David Siegel, a leading myeloma researcher at Hackensack University.

Dr. Siegel on Myeloma Crowd Radio

 Full Transcript

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank today’s episode sponsors, Celgene Corporation, for their support of Myeloma Crowd Radio.

Before we get started with today’s very important show, I’d like to share a short update on HealthTree, an online tool we created for multiple myeloma patients. Currently, over 4,000 patients have now registered for HealthTree. Patients are using it to track their disease in a single place, find treatment options they could consider at every stage of disease and find clinical trials that they can join.

With the new update we made last week, your clinical trial list got even more specific for your individual situation. We’re now passing your latest lab values like your kappa or lambda light chain numbers, platelets and other numbers that are used in qualifying you for clinical trials with SparkCures, which is embedded inside the HealthTree. Your clinical trial list will show only those studies you qualify for based on the studies’ eligibility criteria.

Now, we’re also customizing your list based on genetic features. So now for most of the clinical trials, genetics of your disease doesn’t really matter that much, but there are clinical trials coming soon that are specific to a gene feature like a translocation of a 4;14 or even what they call a point mutation like NRAS or KRAS. We want you to be aware of these studies when they open, so now your list is even more personalized than before.

Now on to today’s show. CAR T therapy is expanding in clinical trials as many of us know. Most CAR T therapies are customized and created for each individual patient with the most common target being BCMA. Today’s show is a great departure from that norm. It’s going after a new target. It’s an off-the-shelf approach so it doesn’t need a waiting period to be manufactured. Here to share this idea with us about this product from a company called Cellectis is Dr. David Siegel, Chief of the Myeloma Program at the John Theurer Cancer Center at Hackensack University. Welcome, Dr. Siegel. Thank you so much for joining us today.

Dr. Siegel: Thank you very much for inviting me.

Jenny: Well, let me introduce you just before we get started. David Siegel is a Chief of the Division of Multiple Myeloma at the John Theurer Cancer Center in Hackensack, New Jersey and has made the facility one of the premier academic centers in the country. Dr. Siegel has practiced previously at Memorial Sloan Kettering, UAMS and Atlantic Health Systems. He’s also the Clinical Professor of Medicine at the New York University Medical Center and Professor of Medicine at MedStar Georgetown University Medical Center.

Dr. Siegel is the founding director of the Institute for Multiple Myeloma at the Hackensack Meridian Health Center for Discovery and Innovation, which is a new center that he helped create. Dr. Siegel’s research has almost exclusively focused on Multiple Myeloma and has been published in many leading medical journals including Nature, The New England Journal of Medicine, Blood and the Journal of Clinical Oncology.

Dr. Siegel served as the lead investigator on a pivotal multicenter study that helped obtain FDA fast-track approval for carfilzomib. He’s also one of the 11 investigators nationwide who brought Velcade to multiple myeloma patients through his clinical trials. As you’ll hear today, he continues to be on the leading edge bringing even more new therapies to the myeloma clinic like this one. Thank you again, Dr. Siegel. We’re really excited to hear about this today. But maybe we want to start with just a brief overview of the immunotherapy landscape just in general.

Dr. Siegel: I’m glad to speak to everybody. I’m glad to speak about immunotherapy. Immunotherapy is a broad term and I think, unfortunately, has become almost an advertising catchphrase in some ways. A lot of what we do in oncology, but more specifically in myeloma care can be considered immunotherapy. The most widely used drug in multiple myeloma, lenalidomide, Revlimid, is an immunomodulatory drug. That’s what we call that class of drugs. While these drugs directly impact on the myeloma cell itself, much of why they are effective is because of their ability to change the way the immune system works. Stem cell transplants from both autologous, from the patient themselves, and from donors are the classic immunotherapy. The reason that patients can do extremely well for long periods of time after a transplant is because the transplant gives the immune system an opportunity to reset itself. When we use transplants from donors, really, what we’re doing is bringing in that donor’s immune system and saying, “Please take over where the patient’s immune system failed,” and then see the cancer and try and kill it.

