Thanks to our episode sponsor, Takeda Oncology Dr. Alfred Garfall, MD, MS University of Pennsylvania Interview Date: July 21, 2015 Summary Training CAR T cells to seek and destroy specific proteins on the surface of multiple myeloma cells (and the cells themselves) are an exciting new area of study. Dr. Alfred Garfall explains how the work began in leukemia and lymphoma and is now being tested in multiple myeloma. It is a strategy that hails from the same philosophy as the allo (donor) transplant - embolden the immune system and arm it with enough power to fight off the myeloma. Dr. Garfall of the University of Pennsylvania describes how CAR T cell therapy works and how the first target of CD19 was used in combination with autologous stem cell transplant. Used for patients who had already relapsed after transplant in a clinical trial of 10 patients, he shares the mixed results to date with one del 17 patient that never achieved complete response (CR) in the first transplant, achieving it in the second transplant with the addition of CAR T cell therapy. Dr. Garfall explains how this is completely personalized treatment and how additional protein targets are now being considered. Dr. Garfall shares the growing interest in additional targets and an upcoming clinical trial targeting BCMA. The Myeloma Crowd Radio Show with Dr. Alfred Garfall, MD, MS
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m you're host Jenny Ahlstrom. We’d like to thank today’s episode sponsor Takeda Oncology for their support of Myeloma Crowd Radio and myeloma patients as a whole. Now, this is our 58th show. As you know, during April and May we had shows about the MCRI. We are in the voting process for the Myeloma Crowd Research Initiative and the final projects will be named in mid August. We would like to encourage you to take advantage of having a little more free time this summer. Help us get ready by creating your own fundraising page. You can do that on https://mcri.myelomacrowd.org and click on build a team. Summer is also a great time to host events that are outdoors, like a neighborhood bake sale. It’s also a great time to keep your kids busy by helping them volunteer their time for babysitting or yard work and donating the proceeds to the MCRI. This summer our family will be hosting an outdoor movie and end of the year Summer Salsa Party. We decided to have a service auction and we encourage you to do something similar. Now, today we are very privileged to have with us Dr. Alfred Garfall of the University of Pennsylvania. So welcome doctor. Dr. Garfall: Thank you very much for having me Jenny. It’s great to be here. Jenny: Please let me introduce you before we get started. Dr. Alfred Garfall is Attending Physician of the University of Pennsylvania Hospital and Instructor for the UPENN Perelman School of Medicine. He’s a reviewer for the Journal of Molecular Diagnostics and has received awards including the Alpha Omega Alpha Medical Students Research Fellowship, Distinguished Resident Mentor Award, Brigham and Women's Hospital Finalist and Finalist for the ASH Research Training Award for Fellows. He’s a member of ASH and ASCO and he’s a popular lecture/speaker on an Anti-CD19 CAR T Cell immunotherapy for multiple myeloma. This week will be a busy week for him and tomorrow he will be participating in a Tweet chat about CAR T-cells, so I encourage you to also participate in that. Dr. Garfall, with that; you have been participating in this CAR T-cell research for quite sometime even before myeloma. So maybe UPENN has really been on the cutting edge for this type of research. So maybe you can give us a little background about how UPENN started with this and how the results that you saw in leukemia and now, how you are bringing it to multiple myeloma?
Dr. Garfall: Sure. I should just make one small correction. I’ve actually only been involved with this in any serious way with multiple myeloma. And then much of the work, this field goes back along ways and a lot of this work has been done clinically here at PENN and started I think in the 2008, 2009 range. But of course the ability to do clinical trials with this technology is the result of many, many, years probably over 20 years worth of work in basic immunology and in laboratories here at PENN it’s been led by Dr. Carl June and a large group of investigators that work with him in the laboratory. There have been other centers who have contributed in major ways to the development of this technology and the way that we know it today which is as a technology that can be taken into the clinic to do clinical trials. So, I think there were several very small studies with CAR T-cells that predated the one that was published by University of Pennsylvania in 2011 in CLL by Dr. David Porter and Dr. Carl June here. I think everybody recognizes that that publication in 2011 was probably the first of the sort of modern era of CAR T-cell therapy for cancer. And it was the first time that really long-term remissions were induced with safety. I’ll be in just a few patients that were reported of that initial report in 2011. And this work has been basically on going here at PENN since then and has expanded in from the initials studies and kind of Chronic Lymphocytic Leukemia to Acute Lymphoblastic Leukemia, Non-Hodgkin’s Lymphoma and now just over the last year in multiple myeloma.
Jenny: We’re thrilled that it’s moving to multiple myeloma. Maybe you can give us a little bit of background about what work you’ve done to start using it in multiple myeloma. But maybe before that you can just a give us a brief overview. We’ve have some interviews on CAR T-cell but I think for those who haven’t listened to those, it would be beneficial for you to take a little bit of time to explain what those are and how CAR T-cell therapy works?
