Dr. Carl June at the University of Pennsylvania has been working on the use of CAR T cells against blood cancers for over a decade. Work by him and his group is now bearing fruit. In a recently completed study, Dr. Adam Cohen and the team at UPENN targeted a protein not normally found on myeloma cells - CD19. The CD19 approach had been used with great results in CLL, non-Hodgkins Lymphoma and in ALL, with 80-90% response rates in ALL. Even though this target is not on the surface of most myeloma cells, they decided to try the therapy in myeloma in combination with autologous transplant. The rationale is that CAR T cells are very sensitive to even low levels of markers and that precursor myeloma cells could actually have CD19 on them. Another reason is that CD19 could actually act as an immunosuppressor, so by getting them out of the way, the treatment could do its job without the immune system kicking in to protect it. In their initial myeloma trial, the results for one high-risk patient (del17p. 1q gain and refractory to 9 prior therapies) were spectacular. She is still in complete remission over a year later. Normally, the longer the CAR T cells stick around in a patient (even 2-3 years later), the better the response. In the myeloma patients, they have not lasted as long, so Dr. Cohen describes how they are working on getting them to persist for a longer period of time. Dr. Cohen describes how they are now looking at varying the time frame in which they give the cells. They are now giving them 12-14 days after transplant. In other CAR T cell work, it could potentially be used without transplant, but because the CD19 is not normally present on myeloma cells, transplant had to be used to kill the myeloma tumor burden.  Their next target is CAR T cell treatment for BCMA because is it a safe target. Now, many other CAR T cell targets are being explored including CS1, BCMA, Kappa light chain and others. The prospects for this therapy are very exciting and Dr. Cohen and his team will continue their exciting work to make it even better over time. Clinical Trials Discussed in This Show BCMA CAR T Cells Without Transplant The Myeloma Crowd Radio Show With Dr. Adam Cohen

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 sponsor Amgen for their support of Myeloma Crowd Radio and all they do for Multiple Myeloma Patients. Now, before we get started, I would like to share a way that patients can help change their own myeloma outcome. Now, I just got back from my Myeloma Patient Advocacy meeting and what struck me was the patient who took charge to advocate for their own disease were better equipped at finding answers for themselves. And once they felt confident with that, they typically became advocates for us all helping hundreds if not thousands of other patients. Now, I believe that we can't sit around and wait for a cure that we can help accelerate our own cure and many of my myeloma friends agree. So we have now joined together to create what we call the Myeloma Crowd Research Initiative. We started with a target for high risk multiple myeloma patients. As you'll hear in this show, our target may be equally effective for all myeloma patients. So with input from six leading myeloma doctors and five highly educated myeloma patients and a very thorough review process, we have selected two critical projects that are immunotherapies that need our financial support. These are ways to use the immune system to fight myeloma. And one of the projects is a CAR T-Cell Immunotherapy which you'll learn a little bit more about in today's show and we invite you to help raise funds for these proposals by creating your own fundraising page that you can share with family and friends. So you can check out the myelomacrowd.org website for links at the top to create your own page and to help us fundraise for this very important initiative. So, on a topic of immunotherapy that is very tightly related to our project and our show today. The University of Pennsylvania has really been leading the charge on CAR T-Cell Work and Dr. Adam Cohen joins us to discuss this important work. Welcome to the show, Dr. Cohen.

Dr. Cohen: Thank you, Jenny and thanks for the invitation to be here today.

Jenny: Well, we're thrilled to have you because you have some very exciting news to share. So we'll get into that in a little bit but please allow me to introduce you first. Dr. Cohen is assistant professor and director of Multiple Myeloma Immunotherapy in a Promo School of Medicine at the University of Pennsylvania. He regularly lectures to internal medicine residents and hematology, oncology follow-up and hematology conferences. He's the member of the oncology evaluation center practice task force, the clinical trial, scientific review and monitoring committee and as a clinical advisory board member for managing myeloma which is an online educational resource and has extremely valuable videos for oncologists if you have never seen it. He is on cancer immunotherapy guidelines and hematologic malignancy task force, the society for immunotherapy of cancer and as a member of ASCO's Scientific Program Committee for hematologic malignancies. Dr. Cohen wrote videos journal publications from blood, amyloid, clinical cancer research, journal in translational medicine, house of oncology, psychotherapy, leukemia and immunotherapeutics, in addition to many others. His most recent awards include best abstract in myeloma, in lymphoma and myeloma at the international congress on hematologic malignancies, the Fox Chase Leadership Forum Excellence Award and the ECOG Young Investigator's Symposium. He is a member of the Multiple Myeloma Committee of the Eastern Cooperative Oncology Group which helps create and oversee myeloma clinical trials and is a scientific advisor for the will of Myeloma Beacon. Dr. Cohen, thank you so much for joining us.

Dr. Cohen: Thank you for having me.

Jenny: Now, we did a show with Dr. Alfred Garfall who is in your group as well. He gave us some insights about a project that you were working on but at that the time that we did the show, the final paper wasn't written. So we're going to be talking about that today but maybe you want to just give us another refresher about the history of CAR T-cell use at UPenn and maybe just a review of part of his show to start.