Then probably the most talked about thing over the past perhaps even decade in oncology have been the drugs that we call checkpoint inhibitors. You see them advertised on television now. That’s how important they’ve become. Checkpoint inhibitors and immune activators, which are a new class of molecules that are coming along, affect the way our immune system turns itself off and turns itself on. These are very nonspecific kind of drugs. But I think what most people really are starting to hear about are monoclonal antibodies. We have been fortunate to have two monoclonal antibodies approved in multiple Myeloma. Darzalex, daratumumab, and elotuzimab, Empliciti, are monoclonal antibodies. Somebody took a myeloma cell, injected into the mouse, let the mouse make antibodies against the cancer cell. Then those antibodies are engineered to look more like human antibodies. That’s one of the classical immunotherapies. But I think what most people are talking about in the myeloma world over the last months and perhaps years are the CAR T cells. That’s not just specific to myeloma, but lymphomas and leukemias and now even starting to be used in solid tumors.

Jenny: That’s amazing. The first word that I remember hearing about it was in leukemia, but now, I hear about it all the time. That’s so exciting that it’s moving forward.

Dr. Siegel: Yes, this is exciting.

Jenny: It is amazing. The work that you’re doing to bring it forward is so appreciated by patients. First, maybe you want to give us an overview of the idea behind CAR T cell therapy, because while a lot of patients have heard about CAR T therapy and cellular therapies in general, maybe they’re not as familiar with it as others might be.

Dr. Siegel: Well, we all have cells in our bodies that are capable of killing cancer cells, virally infected cells, sometimes even bacteria infected cells. These are a class of cells that we call T cells. They are very specific. Maybe to use an example that’s in the news these days is if have you have a cell that’s infected by measles, the reason that your immune system ultimately can win that battle is that it makes T cells that can see the measles virus being expressed on the surface of the infected cells. It will sit on that cell and punch holes in it and kill the cell. We have cells that can do that for myeloma. The problem is that the cells are very often tricked by the cancer into being quiet. Part of why we have smoldering myeloma and perhaps even why we have MGUS is because of exactly those kinds of cells. But eventually they get tired and they give up.

One of the goals in oncology over generations now has been to be able to take those cells, grow them up, teach them to be angry again and put them back in the patient. But unfortunately, these kinds of efforts have not been particularly fruitful. The problem is that when you take this cell out and you manipulate it and you tried to get it to grow, it loses its interest in homing to a cancer. What could we do to overcome that? Well, we can take large numbers of these kinds of cells out of the patient. But when we take large numbers of them out, they’re against any target that you might add. The mumps, the measles, whatever, some of them might be against the cancer, but they don’t grow and they don’t get angry. So what could we do to manipulate them? Well, we can actually take the receptor that these cells have that makes them angry and to take a gene that represents them and cut it into parts that are normally involved in a number of processes. One is recognizing the target. A couple of the other ones are involved in activating the cells and making them angry. It was first devised by a scientist named Zelig Eshhar a number of years ago, but more recently rejuvenated as a potential cancer therapy by a gentleman named Carl June.

These genes could be put together with a monoclonal antibody, what I was talking to you about before that had been grown up in a mouse. You can put these all in one little structure. You can introduce them into all of these nonspecific cells. When this is expressed on the surface of the cell, it will now recognize whatever target you’ve chosen. The commercially available ones are against the target called CD19, which is important in lymphomas and leukemias. But in myeloma, there’s been a number of targets that have been identified. The most important and well known so far is a target called BCMA. This is a target that is not unique to myeloma cells, but unique to plasma cells, the cell that becomes the cancer cell in myeloma. You can make a construct that, on one end, recognizes BCMA and on the other end is able to transmit the signals into a T cell to make it angry enough that it will kill a BCMA expressing cell. Most myeloma cells express BCMA so you can put this construct into the cell, put it into the cancer patient and they will now recognize the cancer, grow, get angry and kill the cancer cell. That’s my short version of this.

Jenny: That’s great. These BCMA targeted CAR T cells have been, in clinical trials, about two to three years, right?

Dr. Siegel: Yes. They have been successful at some level. I mean patients whose disease had become refractory to basically all other therapies. It can be instructed to be killed by this kind of construct.

Jenny: In those clinical trials, it’s really personalized for each patient, right?