Dr. Garfall: Sure. T cells are immune system cells in your body that have the ability to kill other cells in your body if they’re infected with the viruses or if they start to become cancerous. And we know that the immune system and T Cells are able to naturally stamp out small cancers before they become real problems for patients, but unfortunately in patients who have developed a cancer by definition, the immune system has failed to control that cancer. So investigators for a long time for decade have been trying to figure out ways to kickstart the immune system to allow it to go after cancers that have been established in patients. So CAR T-cells are just one mechanism or one method to do that, there are actually a real number of really promising modalities within the realm of immunotherapy that are really paying clinical dividends as we’ve seen the last few years. I think the one that people know the most about right now is Anti-PD1 and PD-L1 therapies, but certainly CAR T-cell are one of the very promising modalities for immune therapy for cancer. The idea of CAR T-cell is that, every T cell in your body or almost all T cells have an ability to recognize another protein and another cell intrinsically within them but every T cell is different in this regard. What you are able to do with CAR T-cell is take a bunch of T cells out of the body that may or may not recognize the cancer intrinsically and by genetic engineering give them the ability to recognize a protein on the surface of cancer cells. And that’s what the CAR is, a chimeric antigen receptor. It’s a genetic modification to the T cell that allows the T cell to recognize a cancer cell as though that were the natural target for that T cell. So that way when all these cells are infused back into the body after they have been grown outside of the body and expanded, they can go into the body on reinfusion and recognize the cancer cell and kill them. And so, in addition to the CAR T-cell by the genetic modification to the cells that makes them CAR T-cells, within that genetic modification in addition to putting that molecule on the surface of the cell that gives you the ability to recognized the cancer cell, also built in to this whole process are mechanisms to activate the T cells so that it’s active when it goes back into the body and is able to kill other cells and also allow that T cell to divide and expand in the body and also to persist. So that at the end of this process in addition to killing off a bunch of cancer cells, you get some kind of long term immunity against the cancer and that seems to be important reason, some of the experience with CLL and ALL to be important for making this a really durable remission.
Jenny: That’s a great explanation thank you so much. Can you tell us a little more about the results that were found in leukemia why the group has thought this is so promising? What was so exciting about that?
Dr. Garfall: Sure. The initial results in the first study done at PENN was in patients with Chronic Lymphocytic Leukemia and this study was done by Dr. David Porter in collaboration with Dr. Carl June’s group and the rationale for starting a Chronic Lymphocytic Leukemia was first is, every CAR T-cell needs a target and in this case they use CD19 as the target, which is a target that expressed on most B cell malignancies and Chronic Lymphocytic Leukemia along with the Acute Lymphocytic Leukemia and other Non-Hodgkin's lymphoma - other hematologic cancers are B lineage cancers that express CD19. And I actually don’t know all the details about how they selected CD19 as the first target but it was a good target to choose because it was fairly restricted and its expression to cancer cells and to normal B cells. It turns out that the concern of course with the target selection is toxicity. So if you infuse a bunch of cells that have the ability not only to recognize cancer cells but normal cells you can get a lot of toxicity. And it turns out you do get elimination of normal B cells with anti-CD19 CAR T-cell but that’s actually fairly well tolerated. Patients can live without their B cells but are at some increased risk of infection but that can be dealt with amino globulin infusions. So it was a target that was very well characterized and expressed on a large range of B cell malignancies and it was also one inso far it was expressed in normal cells that the loss of those cells could be tolerated. It was a good target to start with and one that they had done a lot of work in the laboratory using mouse models of leukemia to test and find tune the design of the CAR T-cells. I believe that’s why those diseases were chosen as the first clinical trials to try this in humans were diseases that were CD19 positive. Why CLL versus ALL, I’m not actually sure why CLL was chosen as the first disease. But in short order after some of the promising results were obtained with CLL ,the team here went on to design studies in Acute Lymphocytic Leukemia and in Non-Hodgkin's Lymphoma. And those studies have also been popping up in some of the other sites around the country and indeed around the world that are leaders in this technology. Like the National Cancer Institute and Memorial Sloan Kettering Cancer Center and Baylor College of Medicine, all of those groups have basically worked in parallel doing studies in these diseases. The most of them have chosen CD-19 as the first target but now with some experience starting to move in the other targets for both other hematologically malignancies like multiple myeloma for which CD19 may or may not be a good target and then of course other solid tumors like pancreatic cancer, brain cancer where we have some studies ongoing at PENN using other targets for those diseases.
Jenny: Perfect. Well, do you want to talk about the target for a minute because you mentioned how you can target different proteins? The expertise it sounds like it was CD19 in leukemia because it had that present probably as a single target. In myeloma can you describe why you’re going after CD19 and if there’s an advantage to doing just one target vs. multiple targets?