Dr. Cohen: Absolutely. I'd be happy to. Probably many of your listeners are familiar with the concept of CAR T-Cells since it's been a hot area and oncology lately but just to briefly review, CAR stands for Chimeric Antigen Receptor and basically the whole concept is trying to reengineer a patient's own immune cells, usually T-Cells to be specific for a molecule that's expressed in the surface of the cancer cell. This technology actually would first developed over 25 years ago but it's really only in the past five years or so that we're really starting to see impressive clinical response. And so the CAR T-Cell Program at Penn is really been driven by scientist named Carl June who has been working on this for probably over ten years now and basically by improving the ability to get the CAR, Chimeric Receptor to persist in the T-cell. We have been able now to give this to patients with a variety of different cancers and found that the CAR T-cells can survive and survive within the patients and actually try to kill off the cancer cells. The first studies at Penn were done in another type of bone marrow cancer called Chronic Lymphocytic Leukemia or CLL. This study was lead by David Porter here. What they found in actually treating one of their very first patients who had extreme refractory disease was that patient actually went into a complete hematologic remission and remains in remission over four and a half years later without any evidence of disease. Based on that to the promising initial experience, we have now been treating patients with CLL as well as other cancers, one called ALL, Acute Lymphoblastic Leukemia another is called Non-Hodgkin's Lymphoma and I should point out Penn is of course not the only place doing this. This is being done at Sloan Kettering and Baylor and multiple other centers around the country and in fact around the world now. And what we are seeing is that with these Chimeric Antigen Receptor expressing T-cells particularly the first CARs were against them who called CD19 that you're generally getting responses between 40 to 50% of patients with CLL and Non-Hodgkin's Lymphoma and responses anywhere from 80 to 90% of patients with ALL. And so this really has been very exciting particularly in those cancers but for the field in general is lead now to be exploration of using these CAR T-cells and multiple other cancers including multiple myeloma.

Jenny: Okay, great. It seems promising and there was a review and you brought it to myeloma and then there was a recent article in the New England Journal of Medicine and that talked about how you did use that. So do you want to describe how you use that in multiple myeloma and then what the outcome was?

Dr. Cohen: Absolutely. First, just to give I guess a little bit of the rationale behind the first study in Myeloma and as you mentioned this study was actually led by a doctor Dr. Al Garfall here in conjunction with Ed Stadtmauer and Carl June and the group here at Penn. So normally, we wouldn't think initially of CD19 as being a typical target in multiple myeloma. Historically if you look through literature, CD19 wasn't thought to be expressed on the surface of myeloma cells. However, there is I guess a couple of hypothesis as to why we thought might work in myeloma that led to the initial trial. The first is that even though myeloma traditionally has been taught to be CD19 negative, there may be very low levels of CD19 of this molecule expressed on the surface of the myeloma cells. Perhaps even below the limit of our usual ability to detect it and we know that these CAR T-cells is reengineered immune cells are very sensitive to picking up very low levels of a molecule on a self surface so it thought perhaps that they might work even if there was very small amounts for CD19 on a myeloma cell surface. The second potential rationale is based on hypothesis that again is still fairly controversial that there maybe precursor cells that give rise to the bulk of the myeloma cells and a patient and that these precursor cells are actually CD19 positive that they are living in a population of the patient's immune that are called B-cells that normally are precursors to abnormal plasma cells and in this case, the thought is there might be a malignant myeloma precursor cell that expresses CD19 that gives rise to most of the myeloma and actually made a source of resistance to most of our commonly used therapies. The thought was perhaps if we could target that with this what we called CAR19 cells these T-cells that are specific for CD19 that maybe you could eradicate that myeloma precursor and help extend the duration of our mission. So with that rationale in mind, this trial was designed and basically it was specifically for patients who have previously been treated for their multiple myeloma with an autologous stem cell transplant and their disease had come back in less than 12 months after the transplant. This is a difficult situation patient's disease back in that short time frame often have more aggressive relapse and maybe difficult to get long-term disease control. These patients, most of them had undergone other therapies to try to keep their disease in control after they relapsed. And then when they come to this trial, their T-cells were collected. They were then engineered to express the new CAR specific for CD19. They could get additional myeloma therapy while that manufacturing process was going on because that takes three to four weeks. And then they actually came in and we're given another autologous stem cell transplant with a called melphalan which is our chemotherapy that we use for transplant. Then about 12 to 14 days later, they got their engineered CAR T-cells back. And then they were watched after that to see what the impact of that therapy was on their disease. Patients also had the ability if they wanted to or if their doctor decided to get lenalidomide (Revlimid) starting about three months after the transplanting T-cells went in. So that was the basic design of the trial. In terms of the results that were published, the paper that was in the New England Journal was really focusing on actually one of our first patients who were treated who was very refractory, resistant to therapies. She had a transplant previously and progressed within the first six months. She had, had almost all of the available myeloma therapies and was progressing on her most recent treatments. Somewhat amazingly, after she got her transplant followed by the CAR T-cells, she went into a complete remission which she had never really achieved with any of her prior treatment and that complete remission has actually been sustained now for close to 15 months without any evidence of these coming back. She has been getting Revlimid sort of on an intermittent basis a couple of times a week as her sort of only maintenance therapy right now. So that was the main focus of the paper just because her disease which was highly refractory and also had a lot of high risk cytogenetic features, this response to this last treatment was better than any of her prior responses and better than I guess we might have expected just from doing a transplant alone.