Dr. Siegel: Yes. The problem amongst many is that you need to have a patient who has enough lymphocytes being produced. In sick patients who’ve gotten a lot of chemotherapy, that is a potential problem. These cells have to be collected from the patient in adequate numbers. They then need to have this genetic material that codes for the receptor put into the cell. Those cells have to be grown up. This process can be done relatively quickly, but because of the need to collect and then to grow and then to make sure that these cells aren’t contaminated by bacteria or anything like that, it can take about a month to grow up enough of these cells to give back to a patient. While most of the time this can be done successfully, occasionally it doesn’t. That certainly limits the ability to apply it because the patient has to be able to sit there for a month and wait. Sometimes, that’s not feasible. Beyond that, the fact that it has to be done like this for every single patient makes it extremely expensive to build this personalized product. It does have limitations.

Jenny: Right. Data just came out recently on one of the first studies on the Celgene CAR T. It looks like it is having some impact. I think it showed like a median progression-free survival of about 11, 12 months, something around that.

Dr. Siegel: Yes. The publication in New England Journal Medicine from just this week, we were fortunate enough to participate in those studies. It has to be understood that that medians don’t always tell the story. If we have some patients who are cured that that will be different, the problem is we really don’t know whether that’s the case yet. The patients who were going on this trial or these trials have been very, very heavily pretreated patients. If we compare the expectations from a more conventional drug in that setting, having median progression-free survivals approximating a year is actually very exciting number, but we don’t know whether any of that translates into patients having their disease controlled five years later or ten years later.

Jenny: I think earlier use will be so exciting to see with some of these clinical trials. I think the whole field is just so, so fascinating. Well, let’s talk about this one. This product is called you UCART CS1. Maybe you want to explain what that is and how it was developed?

Dr. Siegel: Well, the limitations of having to manufacturer for an individual patient, we just talked about. There are potential limitations with BCMA as a target as well. It is essential for the biology of the cell. Then there’s some questions as to whether the target can be lost and things like that. We have two issues: one is the amount of time, the amount of money that it takes to produce the product and number two, whether the target is the perfect target. This trial attempts to address two of these things. One is that we’re manufacturing a large amount of a product that will sit on the shelf and when a patient comes in who needs it, the product is there and can be administered relatively quickly, no need for manufacturing for the individual patient. The second is that this is specific to a different target, to a target called CS1. Sometimes, it’s called SLAMF7. I know that all of these this nomenclature can be a little bit crazy, but any of you who have heard of the monoclonal antibody, elotuzimab or Empliciti, this is the target that that antibody is directed against. What has been done is any antibody very similar to the elotuzimab antibody, the gene for that antibody was taken and was made into the construct that we’ve talked about a few moments ago. It is being put into the cell.

Now, it is being put into the cell, we’re using slightly different kind of approach. The clinical trials that have been ongoing mostly use a virus to introduce the construct into the cell. This is using a much different kind of technology. It’s being put into the cell in a very specific spot. The TALEN technology that they speak about in connection with this is an artificial construct that allows a piece of the DNA in the cell to be targeted. Material can be inserted very specifically into that site. It allows it to be done in a much more controlled fashion than the virus that does this nonspecifically. Not only is the construct being put in a specific site, but that same kind of technology can be used to manipulate the cell. Since this is a cell that is not from the patient, the patient’s immune system is very likely going to respond to it. Well, what do immune systems respond to? They respond to — you hear the term self and nonself. But the way that our immune system recognizes self from nonself is by a series of very specific molecules, histocompatibility molecules that are part of the biology of all cells. This TALEN technology has been utilized to knock down the expression of these kinds of molecules so that most of what our immune system responds to saying, “This is not part of me,” is being eliminated that technology.

In addition, the target CS1 is also expressed on many cells including the CAR T cells, the cells that are normally made into CAR T cells. That same TALEN technology is being used to eliminate the expression of the target. We don’t want to put the CAR T cells and to have them killing each other. We’re stripping that target as well as the self, nonself target from the surface of the cell so that these cells can persist in the patient and do their job. This is a very exciting step forward that the idea of having a much less expensive, much more readily available system that can be given to patients relatively quickly is potentially transformative. It’s going to make it much more available to many more patients much more easily and much less expensively.