Dr. Garfall: Yes, sure. The study that we have been doing for the last year has been using these anti-CD19 CAR T-cells - the same CAR T-cells that Dr. Porter has been using in CLL and Dr. Fry here has been using an ALL and Dr. Groth has been using a pediatric ALL. These are the same anti-CD19 CAR T-cells we’ve been using in multiple myeloma. And multiple myeloma was not initially thought about as a target for anti-CD19 CAR T-cell because most multiple is considered CD19 negative. In other words, if you look at patient with multiple myeloma by standard techniques, you don’t really find CD19 on multiple myeloma plasma cells. So it’s a little bit of a round about story how we ended up deciding to try the anti-CD19 T cells in these patients. So the story starts with several collaborations between my mentor, Dr. Edward Stadtmauer, who’s the head of our multiple myeloma program here at PENN. He had actually collaborated with Dr. Carl June on a number of studies that predated the clinical use of CAR T-cell using other types of cellular immunotherapy, other manipulations of T cells, genetic engineering, vaccine priming and did several studies in multiple myeloma patients over the last -- I think they started in the early 2000s with this and published a few papers over the last 10 years, reporting results from the studies. There is a nice collaboration already in place between Dr. June’s group who is developing the CAR T-cell and our myeloma program here and so when they started doing work in CLL there is a natural tendency to try and of think ways to incorporate that work into multiple myeloma. Meanwhile, as I mentioned, CD19 is not an obvious target in multiple myeloma but there is this sort of messy string of reports that have been published over the last 20 years or so suggesting that either a small portion of myeloma cells or other CD19 positive cells that kind of live among B cells in myeloma patients might be part of the multiple myeloma and contribute to its ability to grown and develop and resist therapy. Even though in most patients the lion's share of myeloma cells, the plasma cells you see under the microscope and the bone marrow and the cells that are turning out, the immunoglobulin and causing the bone damage - even though most of those cells maybe CD19 negative, there might be a small population of mother cells or queen B cells you might call them, that are really important for perpetuating the disease in response to therapy and promulgating drug resistance. That’s kind of confusing literature and some studies have suggested that getting rid of these cells, getting rid of these CD19 positive B cells or these small subsets of plasma cells that express CD19 might be an effective way to treat multiple myeloma ,but it had never been really been tested in humans. There are a bunch of mouse studies that looked at this in some studies examining patient’s plasma cells in the laboratory but nobody had ever really subjected this to the test of clinical trial. So we’re really interested in CAR T-cell from myeloma. The newer targets from myeloma weren’t available at the time when we started thinking about this idea. But we did have available here at PENN, these anti-CD19 CAR T-cells that were showing to be effective at least eliminating CD19 positive cells and patients with CLL and ALL. So we started thinking about a clinical trial design that would just put a small number of patients with very, very high-risk disease and not many standard therapy option just give this idea a try that had shown some interesting results in the laboratory over the years, that maybe getting rid of the small population of the CD19 positive cells might be effective. What we did was, we didn’t think that just infusing the CAR T-cells against CD19 would work in and of itself because we only thought that maybe a small portion of the myeloma had CD19 on it. So what we did was couple the infusion of the CAR T-cell with another therapy that’s very effective in getting rid of the bulk of plasma cells in patients and that’s autologous stem cell transplantation so high dose melphalan and autologous stem cell transplantation. And that was a convenient companion therapy to the CD19 CAR T-cells because it turns out, that before you give someone CAR T-cells you really should give them a little bit of standard chemotherapy first because it helps the CAR T-cells when they’re infused into the patient grow and expand and also last over the long term. So we thought we actually have two things that this high dose melphalan and autologous stem cell transplantation can do here. Maybe I can get rid of a large portion of the plasma cells that might be CD19 negative and also create an environment where when we put in the anti-CD19 CAR T-cell that can grow and expand and persist. And in the process get rid of some of the small population of CD19 positive cells that might be part of the multiple myeloma but resistant to traditional chemotherapy. And see if we can with those two therapies together get longer responses that we would expect with just doing the transplant alone. So, that’s a round about and complicated answer but I hopefully explained a little how we ended coming up with the trial design that we did combining anti-CD19 CAR T-cell with auto transplant for myeloma.
Jenny: That’s great. It sounds like you’re going to debulk the melphalan and then follow it up to see if you can wipe everything out. So I think it sounds great. So can you tell us a little bit more about the study, is this study still open and how many patients do you want to have in it total? Are you recruiting for it?
Dr. Garfall: So we’d actually just today infused our 10th patient on the study. And the study was designed as a 10-patient pilot study just to kind of see what kind of results we saw with the small group of patients. So we opened the study and infused our first patient last July and over the course of the last year we’ve now infused 10 patients with myeloma with anti-CD19 CAR T-cells and we are thinking about expanding the the study slightly with some modifications to make some improvement based on our results so far. But we have not made final plans for that. We’re still waiting to hear about some feedback to the protocol amendment from our regulatory agency and also see about funding to treat a few extra patients. So, right this minute we are not recruiting patients for the CD19 CAR study. We are going to be opening next month and this should pop-up on www.clinicaltrials.gov in the next month or so. This will be a CAR T-cell study that will be lead by Dr. Adam Cohen another one of the myeloma investigators who focuses on immunotherapy in our group and that will be a study using the CAR T-cells against another target called BCMA which is the same target that the NIH is currently doing a CAR T-cell study with. So we’re not accepting patients for the anti-CD19 CAR T-cell we should have CAR T-cell open for the myeloma patients in the next month or so.
Jenny: Fantastic so, that’s for relapsed/refractory patients, right? The ten that you have right now?