Jenny: I think I want to highlight this because I mean, I know you're very careful about how you speak about your result and things. I know you don't want to be inflammatory at all. But for me as a patient, I read the paper and it -- this is a patient with the deletion 17 with a 1q gain with 95% of plasma cells being myeloma cells, before she started the second transplant with nine other therapies that hadn't worked including a recent monoclonal antibody and you just say, "Wow." So I looked at the paper and it has this little chart where it shows the two doses of cyclophosphamide or whatnot that she got beforehand. Was that accurate?

Dr. Cohen: That's correct.

Jenny: And then as you as you gave the CAR T-cell -- and they kind of dipped and then went back up and then dipped and then went back up and then it dropped completely to the bottom. So it's so significant because nothing else was working.

Dr. Cohen: I agree. I think this patient has had an amazing response and it's incredibly exciting and incredibly promising. I think that's what got it published in the New England Journal. So I think you're right, our natural tendency is to be concerted and say it's one patient and to not try to as you say over-express the results here. But I think it certainly said something about the potential of this approach and the other thing that I think was interesting and just in terms of the hypothesis of why these might work was that Al Garfall who led the study did a very detailed analysis of these patients, myeloma cells and the other cells in her own bone marrow and really her myeloma cells, 99.9% of them did not express CD19. It was a tiny little percentage, 0.05% were CD19 positive. So the majority of her cells would not expected to be recognized by the CAR T-cell. There was only this very small amount there. And so it really begs the question of what was this therapy doing and how exactly was it working. Certainly the high-dose melphalan given before the transplant was probably critical here to get rid of the bulk of those CD19 negative cells. And then the question is, did the CAR 19 cells worked by eliminating that very small percentage of 19 positive cells as well as there were other CD19 positive non-plasma cells that were in the environment. And there are some data that are emerging that even normal CD19 positive B-cells or plasma cells that are not myeloma cells may have some immune suppressive effects in the setting of cancer and so possibly taking out those cells with the CART 19 cells may have helped and allowed the transplant to work better. And then of course, there is this whole hypothesis, did we take out the myeloma precursor cell and I think the answer is, we don't know. We are trying to investigate that and do additional studies looking at these cells. So I think that maybe I guess another promising way this might work if we can really demonstrate that those cells were present in the beginning and are no longer there.

Jenny: Maybe let's go back to the stem cell idea for a minute and let me just ask you, what does CD19 do and some of these proteins that are on top of the cells serve a certain function. So if there is something specific that they -- I know they were present in mostly on all cells that you're looking at leukemias and lymphomas. For these patients, they weren't there but or maybe the 0.05 that you're talking about. But what does CD19 do in general? I don't know.

Dr. Cohen: So it's interesting. We really don't know that the clear function of CD19 and it hasn't at least been demonstrated to have an important role in myeloma itself. It's more sort of a marker of B-cells which are the precursors to myeloma cells. But whether it actually has a function itself, I don't think is clearly known and we don't think it's actually critical for the survival of the cells because unfortunately we have seen in some of the Acute Lymphoblastic Leukemia, ALL patients. When their disease comes back, it has lost CD19 expression. So the cells unfortunately can learn to evade this therapy at least in the other cancers by dropping CD19. It may not be critical for the survival of the cell but rather just to a marker that you can use to identify the cancer cell. This is an important point because I think as we go forward trying to find targets to hit with CARs or antibodies that it may be useful to try to identify targets where it's really critical for the cancer cell to survive. So that cell can't just lose expression of the cell to evade the treatment.

Jenny: I think that's a really important point that you are making because I have heard that from other people before that the cells get smart enough to drop the signal so they say "well you can't attack me because I don't have the signal anymore" when they are going after a specific protein. In the leukemia and lymphoma work, did you -- I know you're probably digging through all your data. But was there a way of telling who responded to, like you said, the 40s or 50% CLL and 80 to 90% patients and ALL were responding to these treatments. Is there any way digging into why they're responding or I'm sure you are looking at that.

Dr. Cohen: Absolutely. The leukemia group here is definitely looking at that and David Porter who has led the CLL studies, they have recently published a follow-up paper just a couple of months ago with long term data on their initial 14 CLL patients. They really did try to see if there were any pre-treatment characteristics that could predict who was destined to respond and who is not and thy really did not find anything obvious that jumped out at least pre-treatment that could help you select patients. What they did find and this has been predominantly in our experience at Penn is that the longer the cells persist, the CAR T-cells after you've transferred them into the patient, that seems to be associated with better responses and more durable responses at least in the CLL and ALL setting. Those patients who lost the T-cells relatively quickly either had minimal responses or responses that really weren't durable whereas the first patient in CLL was treated over four years ago, you can still find these CAR T-cells circulating. The patient hasn't had any therapy since.

Jenny: So they are sticking around and still doing their job?

Dr. Cohen: We think so. We think persistence is important and those diseases. Now, it is interesting in the myeloma setting at least so far and again we just have these first ten patients that were published in the journal paper. The CAR T-cells don't seem to be sticking around indefinitely. Most of them between 60 and 90 days are starting to disappear and we're seeing actually the patient's normal B-cells starting to come back. That's something I think we're very interested in trying to see if we can improve upon in subsequent studies, other ways to get these cells to persist longer, are ways that we can maybe give multiple infusions of these cells, this initial protocol to patients were all written just to get the cells on time. So it's really a safety experiment. We really needed to make sure that we could give this safely after our transplant and I think we have shown that. But it's not clear. Even in the one patient who was described in the New England Journal paper who has this prolonged remission -- She does not have detectable CAR T-cells at least right now and that's different from the experience in the leukemias. Clearly, there are differences in these diseases that I think we really need more study to understand how they are working in different settings.