Jenny: Right. Then you don’t have to wait for the manufacturing, like we’re talking about earlier. Well, I love this. It’s so sophisticated that they’re able to remove this potential self-destruction and they’re able to produce it and manufacture it. I know a lot of different approaches are being looked at in terms of manufacturing, not just the viral methods. It sounds really interesting.

Dr. Siegel: This kind of technology is going to change the way we deal with many things, cancers in this kind of fashion but diseases like sickle cell or thalassemia or Tay-Sachs or things like that where there are very specific mutations. This kind of ability to edit the DNA is going to allow us to address all kinds of illnesses in ways that we just couldn’t imagine even just a few years ago.

Jenny: That’s so amazing. Now, in the BCMA CAR T trials, I know a lot of them give a little bit of chemotherapy prior to the BCMA CAR T because they’re trying to do what they call lymphodepletion. When I was reading about this TALEN or this gene editing technology for this new CAR T, it sounded like it had some kind of lymphodepletion embedded into it already. Is that how it works?

Dr. Siegel: No. I think that that’s not the most important part of this. We don’t understand yet how important lymphodepletion is. When we give this kind of chemotherapy before the CAR T cells, it’s being done for a very complicated reason. Partly because we don’t want the immune system to be that competent so it won’t reject these cells, but also because when we kill lymphocytes, the body responds by putting out a signal, “Lymphocytes, please grow back.” That signal for lymphocytes, “Please go grow back,” is at some level responsible for stimulating these cells that are being put in to grow. The lymphodepletion is very complicated. We don’t know how important it is yet in treating these patients. Whether we’re going to have a platform that really avoids that is not entirely clear at this point.

The ways in which we lymphodeplete may be different as well. One of the institutions that has pioneered this kind of work, particularly in myeloma, has been the University of Pennsylvania in Philadelphia. They have used a number of situations in which to apply this kind of therapy including doing a stem cell transplant, an autologous stem cell transplant like we have been doing for years in patients. In the aftermath of that, the immune system gets pretty disrupted. The signals for the immune system to expand rapidly are quite prominent at that point. How much of that we need and how much of it we don’t need? We’re still not sure. I don’t know that there should be a big emphasis on whether there’s lymphodepletion done or not done. It can be done in many, many different ways that we have to see where that leads us. I don’t know that that’s the most important part of this at this point.

Jenny: Well, that’s a great point so thank you. Just as a reference, sometimes people will hear about auto CAR Ts and an allo CAR Ts. We use that all the time when we hear about stem cell transplant. But do you just want to define it for this CAR T experience for patients?

Dr. Siegel: Yes. This is an allogeneic product, meaning it’s from somebody else, from a donor as opposed to when we make the product for each individual patient where we’re using their own T cells that’s an autologous product. This allogeneic product, it’s the fact that it’s allogeneic that allows us to have it sitting there on the shelf rather than needing to be manufactured. There’s another subtle advantage to this in that we’re not trying to collect the cell from a patient. That means that the donor is healthier. Their cells haven’t been stressed as much as the cells in a patient who has been getting a lot of steroids and a lot of chemotherapy in the years perhaps before they receive the CAR T cells. Maybe the actual product is healthier and more viable in terms of its ability to grow and be sustained because it’s not coming from a patient whose cells have been so compromised.

Jenny: That was a very interesting point. Do you mind expanding a little bit more about the CS1 target? You talked earlier about how it’s the same target that elotuzumab was going after. I know when they’re thinking about CAR Ts, you’re trying to think about the target. You said it’s on CAR T cells, but it’s also on myeloma, so doing this off target is always a concern. Is there a concern on this or is this similar to BCMA?

Dr. Siegel: I mean what has been so attractive about BCMA as a target is it’s so tightly restricted to mature plasma cells, the kind of cell that is the cancer cell in myeloma. There are very, very few other cell populations that have it as a target. That makes BCMA sound like a perfect target. There’s little off target specificity in BCMA specific CAR T cells. Now, that doesn’t make it perfect in that the cells may just lose it. They don’t need it.