Dr. Garfall: So, all these patients on the CAR 19 study, the anti-CD19 CAR study are patients who have had a previous autologous stem cell transplant and had a short response. So as you know if a typical patient with myeloma who has an autologous stem cell transplant and then goes on to some maintenance therapy, the disease stays under control for a number of years maybe three or four years is the typical duration of response. But of course there are some patients in whom the transplant doesn’t lead to that nice long period of disease control and the disease starts growing in a much shorter amount of time. And those patients are patients that we call high-risk patients meaning that even though some other therapies might be available at work for them, we know that the disease is aggressive and it’s not likely to respond for very long to subsequent therapy. So what we did was design the study specifically for those patients. So patients who had a short response to their first autologous stem cell transplant. So all of our patients had less than one year of response to a prior transplant and all of them have progressed through other therapies that they received after that transplant. So they came to our study with fairly advance disease having had multiple prior therapies having progressed with those therapies. In some cases having progressed through experimental therapies as well and so when we treated them on our study they had quite advanced disease and what we did was because we wanted even though we only we’re able to treat just 10 patients we wanted to get a sense of whether this was working. And that might be tough to do if we’re just combining it with transplant, because transplant itself even in patients with with aggressive disease does have the ability to control the disease for some amount of time. So because these patients will have a prior stem cell transplant and we know from experience that patient who get second or third stem cell transplants, the responses for the second or third stem cell transplant while they can effective at controlling the disease for some time, the responses are typically short and they are shorter than the responses to the last transplant in any particular patient. So what we did was to take these patients who had quite advanced disease, gave them a second transplant with the CART-19 cells and then in addition to just making sure that the cells are safe in the setting and looking at how they grow in the patients and whether they hit their target, we’re also at the same time comparing their responses on the study to this response they had to the prior transplant to get a sense of whether the addition of CAR T-cell of the transplant is adding anything. We presented at ASCO in June the result of just the first five patients that we’ve treated who we have some longer follow-up and that we could really get a sense at least in preliminary form about how they were doing with this transplant with CART-19 compared to the transplant they had previously. So it’s a long answer to your question about whether these patients are relapsed refractory and the simple answer is yes. As well the phase 1 study, the BCMA CAR T-cell that would be opening will be also for patients who are sort of relapsed and refractory. So in that stage of the treatment, where the disease is growing and physicians are moving between different therapies trying to keep the disease under control as long as possible, it’s those kind of patients that we’re going after in this early case studies.
Jenny: That’s a great explanation, I think we like the more detail understanding who you have tried this on so I think it’s perfect. So what did you learn? You presented at ASCO but maybe you could give us a very short explanation of your presentation.
Dr. Garfall: Sure. So what we presented at ASCO were the early results from our first five patients. And again the first patient we’ve observed for quite a long time now because she received therapy on the study over a year ago. So the first thing we learned is that the cells seem to be safe when given 14 days after high-dose melphalan and autologous stem cell transplantation. There’s always a concern about safety about CAR T-cells. There’s the potential for the cells to hit targets that we don’t anticipate that they’ll hit and there’s also the potential that even if they are just going after the targets we think they’re going to go after, that the cells begin to expand very rapidly in patients and cause this thing called “cytokine release syndrome” which has the potential to make people quite ill and low blood pressure, difficulty breathing, requiring care in the ICU. We were nervous just because these cells have behaved a little bit differently in the different disease in which they have been tried. The cells that they have the same cells, same exact cells that behave differently in patients with CLL versus patients with ALL. We were wondering if we were going to see some unexpected things when we tried them in myeloma patients. Fortunately, with the dosage that we chose and the schedule that we chose at least for this early phase study we didn’t see any unexpected or severe toxicity. In terms of how the patients did, as I said we are comparing their response to the first transplant, to their previous transplant, to the response they had on our study where they got a transplant plus the CART-19 cells. When I went through in the ASCO presentation was the data for just the first couple of patients. So the first patient who’s been a really dramatic success and fortunate success for us to have such a patient do so well as the first patient on our study and of course a fortunate success for this patient. She had a high-risk disease with the deletion of 17 P, the P53 deletion and complex cytogenetics. She actually had a prior transplant back in 2010 and the disease began growing again just three months after that first transplant and she met the official criteria for progression six months after her first transplant and that’s despite that fact that as soon her disease started growing she began receiving therapy with lenalidomide and other agents. And she only had a partial response to her first transplant and so on our studies she fortunately went into a complete remission and that remission has been sustained now. When I presented it with ASCO it was just nine months but now we just saw her a few weeks ago and I can tell you that she still in a nice remission, a complete remission at least by the criteria of negative serum protein electrophoresis, negative urine protein electrophoresis, a year after therapy. So this was the disease that we wouldn’t expect to be under control this long just with the transplant because her last transplant didn’t work very well. With this therapy has been in remission, a very deep remission for over a year. She really has no evidence of disease complications. She has a normal CBC. She is living her life. Now of the other four patients who have been treated we don’t have a story quite like hers yet. We have another patient who has had a response that’s lasted longer than her prior response. And she still has some measurable disease and not a complete remission but it’s not behaving nearly as aggressively as it was before. And it sort of just flat and stable and not really growing in any substantial way, so that is another patient we feel like the therapy may have been affected in. And will have to see over time. We haven’t followed her quite as long as we have the first patient. Another patient had a five-month remission and she had plasma cell leukemia, so a very high risk disease a five-month remission and previously after her first transplant she had a six-month remission. So not a dramatic story, but perhaps some benefit from the T cells. Then we’ve had two patients whose diseases that progressed pretty quickly after the transplant on study. So, one patient whose disease progressed within just 42 days of the transplant on study and another patient whose disease progressed about 60 days after the transplant on study. So all total, we have two of the first five patients who have not had their disease progress including one patient who’s had a very long sustained, complete remission and then one other patient who we think may have benefited and actually we’re about to re-treat her, because she had a nice remission and we found actually, she had some CD19 expression on her myeloma cells which is not the typical pattern that we see. And so, we think she may benefit from another infusion of the cells. So we’re going to give that a try next month and then the two other patients who progressed very quickly after the study we don’t think benefited so we didn’t consider reinfusion in those patients.