Jenny: Do you think that the persistence issue might be because the leukemia and lymphoma patients have more CD19 present cells? And so, I don't know, in Myeloma, they are not like a major target. And so they are persisting more in leukemia versus --

Dr. Cohen: I think that's one of the leading hypothesis and I think that certainly intuitively make sense. I think that's one possibility. The other is just, the setting that cells were given, they were given after stem cell transplant and they were given 12 to 14 days after the transplant. At that point, you are already starting to get recovery of the patient's white blood cells around day 12 or so and so there may have been competition with the cells that were already recovering perhaps effective ability to cells to persist. There may also be differences just in the bone marrow. It's called microenvironment. In myeloma, they may be less hospitable to these transferred cells than any other cancers. I think these are real important research questions that'll hopefully help us refine this therapy and understand how to use it. For now though, I think just kind of come up with strategies to see how we might be able to get them to persist either tinkering with the intrinsic signaling of the cells with the receptor itself or perhaps giving them as multiple infusions for patients.

Jenny: Let's talk about the administration of the CAR T-cells in your timing because I don't know what you did in Leukemia, Lymphoma but it sounded like you may have tried it immediately after transplant on other patients, is that correct? And then you saw more of what you can maybe explain as cytokine release syndrome or am I making that up?

Dr. Cohen: No, not at all. That's absolutely correct. Actually, while this protocol was being written and going through the regulatory approvals, there was a patient who was in dire straight with plasma cell leukemia. So the team was able to get compassionate use approval to treat this one patient even before this protocol was officially opened. That patient, the way it was originally given the T-cells were used actually, the ten-fold higher dose and was eventually given in the protocol that's described in the New England Journal paper and her T-cells were given earlier only day 2 after the stem cell transplant. What we saw was that when given really that early after the high dose chemotherapy and the stem cell infusion, there was a much greater expansion of these cells very rapidly. There was certainly greater toxicity and particularly the patient did have what's come to be called cytokine release syndrome which is now a well recognized complication of these CAR T-cells where basically the cells just start dividing and growing and multiplying so fast. As they're killing of cancerous cells, they are releasing cytokines or inflammatory markers if you will into the blood and this sort of revs up the whole body's immune system, you could think of almost having the most flu of your life, and at some case it could even mimic sepsis where the patients can become hypotensive, their blood pressure drops. They have difficulty breathing. They may have to go to the ICU. This can be very severe and so that particular patient did develop more of that type of syndrome as well as some neurologic changes and this also has been described in the leukemia studies. She did eventually recover from those. Her disease did go into a remission initially but then she ultimately progressed a few months later. So because of the toxicity seen with that initial patient, the subsequent patients were all treated later. The CAR T-cells were given 12 or 14 days after the transplant sort of separating it from the high dose chemo and also we gave a lower dose, a ten-fold lower dose of the cells. So far, at least in the ten patients treated, we have not seen this significant cytokine release syndrome. There has been one patient with very mild fever and cytokine release but no one has had any severe toxicities. I think by separating it out, we certainly made it safer.

Jenny: Oh yeah, that's great.

Dr. Cohen: We were learning more again. We don't know if 12 to 14 days is the best time. That's the time that was chosen and there may be more studies that are trying to look at that timing.

Jenny: What about the use of CAR cell therapy without transplant? When you look at the rationale to do the transplant first and then give it to her, what is your plan? I mean what are you trying to accomplish with the transplant as well?

Dr. Cohen: The reason that this particular study was done with transplant was really because of the target in this case was the CD19 that we really thought is only going to expressed on a small minority of cells. And so we thought we had to give it with something that had known activity against the bulk or majority of the myeloma plasma cells that may not have CD19 and especially needed to control, something to control the disease while those CAR T-cells were growing and expanding in the patient. And so that's the reason we really decided to give it with a stem cell transplant in the setting, the high dose chemo that's given before transplant we thought could hopefully kill off the large portion of the patient's myeloma cell and also give time to those CAR T-cells to expand and grow and hopefully do their work. It's mostly now been tuned in a number of studies that giving some type of chemotherapy before you transfer in T-cells and the patient does help those T-cells expand and perhaps survive. That was really the two-fold reason for it. We felt maybe it's to do something to at least maintain some control the disease and thought there may be a benefit of giving it with transplant. That doesn't mean you have to it with transplant then as I think that we'll talk about later are our next trial that we have just opened with a different CAR is going to be without transplant. But I think there is a reason to explore both avenues.

Jenny: Okay. Well that's terrific. Before we move on to another question that I have, do you want to talk about the other results because you have this very dramatic result. But that's one patient and then you have very positive results with several other patients, do you just want to share what those are?

Dr. Cohen: Absolutely. It's still very preliminary but we have treated ten patients and this was described in the paper as well. In addition to this first patient who has had a really dramatic response, we have had at least one other patient so far who has had what we call the remission inversion meaning the time they got in remission after their transplant was actually longer than the time they got off to their first transplant. That's something we really don't see very often in myeloma. Usually when you repeat the same therapy, it can work again but many times it doesn't work for quite as long. That also has been very encouraging. So that patient hasn't gone into complete remission but had a very good posture remission and was again progression free longer than she was after her first transplant. We've also had several other patients who have had partial responses right now and remain progression free although again it's still relatively early. Some of these patients were only two or three months out from getting their therapy. And then unfortunately we have had at least three or four patients where it really didn't seem like it worked and they did have progression within the first few months through the therapy. Clearly, there is obviously still more we need to do and more room for improvement.