The CS1 is clearly more widely displayed. One of the places that it is most prominent is on a class of cells called natural killer cells. Natural killer cells are very important part of our immune system. There is a chance that when you give a CS1 specific CAR T cell that you’re going to be wiping out these other kinds of cells that may lead to different kinds of immune compromise, although our body continues to make these cells. It also means that there’s more chance for toxicity, that there’s more drive for these cells to continue to proliferate even as the cancer cells are eliminated. That has not turned out to be the case with the CAR T cells that are directed against lymphomas and leukemias that we still can cure patients see even with significant toxicity but even with the CD19 being expressed on cells that are clearly not associated with the cancer. While this is a concern both in terms of its impact on the immune system, but it’s also — there’s a precedent saying that this can be done in other diseases with targets that are even more widely displayed. We will find out as we move forward with these clinical trials. I don’t think that it’s likely to be a huge issue, but we’re really not yet in a position to answer that question.

Jenny: It seems like elotuzumab might pave the way for some of this, right? You already know that you can go after this as a target.

Dr. Siegel: And not have the patients get particularly ill. Elotuzumab is a very easy drug to use. You’re exactly right that we have this precedent out there. I think we should be very excited about both CS1 as the target and the fact that we have an off-the-shelf product.

Jenny: That brings up another benefit because you talked a lot about the benefits earlier in the show, that this might be a benefit or might be enough for everyone, right? You don’t have to take the time, I guess, to do the individualized manufacturing. Could you produce enough? Does it have like a shelf life? That’s a weird question. How was this produced? Can they produce a lot at once? Maybe when you’re running these further along clinical trials, you can have more patients?

Dr. Siegel: Yes. They obviously will have to continue to manufacture. They’re going to have a pool of donors that are involved in this process. The actual shelf life, I have no idea what that is. I mean it’s prolonged enough that we anticipate having it in stock for patients as they come in to the trial. I don’t anticipate that that’s going to be a major concern. Listen, we’re living in a world where resources are going to become much more limited. I think the fact that it can be manufactured in bulk and be ready for patients as they come on is important clinically, but it’s going to be as important from a health economics perspective as well.

Jenny: Well, this is so exciting in my opinion. I just am so happy to hear about this. Let’s talk about the actual study because it’s going to be open at your center and a few others. This is a Phase I study, right?

Dr. Siegel: Yes. We don’t know precisely what the best dose is, what’s the dose that is going to be tolerated. We’ve just gone through this experience with the individual patient manufactured products so we have a lot of experience. When I say we, I mean us as an institution, but the myeloma community as a whole. Doing this kind of study, I don’t anticipate that the Phase I part of this should take an extraordinary amount of time. I think that that we’re probably talking about the relatively short-term future before we know the dose and or treating patients in much larger numbers.

Jenny: Where and when will it be open?

Dr. Siegel: Well, I think that’s partly a bureaucratic question. I know that MD Anderson Cancer Center is one of the sites that have driven the development of this product. We should be open fairly soon too, but the first patients will be getting treated this year. In fact, probably in the next month or two is when the first sites will be opening.

Jenny: Oh, wow. I think it’s so exciting. What type of patient will be eligible to join this particular study?

Dr. Siegel: Well, right now, these are patients who have been fairly heavily pretreated and have seen most of the major classes of drugs that are available for treating myeloma. What’s unique about this trial in terms of the eligibility criteria is that the patients have to have been treated with elotuzumab or not be eligible to be treated with elotuzumab for some reason. There is this unique requirement in this particular trial.

Jenny: Oh, so they had to have received elotuzumab already or they are not eligible to get it.

Dr. Siegel: Yes.

Jenny: Well, that’s fascinating because usually, it’s the opposite.

Dr. Siegel: Yes. You would think so. This is not just the company that is making the eligibility criteria. It’s the FDA as well. The requirement as it is stated right now is that the patients have to have received elotuzumab or the clinical team has to feel that elotuzumab is not a reasonable alternatives.

Jenny: That’s so interesting. Do they have to have had a monoclonal antibody, like daratumumab before?

Dr. Siegel: Yes. Or it has to be felt that the patient is not eligible for that as well. But right now, most of these kinds of clinical trials are not just CAR T cells, but a few of the developing platforms like BiTEs, the bifunctional antibodies, the antibody drug conjugates. All of these technologies in their early drug development are mostly being targeted for patients that don’t have really obvious alternatives. They don’t want a patient who haven’t seen the most effective drugs to jump to this when we really don’t know both the efficacy or the toxicity that is associated with them.