Jenny: Myeloma is also unique, right? And we have such different features in talking to some of the other doctors. They said the average myeloma patient has five different kinds of myeloma at diagnosis. So are you looking at some of the genetics because when you go to do a clinical trial design and you say okay, “Well it worked fabulously for three patients and it worked okay for three patients and for two patients it didn’t work well,” and sometimes you don’t want to throw the baby out with the bath water and say “Well, therapy A might be not a good therapy but therapy B it worked in few more patients. But it might work for that patient A, a 100% so you want to find all the patients like that and then maybe do a clinical trial with just those patients?
Dr. Garfall: You’re exactly right. That’s why in a pilot clinical trial like this, we’re really just looking for the first sense of whether and for whom a new therapy might work. We’re looking very carefully at all the things you mentioned. So were looking at their genetic subtype, we’re looking at things as simple as whether they have IgA versus IgG myeloma and then we’re also looking at a much more sophisticated level at things like, is there actually any CD19 in the patient’s plasma cells? Are their tiny subsets of the plasma cells that have CD19 on them? Are there any other features that might establish whether or not somebody responded? We’re looking about at how long the T cells persist in patients and whether we can find, right after the transplant, can we find small bits of minimal residual disease and can we study that minimal residual disease to understand that biology of it that might allow us to understand how the therapy is working. So, we’re doing a lot of analysis like that and a lot of it is a little bit too preliminary to talk about the results of. But we have some ideas about these issues and we’re going to do our best to learn from the second five patients that we’ve created just over the last couple of months as they have longer follow up whether we can learn anything from their patterns of response and relapse about how this is working and not only for whom it might work in this current form but what modifications can we make to the therapy and the way we’re delivering it to make it work as well as it did for our first patients, for more patients.
Jenny: And I would imagine that with five patients, it’s hard to see those patterns but I know that you have the tools to be able to do that.
Dr. Garfall: That’s exactly right. In small number of patients it’s hard but we chase anything we find and then we’ll try and follow things over the next five patients and then perhaps we’ll have the ability to make some modifications to the protocol and test them over a hypothesis about how we can improve this with another group of five patients. And then in the meanwhile, as I mentioned we’ll have the BCMA CAR study where we hopefully will learn about the potential efficacy of another target and depending on the results there, who knows we maybe in a situation down the road where we could potentially combine targets or if one looks much better than the other go with one target. But I think you alluded earlier to the potential for combination strategies and basically all those things that you suggested are all ideas that we’ve had and that we will consider in the context of our big team here about ideas going forward.
Jenny: I think that’s a challenge for you because when you look at something like this and you say “Okay, there’s BCMA as a target, there’s CD19 as a target. Maybe there’s CS1 as a target and as a patient I would say “Gosh give me them all.” I know you’re trying to test them one at a time but if my myeloma is so wiely and sometimes it hides and sometimes, something might knock three types of myeloma down. Like your transplant might do that, but the other kinds maybe potentially more aggressive then grown up after that part is knocked down - it’s interesting to see how clinical trial design is created because maybe together they would be hyper effective and maybe alone they might be moderately effective. I don’t know.
Dr. Garfall: I completely agree and it’s interesting because CAR T-cells are very hot new topic, an amazing opportunity for cancer therapy. And there are very unique issues that go with CAR T-cell clinical trial design but actually the same old rules also apply about how you test these things. And just as we’ve seen if you think back to the mid 2000s when the studies were being done Revlimid and Velcade, and then eventually people figured out that if you combine them you get synergistic activity and we saw just recently with the publication of the study that combined elotuzumab which is the anti-CS1 antibody with Revlimid. Elotuzumab showed in the laboratory you could see that there were some promising signs in terms of its ability to generate anti-myeloma immune responses in the clinic as a single agent it wasn’t as impressive but then when it was combined with Revlimid suddenly, you get real activity. And I think we’re going go through the same process with CAR T-cells. Unfortunately and we’re as impatient with this as the patients are, but you know the first test that any new therapy has to overcome is whether it’s safe and it’s very difficult to evaluate safety when you’re combining it with other therapies that has other side effects. So I think we will see at first the T cells against these targets will be tested in patients as single agents. But then I think everybody is very excited about many, many different combinations. So combinations of different CAR T-cell against different targets, combinations of T cells with some of the other drugs that are established from multiple myeloma such as drugs like lenalidomide and pomalidomide that have the ability to stimulate the immune system and also some of the other exciting immunotherapies that have shown a lot of success and other malignancies like lung cancer and lymphoma namely the PD1 inhibitors. And I think we will see very soon combination studies start to pop up with CAR T-cells probably first in the diseases where they are a little more established like ALL and CLL but hopefully before long in myeloma also.
Jenny: And a couple of questions about that so when you say soon, I do believe that’s true and I know a lot of people are working on it. How soon do you think that could happen where one CAR T-cell therapy gets “approved” and then can be used in combination with others?
Dr. Garfall: I just don’t know exactly the timelines for these things, but it just seems like things are moving quite quickly and now that we have FDA approved agents that are targeting PD1 and PDL1 that these are very safe agents to give, I think we will start seeing studies popping up in the next year or so combining CAR T-cell and this not based on any inside knowledge I have about particular plans at PENN but just seeing where the field is going, and the availability, and the activity of these agents, and the interest basically across all the centers that are working on CAR T-cells and immunotherapy to combine them. I think we start to see studies popping up in the next year or so.