Jenny: Well in a past show, one of the doctor said that when you're working with these immunotherapies, there are kind of windows of opportunity to use them. Do you see that as well or and what do you see as the ideal window for something like this?

Dr. Cohen: I think as with most therapeutic cancer, new treatments are often first done in patients who are very heavily pre-treated. Especially for immunotherapies, that may not be the optimal time because the accumulative chemotherapy that they've had before may take its toll in their immune system and therefore, if you are trying to utilize that immune system, it may not be the optimal time. I think ultimately if safety is demonstrated in a larger population of patients, we would like to move earlier in the treatment course and so you could imagine perhaps if this is going to be done in conjunction with transplant, maybe you could do this even a first transplant rather than a second transplant perhaps in high risk patients who were high genetic risk or other factors that you know may put them at higher risk for a relapsing quickly after the transplant. The hope is that, you know, again as we get more of a safety profile and feel more comfortable using this that it would start to be moved up earlier.

Jenny: Okay. That's great. And then while we were talking about it a little bit earlier, let's just go back to that about the stem cell clones and because it may -- the ones that your second hypothesis was that it could be that the CD19 target might be killing off the stem cell clonal cells and you talked about -  I had this written down so I would not forget it. But in your paper, you talked about non-neoplastic CD19 cells. Are those just cells that don't have that CD19 target or what are those? And if this is related.

Dr. Cohen: Sure. That was almost like that third hypothesis. These are cells that they do actually express CD19 but they don't really appear related to the myeloma clone in any way. They are not expressing the same immunoglobulin or antibody on the surface of the cells that the myeloma cells do. They may just be normal or at least normal appearing B-cells but they may be subverted in the environment of a cancer to now be immune suppressive. This has been shown at least in a couple of different cancers, more in solid tumor so far that you could get infiltrations of these CD19 positive cells into the environment around the tumor where they act as immune suppressants and they block the ability to T-cells to get in. Again, this sort of I think possibly a third hypothesis not just targeting the main myeloma cells, not just targeting the possible myeloma stem cell of precursor but actually just other bystander CD19 positive B-cells that are in the environment and whether those may be exerting an immune suppressive effect and you're clearing those out that allows your therapies to work better. I think this one is sort of the -- I guess most hypothetical right now with the least amount of data. It's really extrapolating from some of the solid tumor data. But I think that was a point that was just brought out that that was another population that was seen in a bone marrow of this patient that was potentially cleared out. So that was referred to these non-neoplastic CD19 positive cells.

Jenny: Oh, so they might just be there working treatment and you're saying let's just clear the decks and move it forward.

Dr. Cohen: Exactly. That may be at another way that this is working separate from the whole stem cell hypothesis.

Jenny: Okay. With the stem cell hypothesis, we did a show a very long time ago where we talked about that. It sounded like that was the ultimate target and I know maybe you want to explain the controversy to us as patients and how we find out, is a detection there to be able to even detect at this point? What we can even with all the new MRD testing and all that, how do you determine where the stem cell clones are if they are there and how do we dig deeper into this disease, I guess?

Dr. Cohen: Sure. It's a great question and as you mentioned, it is controversial. There are those who really believed that myeloma stem cells exists and there are some that believe that they really have not been conclusively proven to exist and what the I guess people are talking about is that as you know when Myeloma patients are treated, we're usually very successful in the beginning at getting rid of the myeloma cells and we can get there spiked down and get them into remission but the disease in evidently relapsed unfortunately in most patients. The thought perhaps is that there were some chemo resistant cell that gives rise again to the entire tumor population of myeloma cells even after the patients have gone through their treatment and appeared to be in a great remission. And so people have been trying now for years to try to identify where is that cell and is that cell truly what we call a stem cell. So that's capable of what's called self-renewal indefinitely that is just very difficult to get rid of and can just continue to divide and give rise to the rest of the tumor. And so there have been studies now dating back over 15 years suggesting that the myeloma stem cell, if it exists, may not have the classic features of other myeloma cells. There is a marker called CD138. That's usually expressed on myeloma cells and yet in some original studies done by Bill Matsui at Hopkins and others, they found that you could actually recapitulate a myeloma in a mouse not using the CD138 positive cells, the bulk of the myeloma cells but a small population cell that didn't express the CD138 and expressed more B-cell features CD19. So that was the first set of idea that perhaps CD19 might be a marker for a myeloma stem cell. However, subsequent papers did not reproduce those results and there has been this back and forth controversy really wondering whether there is a true myeloma stem cell or not. I think what is clear at least in most recent studies is that there is something called plasticity in the markers that are on the surface of myeloma cells that myeloma cells can look one way early in a patient's disease. And then after a patient has been treated, there is actually an evolution and the myeloma cells can acquire additional features. In some case, that features include more of a B-cell or CD19 positive phenotype and that's often associated with being more resistant to treatment like bortezomib or velcade or treatment with chemotherapy. So the treatment resistant cell may be a CD19 positive cell. It's a little complicated to explain and I'm not sure if this is helping or not. I think regardless of whether you believe these are truly stem cells that are immortal and can give rise to everything or they are just a set of reservoir of drug resistant cells that happen to express CD19 and the cells are just interchanging back and forth. Either way, I think there is rationale to try to target these cells. It makes sense to potentially hit the disease with more than just our current therapies but think about ways to perhaps hit these myeloma precursors that may be more resistant. So this is one approach to doing that and hopefully there will be others as people seek to understand a little bit more about them.