Jenny: That’s so interesting. If you have failed a prior CAR T therapy, like let’s say a BCMA, can you be on this study?

Dr. Siegel: You know what? I don’t know the answer to that question.

Jenny: I’ll look it up.

Dr. Siegel: The answer to that may be yes, but I don’t actually know that.

Jenny: Well, I’ll look it up just because I have some friends who have gone through that experience and are looking for things. I’m thinking about them at the same time. Of course, this is like you’re escalating the dose and you’re trying to see how safe it is and things like that so you don’t have a lot of data all ready, but do you have any insights or thoughts about any potential side effects that you might see? I know the cytokine release syndrome can happen in the BCMA trials, but not so much in myeloma. Do you have any thoughts around that or you’re just going to have to wait and see?

Dr. Siegel: I think that right now we have an expectation that there will be cytokine release syndrome that as these cells grow and become angry, the cytokine release is part of that process so it can’t be avoided entirely. Although I think these off-the-shelf platforms perhaps can be engineered so that the production of these kinds of cytokines is specifically removed from these cells. But I think that’s mostly stuff that is going to happen down the road.

Jenny: Is it just a one time in administration or do you get boosters over time? How does that work?

Dr. Siegel: Most of these trials the patient gets treated, the option of we treating the patients in the future is, I think, still an open question. I think it is very much dependent on the kind of activity that we see as we begin these Phase I trials. There’s always the possibility of amendments being introduced to more clearly delineate that. But I think the question about getting boosters in the future is very much getting ahead of ourselves. We really need to see whether this works in the first place before we start talking about how important boosters down the road will be.

Jenny: Yes. That makes sense.

Dr. Siegel: I mean, I would be very excited about it.

Jenny: That would be great if it helps sustain remission or something. In this study, how will patients be watched? I know in the BCMA CAR T experience, it’s like you’re watched very closely for first couple of weeks. How does that work for this study? How long are patients watched? How long do they need to stick around the study site, those types of things?

Dr. Siegel: In any Phase I trial and not just the CAR T Phase I trial, the monitoring has to be very, very careful. I certainly think the prior experiences with CAR T cells substantiates the need for that. The monitoring is very intense for the first month that these patients are treated. The patients need to be local to the institutions that are treating them. Whether this will change as the trials expand into Phase II type clinical trials isn’t clear. I mean certainly, the experience with the BCMA trials was surprisingly — I don’t want to say nontoxic because there certainly were consequences – but I think that how that is going to be managed in the future is very much dependent on the experience in the Phase I setting.

Jenny: Is this going to be considered like an inpatient administration of this or does the patient stay in the hospital? Do they do this outpatient and they just stay locally and you’re watched there? How does that work?

Dr. Siegel: I think that a lot of the CAR T cell programs have managed to make facilities that circumvent some of this by having combined inpatient and outpatient facilities. But I think the initial plan is to do this as an inpatient.

Jenny: Well, it makes sense for a Phase I study, I think. I think that you mentioned this a little bit, but I think this is important also. Just clinical trial participation, you mentioned how carefully patients are watched. I think it’s worth stressing that patients who join clinical trials and participate in clinical trials are very carefully watched. Sometimes, they get just — I don’t want to say better care because I think all the care of myeloma patients are getting as good – but they’re so carefully watched that a lot of them have really great outcomes because they’re participating in clinical trials and because they’re watched so carefully.

Dr. Siegel: Well, I think there’ve been many studies. This is not just in relationship to myeloma or even in the oncology, but the outcomes for patients with the whole spectrum of medical issues is generally better in the kinds of institutions that do clinical trials. Large academic institutions are sometimes very cumbersome. The inconvenience of those kinds of settings can sometimes be real, but the reality of it is that the disease specialized care, the infrastructures that are available, generally mean that the patients are going to ultimately get better care. It will be great to develop products like this that are safe to administer out in the community because unfortunately, there are many, many patients who live in areas where it’s far to get to these kinds of specialized institutions. But yes, big academic medical centers have many advantages both in terms of monitoring and in terms of the kind of resources that can get applied to a specific disease. That idea that, “Well, I don’t want to be experimented on,” which is I think all of our instinct sometimes is in the patient’s best interest.