Jenny: Perfect. Well, let’s talk about safety for a minute because I know you mentioned that sometimes there can be safety issues. So how do you mitigate that and I know you’ve said you’ve learned that post 14 days after transplant is a really appropriate time to give them. But are there other things that you watch for or are cautious about or you’re doing for safety?
Dr. Garfall: We’ve learned a lot from the experience in Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and with the pediatric studies as well. And we’ve learned a lot from studies going on a multiple centers. We’ve learned a lot from our own studies here at PENN but of course we’ve learned a lot from the studies going on Memorial Sloan Kettering. And we even learn some from studies going on with other immunotherapies such as the experience with the ipilimumab where you see some auto immune toxicity – that’s an immunotherapy that’s been approved for a few years now in melanoma. And also the studies of a drug called blinatumomab which is anti-CD19 therapy, it’s called a bite, which is quite an antibody but not quite a CAR T-cell for ALL. And so were learning how to manage some of these autoimmune toxicities , like the cytokine release syndrome fortunately. Thanks to some very clever work that was done early on in the other studies here at PENN that I mentioned previously we learned that there is an antidote to cytokine release syndrome that can be used called tocilizumab which is an antibody that targets Interleukin 6, which is one of the inflammatory chemicals that the immune system releases as the CAR T-cells expand in the body and that when patients get in to trouble with severe cytokine release syndrome and almost all cases the tocilizumab is able to completely reverse that. And those patients actually can still have a nice response to the CAR T-cell therapy even after getting that response or that inflammatory reaction shutdown with the antibody. So that’s one major toxicity that is not completely dealt with by that antidote, but that antidote has been very helpful in making this a safe therapy for development. And then for CD19 I think we’re fairly comfortable with the safety of that as a target in these patients. But I think in terms of the newer targets that are coming out that’s the very important thing to make sure that the CAR T-cell don’t go after some other organ in the body that has a protein that looks like the target or the target isn’t expressed in some other cell in the body and other than the cancer cell. And that’s why these studies start as Phase 1 studies where we use a lower dose of the cells and watch patients very, very carefully and only treat one or two at time. And then as we get sort of comfortable with the toxicicity - fortunately for a lot of these targets, monoclonal antibodies have been developed again for some of the targets before the CAR T-cell are developed. So for example, for BCMA there’s actually a trial going on sponsored by GlaxoSmithKlein using a BCMA antibody and while we don’t have access to all the data from that study right now, that study of antibodies can give us some information about the safety of the target because CAR T-cells and antibodies are often developed against the same targets. And so you can extrapolate a little bit some of the toxicity data from the antibody to the CAR T-cell but you have to be careful about that as well because we think CAR T-cells are much more sensitive and active than antibodies. So an antibody that safe might not necessarily translate into a CAR T-cell that safe.
Jenny: That makes sense and you mentioned one for a CD19 and then there’s a companion, that you’ve been working with and then wouldn’t elotuzumab be the same one for a CS1 CAR T-cell target?
Dr. Garfall: Absolutely, so CS1 is one of the most promising CAR T-cell potential targets. I believe the center that’s closest to opening a clinical trial of anti-CS1 CAR is Ohio State University and I don’t know exactly the timeline for that but certainly the safety of elotuzumab which is an antibody targeted against CS1 is promising with respect to the safety of a CS1 based CAR T-cell.
Jenny: Do you think you could ever use them together?
Dr. Garfall: The antibodies and the CAR T-cells?
Jenny: Like for the same target. Let’s say CD19 or CS1 or something you use a CAR T-cell and a monoclonal antibody?
Dr. Garfall: I don’t see why that couldn’t be tried. I think that’s probably going to be something that it might be different for each specific target and we’d have to learn a little bit more about how they work alone before we thought about combining them, but I think I don’t see any reason why you couldn’t give that a try.
Jenny: How do you test for the presence of this T cells like let’s say you had an option between maybe three different clinical trials and how would I test to say, do I have more CD19 present or do I have more BCMA present or which one would be better for me personally?
Dr. Garfall: So that’s a very, very good question. It’s a question we actually haven’t faced in practice yet because we haven’t had this menu of CAR T-cells to choose from. But it is an important thing to consider. So in an ideal world, the target for the CAR T-cell is something that is so intrinsic to the nature of the disease that is present on everybody. And that’s almost the case with CD19 for a lot of other diseases in which it has been tried. For example, Non-Hodgkin's lymphoma, diffuse large-B cell lymphoma, CLL, basically it all has CD19. BCMA is pretty close to that for multiple myeloma. I think almost all myeloma expresses BCMA at least in the studies that looked at that so far. Now, we’re going to be looking carefully and as I am sure other centers are as well about -- is all BCMA expression the same, is all CD19 expression the same. For example, in a myeloma that’s 90% positive for one antigen, is there a small sub population that’s not positive and that requires some sophisticated laboratory analysis. So I hope we will get good over time at predicting which target is best for which patient - more better yet which combination of targets is best for each patient but I think it’s going to take more study before we can do that.
Jenny: Great. I know sometimes we’ve heard a little about the protein loss like sometimes when you give the CAR T-cells, sometimes the cells will just lose that target on the top even though they are still myeloma cells. So the CAR T-cell therapy doesn’t recognize it essentially. Do you see that? Have you seen that in CD19 studies that have been done and how often does that happen?