Jenny: Okay. Well that takes us into a great topic of combination therapies and maybe you want to just give us some insight about where you are headed next. Now that you have done this with leukemia and then lymphomas and you have success, where are you going next for myeloma patients?

Dr. Cohen: Sure. I think with the CAR19 that's still a bit up in the air as I mentioned, one idea would be to take it earlier, patients perhaps getting a first transplant but with a high risk of relapse. That would be one idea and then the other is really to look at other targets that might be expressed on a larger proportion of the patient's myeloma cells and therefore potentially could be used by itself without the transplant and so that is certainly where we have started to go next and we have just recently opened a second study using a different CAR that's specific for a molecule called BCMA or B-cell Maturation Antigen. This has been identified as being expressed on normal plasma cells but also very highly expressed on malignant plasma cells or myeloma cells and seems to be expressed in almost all of the myeloma cells that have been tested both on patient samples. Importantly, it's not really expressed on a large amount of other cells in the body. It's on some mature B-cells that otherwise seems like a relatively safe molecule to target. Based on some early free clinical studies and mouse studies, again the group here led by Carl June and Mike Malone and others in collaboration with Novartis have actually developed a CAR against BCMA and so we are now just starting a study where we're going to be giving these BCMA specific CAR T-cells in patients with relapsed refractory myeloma. Again, I'll state we're certainly not the only ones doing this, the group that National Cancer Institute has been doing this as well and has a study targeting BCMA and I know there are others in development as well. But that particular study is going to be again for patients who have multiple myeloma that has relapsed or come back after two or three -- at least two or three other lines of treatment. But this one importantly is not involving a stem cell transplant. So the first group of patients are just getting the T-cells alone and we are assessing them again just for safety and then if that does appear safe, there are additional cohorts that make it the cells in combination with Cytoxan, a chemotherapy agent that we think can help the T-cells expand. So that's the current study and we're just getting started with that now.

Jenny: That's great to hear that you have another trial coming up. When does that open or is it already open?

Dr. Cohen: It just opened actually in the last couple of weeks. So we haven't treated anyone yet but we are sort of getting on their way at this time.

Jenny: Oh, okay. Well that's great. Well we'd be happy to show that on our website. So in CAR T-cells, this is an engineering process and when you look at companies that are typical drug companies, they are providing a medication. But this is an actual engineering process, right? So someone like the Novartis or someone else might, they are working on the engineering process. That's what they are providing?

Dr. Cohen: The process itself was generally developed and perfected in the individual academic institutions. I think what the companies are doing are really trying expand that to a large scale production because I think that's probably the only way its ever going to get out of just one or two institutions and get to be widely available because they have the ability for distribution to do that. I guess it's a partnership. They are taking I guess what was developed to these institutions and then are going to try to scale it up and actually try to provide it and make it available like a drug and again I don't honestly it know quite yet how the logistics of that are going to work but I know at least in leukemia that we have started some multi-center studies where these cells are not just given to people at Penn but are being manufactured and shipped to other sites where they can be given at the local center. I think that's the ultimate goal is that a patient will be able to go to any of their local transplant centers or myeloma hospitals have their T-cells collected, shipped out, they get manufactured with the CAR and they get shipped back where they can be administered by the local physicians so that patients won't have to travel just to one site for this. I think that's the ultimate goal but how close we are to that I guess I'm not sure yet.

Jenny: Well that's what I'm sure they are working on quickly.

Dr. Cohen: Absolutely.   Jenny: I know that there are other CAR T-cell targets and you were talking earlier about just different B-cell markers like CS1 and BCMA. Why did you choose BCMA over another one?

Dr. Cohen: It was primarily because of the expression pattern seemed most favorable in terms of a safety profile. I think the one of the things about choosing a target in making these cells is that these cells can be very potent and once they are in the patient, if they see their target, they just start to grow and grow and it can be -- You just have to be very careful I think about where you are going to target because if other cells are expressing that same target, the T-cells could start to attack them and then that could lead to collateral damage. So BCMA seemed to have a favorable expression profile and that it was really largely expressed on plasma cells, thinking of malignant plasma cells. They get a small subset of B-cells but really not on lung cells or blood vessel cells or intestinal tract or other places where you think you might get toxicity. So we thought it might be a good way to target the plasma cells and kill those off and then potentially not have more off-target toxicity. It's certainly not the only target and you mentioned CS1 also known as SLAMF7 and that one certainly is also being explored by several centers and the group at Ohio State is published about CS1 targeted CAR T-cells and I believe working on a clinical trial as well. And there were others that I know were in clinical development. There is a group in China that's doing a CD138 targeted CAR, a group at Baylor is looking at a CAR targeting kappa light chain, which is expressed in 2/3 of myeloma patients. Again, hopefully there'll be a lot of these out there and will be able after hopefully a year or so to have some at least preliminary data on multiple approaches to get a sense of what might be safe and efficacious.