Jenny: Right. Well, if you wait until a clinical trial is your last potential option, you might not even qualify just because of your physical status or the way your disease is behaving or lots of different reasons. I research that for patients all the time.

Dr. Siegel: Unfortunately, the way clinical trials are put together — and this is for good reasons — is that once you get to be too sick, you’re not eligible for clinical trials anymore that to say, “I don’t want to go on a CAR T cell study. It’s not established care. I’m going to wait until I’ve tried this therapy, this therapy, this therapy and this therapy before I consider those kinds of options,” may very well mean that those options will not be available to you when you get to that point because you have to have both the performance status, the physical wellbeing to qualify but also the biochemical wellbeing. If your white blood cell count is too low, if your platelet count is too low, if your kidneys don’t work well enough because of the stresses and strains of the disease and the therapies, sometimes that opportunity will be lost.

Jenny: Right. Well, I think patients could consider clinical trials really at every stage of disease and especially, the earlier the better. That’s one of the reasons we do this with HealthTree and SparkCures because it’s hard to understand the clinical trials and find one that you are eligible to join. I have one final question before I open it up for caller questions, which I see that we have. How you talked earlier about potentially losing the BCMA signature, is that something that happens with the CS1 too? Do you lose CS1 signature or is it a more durable type signature?

Dr. Siegel: Well, we’re not even sure how important that is with BCMA. I know that there are instances where it is lost, but whether that is clinically important, we don’t know. The amount of selective pressure that these kinds of therapies apply is unlike anything else that we do in oncology. Whether the CS1 can be lost permanently or not is something that is going to have to wait until these kinds of clinical trials are completed. It’s certainly a possibility, but I hope it’s not a probability.

Jenny: Right. Well, I’m so personally excited about this because one of the first projects that we funded with the Myeloma Crowd Research Initiative was the German group going after CS1 as a CAR T product. They’ll be opening their European trial later in the fall. It’s so exciting to see the CS1 target, especially with this off-the-shelf approach happening in the United States. I can’t wait to see what happens.

Dr. Siegel: Oh, I think we all can’t wait.

Jenny: Oh, I feel thrilled that people like you were bringing it to us.

Dr. Siegel: I think we all can’t wait. I mean us who care for the patients, but I think even more so the patients themselves.

Jenny: Well, I’m just thrilled at what you’re doing. I’d like to open it up for caller questions for a few minutes. If you have a question for Dr. Siegel, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Hi, Jenny. That’s me, Jack Aiello. Dr. Siegel, it’s always great to hear from you.

 Jenny: Hey, Jack. How are you?

Caller: I’m good.

Dr. Siegel: It’s been awhile. How are you?

Caller: I see you once a year at ASH at least.

Dr. Siegel: Yes and that’s right.

Caller: I had to tune in about ten minutes late. My question with respect to allo CAR Ts is did you discuss Graft-versus-host disease? Are you expecting it as controlled by immunosuppressants and things like that? If you did this already, I can read this in the transcript.

Dr. Siegel: No. We didn’t discuss that at all. I think that there is a small possibility that cells can be not just alloreactive but reactive to other potential targets and the patient that might drive their proliferation. Right now, I don’t think that just from my insights into how we evolved a random donor, it’s not likely to have large numbers of alloreactive cells. Obviously, the donors are being very carefully selected in terms of having been exposed to allogeneic cells. Where could people be exposed to allogeneic cells? In pregnancy, having had transfusions and things like that. I think the manufacturers are going to be very aware of those kinds of considerations. I think it’s very unlikely that that should be a significant problem.

Caller: So you’re not expecting to see Graft-versus-host disease?

Dr. Siegel: Caused by these kinds of cells? No.

Caller: Caused by these kinds? Okay. Thanks. Good. Thank you.

Jenny: Great question, Jack. Thank you. Okay. Second caller, go ahead with your question.

Caller: Oh, thanks very much, Dr. Siegel. I just had a quick question since this is an allogenic product. Is there an assumption built in that the T cells are going to be the same coming from all these different donors? How do you account for potential variability or such?