Dr. Garfall: So it’s fascinating and it really humbles you, right? That the cells are so clever that they can do these kinds of evasive maneuvers, but of course at the same time it’s a phenomenon we’re very familiar with from other cancer therapies. So we know almost every other therapy for cancer and certainly for myeloma that even when it’s really effective at first, resistance developes And whether it’s down regulation of the target of a CAR or some other molecular trick that the cancer plays to evade a therapy, this is a phenomenon that we deal with for virtually all cancer therapy. So yes, in some of the patients who have developed resistance to anti-CD19 CAR T-cells there has been this escape where the tumor cell just kind of turns off CD19. So ultimately the solution to that might be to have multiple targets for each disease. And that’s why it’s important even though we have some success with CD19 in myeloma that we in parallel in multiple centers around the country develop CAR T-cells against other targets, so that we can ultimately deal with relapse with just another target or perhaps go in with both targets at the same time to sort of circumvent that resistance. Ideally you can deal with some of this by selecting your target wisely too. So the cell can’t turn off something that it requires for its survival. So if you pick a target that’s really required for the cell to survive it can’t turn it off. And that’s not always possible but ideally the target that you develop a CAR T-cell against is one that’s really -- it’s not only expressed on those cells but it’s really important for that cell. So that it can’t easily turn it off and still survive.
Jenny: Very interesting. So now, maybe you want to give a quick description of the therapy overall and my question, I have a second question about it because you said in one of the patients you gave her an additional dose basically? So as I understand it, it’s like a one time shot or maybe you want to explain how that works?
Dr. Garfall: Sure and I think because all the studies or most of the studies that have been done so far, early phase studies, the studies have basically been to give one dose to the cells and see what happens. And we hope that kind of like allogeneic transplant this is a living therapy. So the goal is that when the cells go into the patients that even though there’s just one infusion of the cell, the actually therapy last for a long time if the cells persist. Now, one of the big mysteries and conundrums in this field right now is being able to predict which patients hang on to the T cells and in which patients do the cell survive over the long term. Because we know that it is very variable. So in some patients with CLL the first patients treated here at PENN with CLL, some of them have T cells that have been alive in their body for years. Now you can still detect them. Whereas other patients the cells go in and they just disappear within a short amount of time. The idea behind that just one infusion the first dose is that at least in some patients it seems like the cells can persist for a long time. How likely that is to happen varies and is a patient-by-patient thing. It’s seems to be different in different diseases, it maybe different between different CAR T-cells and different targets and different designs. I haven’t talked a lot about the nuances of how the actual receptors are designed but there are differences between the different ones and the development of different site and that may impact how likely they are to hang around for a long time. Now, as we get more comfortable with the safety and we see in some patients that cells stick around for a short time and then disappear, we’re starting for the first time to try giving additional doses of the cells. And so at least at PENN and for the myeloma study, the dose we’ve chosen to give the patient was actually a lot less than is manufactured. So we have for most of our patients some doses kind of stored on the shelf that we can potentially give the patients a second infusion if we think the first infusion worked but that the just didn’t live long enough. That’s being tried in few different studies here at PENN and sort of case-by-case basis. We’re hoping to learn about whether that works and whether that might be kind of standard thing that should be incorporated into T Cell therapies or CAR T-cell therapies.
Jenny: Before you mentioned that you were using this with stem cell transplant. I know it’s for relapse refractory patients. How long do you think it will be until you could use it in patients just with a low tumor burden if that’s the overall goal is to get it early when there’s not so much bulk of tumor?
Dr. Garfall: So that’s a really good question and that’s really specific for the CD19 targeting in myeloma, because we don’t think the target is on most of the cells, but only on a small subset. We really think that we’ll need some other therapy to combine it with if it’s going to be effective. That may not be the case with targets such as BCMA or CS1 and we’ll have to just see as we see the results of those studies. Ultimately, transplant is a toxic therapy of course and while it’s a really important therapy for patients with myeloma who are well enough to tolerate and it improves survival, it’s a toxic therapy, I think everybody is eager for the day where we don’t need to do as many transplants as we do now. So one of the things were thinking of ,at least for the CD19 concept is perhaps, how can we use other therapies that are effective other than transplant that kind of get rid most of the myeloma cells before we give anti-CD19 CAR T-cell but we’re sort of in the early stages of that. Like I said, only just today, we finished giving the cells to the last patient on the current study.
Jenny: Well you certainly have your work cut out for you. We’re so excited about what you were working on. It’s so exciting to hear about the deletion of 17 patients having great outcomes like that - it’s just thrilling.
Dr. Garfall: One thing that people that I think are optimistic about with CAR T-cell is because they’re targeting molecules on the surface of the cell and not some of the molecular machinery inside the cell, even some of these higher-risk patients, maybe responsive to therapy that targets surface proteins. That seems to be the case with daratumumab, that high risk patients do well with the therapy, and we hope that that’s the case with CAR T-cells that some of these sort of adverse risk features don’t predict a poor response to this type of therapy the way they do to some of the other therapies that we have from myeloma and other diseases.
Jenny: A follow-up question about that. I was talking to one of doctors and he said that he was working on CAR T-cell work that just didn’t target the surface of the protein but they targeted the interior of the cell. What’s the difference?