Jenny: An extension of that. If you look at the CD19 and you say, well part of the purpose is that it might be just clearing things out so other treatments can work. I know you probably can't answer this right now but could you hypothetically use the CD19 CAR with the BCMA CAR with a Kappa Light chain CAR and just say okay, we are going to go for our targets and you probably test for safety I'm sure before you do this.  I mean when people tell me that the average patient has five different myeloma clones on diagnosis, then as a patient, you are just saying okay just kill it all, right? Kill it all.

Dr. Cohen: Right. So I think that actually makes really great sense and I do think there will be studies that are combining these together. And so I think once you show you have safety of each one individually, then you can start to come up with ways to use them together and I think BCMA and CD19 make a lot of sense because they may potentially be hitting different populations of cells that could actually synergize and may do greater eradication of the different clones. Again, I think it's all theoretical right now but I do think we'll start to see combination CAR cell therapies. As the technology improves to manufacture the vectors, you could even imagine even in one cell having receptors that can target two different molecules in the same cell and then you can potentially make it easier just to put in one group of cells with different markers. I think there is a lot of opportunity here, to combine with CAR T-cells together and then also certainly combining with other myeloma therapies, other immunotherapies, I think all of these things are probably going to be coming.

Jenny: Yeah, that's my next question. You have the monoclonal antibodies that are almost or getting close to being approved and then you have the current drugs that still have anti-myeloma effect. So how will you as a doctor decide what to use and when -- Sometimes you'll learn more from things that don't work than things that do and is there any learning that you can garner from the people in the CAR T-cell trial where it didn't work initially that you might want to combine with something else.

Dr. Cohen: Yes. So in the ten patients so far, I think we're still analyzing that data and trying to understand who is likely to respond and who is not and with a small number of patients that maybe hard to tease that out but I don't think there is anything that jumped out quite yet. Again, one thing that we mentioned is the cells aren't persisting quite as long in the setting as they were in the other cancers and so I'm trying to enhance the persistence of the cells I think would be one thing. Certainly we know that the immunomodulatory drugs, lenalidomide and pomalidomide, the B-cells have actually T-cell, the ability to stimulate T-cells. And so that's sort of a logical combination to potentially use with these cells and then I think there is a whole host of novel immune checkpoint inhibitors that are being tested in other cancers but also being tested in myeloma particularly PD1 inhibitors that again may enhance the ability of T-cells to be effective and to live longer and so that to me also sounds like a natural combination. And a lot of this I think is being tested in the laboratory right now. So our scientific colleagues are really going to help guide us here because they may be able to test multiple combinations and then we can take the ones that are most promising and bring that to the clinic and do clinical trials.

Jenny: How do you shorten up that time frame? I mean it's so difficult. I think for you as a researcher to say okay I have to test safety first, obviously, and then I tested a larger group of patients and then I have my phase three trial. That all takes time and there are so many exciting things happening, are there different strategies that you can see that might shorten up that time frame especially all these new immunotherapies?

Dr. Cohen: It's a really great question. It's a big problem not just in myeloma, in all cancers I think is -- patients obviously desperately need new treatments and we want to try to get those treatments into the clinic as quickly as we can but obviously we need to do it so safely and make sure that what we are doing seems safe. I don't know that I have an easy answer. I think that what's happening with the CAR T-cells where there is an industry partner that's starting to get involved fairly early on with the academic centers may help because I think that allows it to scale up faster than probably one center could do on its own so that model I guess which is still relatively new but is happening now I think with a couple of different centers may allow this to become more widely available, at least the CAR T-cell technology. And then in terms of combining with other agents, some of that is related to just being able to get the drugs and get companies being willing to combine their drugs together but I do think there is a little bit more willingness especially with these immunologic agent and say the PD1 inhibitors seem to have a pretty good safety profile and so I think there has been willingness to combine it together and I know of a number of studies of those antibodies going on in myeloma right now combined with lenalidamide or pomalidomide. I think again as we get safety data from those combos, you could imagine, now, maybe I can add a CAR T-cell in with that and see if I can really get a great immune response against the myeloma. I think that'll happen. I know it never seems fast enough but I do think we are trying to move these things into the clinic as quickly as we can.

Jenny: Well, I know you are working hard. Everyone is. We're just so grateful that there are such brilliant people like you out there thinking about myeloma everyday, so we are really thankful.

Dr. Cohen: Thanks.

Jenny: I have one final question before I open it up to caller questions. I know that I started this series with the intent to help patients enter clinical trials so that they could join in greater numbers because the number of people that are joining myeloma clinical trials is very small. It's like 3 to 5%. From your perspective as a researcher who is trying to move things down the road at a faster pace, do you have any words of advice for us as patients about clinical trials?

Dr. Cohen: Yes. So obviously I think clinical trials are crucial and critical to advance a field and help get these new treatments to patients. And so I think it's always worth asking your physician if there might be a clinical trial available when I'm here she is talking to you about your initial treatment. There are all sorts of clinical trials from phase 1 trials that are really new that might only be available to specialize center all the way up to phase 2 or 3 trials with agents that have more proven track record. It might be available in a general oncology practice. And so I think the patient as you, I'm sure have always said, patients to be their best advocate and so when asked if there are trials available and if a doctor doesn't know, then you could certainly go on websites for any of the academic centers in the region and they usually have an easily searchable list of what trials might be available. I'm sure your website will also have links to different places that may allow patients to find trials. Clinicaltrials.gov is a little bit tricky sometimes in searching to try to identify a trial that might be right for you. But if there is one you are looking for there, there is almost always at the bottom of clinicaltrials.gov page, a contact number for that particular study that you can reach out to. I think all of these hopefully can help you find the trial that might be right for you.