Dr. Siegel: I think that that is one of the potential issues. I think that there are ways to test the product before it is administered to have some normalization, but in the end, you’re right, there is going to be some inherent variability in any kind of biological product like this.

Caller: Okay. Thank you.

Jenny: Okay, great. Good question. Okay.

Dr. Siegel: Great question.

Jenny: Caller go ahead with your question.

Caller: Hi, Dr. Siegel. Hi, Jenny. It’s Dana Holmes. Thanks so much for taking the call. Dr. Siegel, would non-secretory patients be eligible for this trial or do they have to have measurable disease?

Dr. Siegel: You’re asking the question I always ask. The answer is that obviously, Cellectis is doing this for the good of the patients, but also because they want to have a product that will get approved by the FDA. The FDA is still very much involved with the biochemical markers of disease. Yes, the options are much, much more limited for patients that have truly non-secretory disease.

Caller: Okay. What about patients who may have had an allogeneic stem cell transplant? Would they be eligible for a trial like this?

Dr. Siegel: I think right now, the answer to that is no. There are CAR T cell programs out there already that allow allogeneic patients to participate. I don’t specifically remember but my guess would be I would remember if allogeneic patients were allowed because we have so many post allogeneic patients in our system.

Caller: Yeah. What about if a patient failed elotuzumab? Does that have any bearing on whether or not they would be eligible for this trial?

Dr. Siegel: No.

Caller: Okay. Could you explain why? Because if they fail that because elo targets the same certain protein, right?

Dr. Siegel: The way that these molecules work is much different than the way a monoclonal antibody works. A monoclonal antibody binds to that target very specifically. It mediates an interaction between certain kinds of cells in our body that that can kill antibody coded things. It activates the complement system and does all kinds of things that are very dissimilar to the way an activated T cell kills.

Caller: Oh, okay.

Dr. Siegel: An activated T cell basically lies on the target and punches holes in it. It is not working through the CS1 or the SLAMF7. It is being approximated and activated by that interaction, but ultimately, the cell is killing via pathways that are independent of what introduced them to this cell.

Caller: Okay. I think you did –

Dr. Siegel: I don’t know if I’m making myself clear here.

Caller: No, I do. I understand what you’re saying. I do and I appreciate that clarity. I appreciate that very much. You did say, I think, earlier that you were not sure if BCMA prior CAR T patients who have now since failed that would be eligible for this type. Is that because – do they not —

Dr. Siegel: Yes. No, it’s just because I didn’t know and I wasn’t smart enough to sit down and read through all the eligibility criteria.

Caller: Okay. So they might be. The door hasn’t been closed for that. Okay. Alrighty. We’ll find that out. All right. Well, Dr. Siegel, thanks so much for your time. Thanks for everything that you do for patients. We’re all rooting for you.

Dr. Siegel: I’m rooting for you guys.

Caller: I know you are. Thanks so much, sir. Have a great weekend. Bye-bye.

Dr. Siegel: Thank you.

Jenny: Okay. Thanks, Dana, for your question. Dr. Siegel, I think you can feel the enthusiasm from patients. I’m sure you have lots of patients who are really so excited to see how this all turns out. I just want to thank you for your extraordinary work for myeloma patients on their behalf, for the research that you do, for the patients that you treat and to move these things forward.

Dr. Siegel: Well, thank you because it’s folks like you who talk to the patients independently from us and don’t have an axe to grind, so to speak. I think that a few wise words from people such as yourself goes a long way in helping the myeloma community. You guys are as important as any in this whole process.

Jenny: Well, I think if patients realize how much power they do have in terms of joining the studies and helping advance research faster, we could just come to conclusions, for you so much faster. That’s why we always suggest that people consider these things.

Dr. Siegel: Yup. I think you’re right.

Jenny: Well, thank you again for joining us. We’re just so appreciative for you today. We’d like to also thank our callers and the questions. They were just excellent. Thank you for listening to another episode of Myeloma Crowd Radio. We’d like to invite you to join us for future shows to learn more about the latest in myeloma research and what it means for you.

About Author

Jenny A

Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio and the CrowdCare Foundation.

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