Jenny: Okay, great. I want to mention too that we just added a new feature to our site and we're partnering with a group called Spark Cures and they have created a very simple clinical trial finder that if you go to a Myeloma Crowd site and you click on "Helpful Links" , (that's a top link) will say find a myeloma clinical trial. So they have all the open myeloma clinical trials and you can search for them based on the type of therapy or based on your disease state and is a very simple tool. It's a really great tool.

Dr. Cohen: That sounds great. I think that's exactly what's needed.

Jenny: Dr. Cohen, we are just so grateful. I would like to open it up for caller questions. So if you have a question for Dr. Cohen, please call 347-637-2631 and then make sure you press 1 on your keypad. Go ahead with your question.

Caller: Hi. Thank you for taking my call. So I'm a myeloma patient. I'm almost four years out. And I just got into a clinical trial about a month ago, so we're not sure how that's going yet but we'll know soon and I just want to make an overall comment that I almost had to beg my doctor to get into a clinical trial. So for all of you patients out there, don't give up. A lot of times and I'm not sure why there are many physicians or treating offices that are very hesitant to try a clinical trial. So I went in armed with many clinical trials that I thought might be good for me and I started rattling them off and then I got into one. With that in mind, I am wondering how we would go about. I'm sure that there are many patients who are interested in these clinical trials that you have been discussing this afternoon and how would we go about finding them and what is the I guess the commitment where would one need to travel, how much would that cost if your insurance doesn't cover it, can you give us a little bit more information about that?

Dr. Cohen: I can say, I think I'm not supposed to actually advertise or recruit for our trial on this forum, so all I can really say for the Penn study at least is that you can go on clinicaltrials.gov and look up CAR BCMA for myeloma and then there is contact information there that you can use to call and then somebody can get back to you and give you information about the study. Most of the CAR T-cell trials are fairly intensive in terms of time commitment in the beginning and again it may vary from trial to trial but most of them, you need to be in the location where the T-cells were given for a few weeks after the study just because they are very close monitoring and follow-up for safety and after that, it becomes less onerous. Other trials, I can think it really just depends on the nature of the study. There are some studies now just for the oral agents where you may only need to be coming in once a month where other ones where its intravenous or it's an earlier phase study there may be more time commitment. In terms of reimbursement that also it also is study dependent. Some studies, there is built in some cost or travel expenses and some are not I think unfortunately just have to ask that the coordinator for that individual study. I know unfortunately it's not easy as it should and I think these the program that Jenny described for her website I think is going to be very helpful because it might be one area where you can search and then I think once you find the trials that sound interesting, you just have to reach out individually to each study and talk to the coordinator there and they can give you more details because it does vary from trial to trial.

Caller: Thank you. I mean it's sometimes disheartening as a patient to be navigating, trying to get into your own different clinical trials and we're not even feeling that great. So someday hopefully it will be a little bit easier but thank you for your time. It's been a great interview.

Dr. Cohen: Thanks for your call.

Jenny: Okay, thank you so much.  Go ahead with your question.

Caller: Hi, Doctor. I just wanted to ask you how long do you think it will be until this type of treatment is available for newly diagnosed patients?

Dr. Cohen: For the CAR T-cells, I do think it's going to be a little while to be honest just because there are risk and toxicities associated with these approaches and there are so many treatments I do work right now in Myeloma. So for newly diagnosed patients, I'd be a little hesitant to try something like this that hasn't yet been proven. But my hope is if we do have more data in another year or two, and especially if it seems safe, then you'll start to see studies going forward and I guess less heavily pre-treated patients. I don't see that at least right in the near future right now at least until we have more data.

Caller: Thank you. I appreciate you taking my call.

Jenny: Okay, great. A follow-up question I have that I think will be our last question is have you found any strategies to minimize any potential side effects from the treatment?

Dr. Cohen: One thing we have learned in at least with Cytokine Release Syndrome and this has been learned in all the leukemia studies is that you can actually treat that Cytokine Release Syndrome with a drug called tocilizumab which is actually a drug approved for rheumatoid arthritis. But it basically blocked signaling through a particular receptor called the IL6 Receptor and IL6 is a cytokine that's very involved in this cytokine release syndrome and if you can block it with that drug, you can get significant improvement and it doesn't seem to affect the ability of the T-cells that don't work. So that's been one very useful lesson that you can learn from the early studies and that's something that we certainly use when we start to see severe cytokine release in our patient that we can usually abrogate it with that particular drug.

Jenny: Okay, great. Well Dr. Cohen, we're just so grateful that you joined us today. We're thrilled to learn more detail. We're very excited about your results and we wish you just Godspeed as you keep working.

Dr. Cohen: Absolutely. Thanks again for having me on. I really appreciate it.

Jenny: Oh, well we're just so thankful. Keep going.

Dr. Cohen: We certainly will.

Jenny: Okay. Thank you so much.

Dr. Cohen: All right. Take care.

Jenny: Thank you for listening to Myeloma Crowd Radio and the new ways that patients can help support the discovery of cures for the Myeloma Crowd Research Initiative. We encourage you to become involved.