Dr. Garfall: Yes, that’s a very good question. If we think just narrowly about a CAR T-cell, they recognize molecules on the surface of the cell. However, there’s another various technology that’s kind of analogous and it’s still genetically engineering the T cells to recognize a different target but it’s called an engineered T cell receptor or an affinity enhanced T cell receptor. And that’s another strategy that can be used and that strategy has the capability to target abnormal proteins that are inside the myeloma cells. Not just ones on the surface. And that’s a very promising technology. In fact we at PENN just recently completed a study using that technology to target a protein called NY-ESO-1 that was a study that was in collaboration with the company called Adaptimmune also, working with Dr. Carl June’s group here and in collaboration with Dr. Aaron Rapoport of the University of Maryland. That study was actally just published online yesterday, I think and that’s been presented by Dr. Rapoport at a number of meetings. So that’s a very promising approach as well. It does not seem, at least in the early studies, to generate as impressive responses that some of the CAR T-cells that he’s have. But I think we’re seeing just like the very first generation of this technology both from the CAR T-cell and the engineer T-cell receptor site. I think in the future we’ll see studies using both approaches lead promising results.
Jenny: Interesting. This is a manufacturing process to make these CAR T-cells, correct?
Dr. Garfall: It is, at least in its current form this is a custom patient-specific product. So the T cells are harvested from the patient in a process that very similar to stem cell collection for transplant. And then the cells are taken to the lab and they’re grown. And this one was one of the big advances that made this possible is work by Dr. Carl June and Dr. Bruce Levine here at PENN many years ago. Just figuring out, how to grow T cells outside the body to the numbers that you would need to give a real dose of these cells to patients. So the cells are taken out of the patients, grown in the laboratory while at the same time their genetically engineered to express the Chimeric Antigen Receptor, the CAR, on their surface and then once they have cultured long enough to grow a sufficient number then they are re-infused into the patient. So that whole process when you factor in some of the quality checking processes that have to happen takes two to four weeks to manufacture the cells with the current technology. Though I think there’ll be some advances in that over time and perhaps that lead time will be reduced over time.
Jenny: Who is working on manufacturing? Are there best of class methods - that people are kind of duking it out in the commercial space to create these?
Dr. Garfall: So there are a couple of different culture techniques that are out there for growing the lymphocytes. And there’s a lot of the nitty-gritty technical aspects where actually I’m not an expert of it all. But I would say a lot of the groups are using this culture technique that uses these things called micro beads where attached to the micro beads are couple of antibodies that stimulate the growth of the T cells. So the cells are actually cultured with these beads. And these beads provide stimulatory signals to get the T cells to grown. There are some other techniques that are out there that don’t use beads that use other cytokines to stimulate the T cells to grow. I am not enough of an expert in this area at all to be able to predict which one is going to be better over time. But I think as with selection of targets, as with the genetic engineering mechanism, this is another area where I think there are a lot of innovations to be done over the years in terms of making the manufacturing process more sophisticated so that the cells that are delivered are more potent and more likely to be effective.
Jenny: Fantastic. I know we have some caller questions. So I like to go ahead and do that and your descriptions are so clear, it’s just so fantastic.
Dr. Garfall: Oh, thank you. Jenny: We so appreciate you taking the time to do that. If you have a question for Dr. Garfall, please call 347-637-2631 and press 1 on your keypad and we will start with caller at ---. So go ahead with your question.
Caller: Hi Jenny that’s me, Jack Aiello.
Jenny: Hey Jack!
Caller: By the way you’ve asked great questions. I had couple of quick ones just to make sure, I’m wondering, was the level of CD19 expression involved in any of the eligibility criteria for this initial pilot study that’s the first question. And do you envision CAR-T Therapy from myeloma ever being used at induction or even earlier at smoldering levels when the myeloma levels are low?
Dr. Garfall: So those are both really good questions. So the first question is no. We did not screen patients for CD19 expression on their myeloma as a criteria to enter the study. And the reason was because some of the data that provided the rationale for this study would suggest that even if there’s no CD19 on the myeloma plasma cells at all but there might be some myeloma cells kind of masquerading as B cells. And B cells all express CD19 and that might be enough alone to make this therapy effective. So we didn’t want to cut-off that possibility by excluding patients who had CD19 -- no CD19 expression on their myeloma cells. In fact our first patient who’s had this very nice response, when we looked at this CD19 expression on her myeloma, using very sensitive techniques like RTPCR, 99.95% of her myeloma cells had no detectable CD19. And there is presence of CD19 on this .05% of her plasma cells, of her myeloma plasma cells. So that is a patient that you would call a CD19 negative myeloma by any standard criteria but this tiny subset with CD19 may have been enough to allow her to benefit from this therapy. So no we didn’t screen patients for that and we have actually found the most patients have small subsets of plasma cells that are CD19 positive, even though most their plasma cells may be CD19 negative. To answer your second question if you could remind me quickly, I’m sorry I’ve forgotten it.
Caller: It’s okay. CAR T therapy ever being used at induction or smoldering?
Dr. Garfall: So I think it all depends on how things develop in the coming years in terms of its safety and its efficacy. I mean certainly a barrier right now of taking somebody who is newly diagnosed with myeloma and is sick with the myeloma for whatever reason, the bone lesions, kidney failure, etc. These therapies take some period of time to manufacture and we have really fantastic drugs that are safe, fortunately. So I don’t see the initial therapy of myeloma being something where CAR T-cells are used, but I think potentially as a consolidation strategy perhaps with transplant or in place of the way we use autologous transplant right now is a possibility. And the smoldering question is interesting. I mean wouldn’t it be great to prevent myeloma? I mean myeloma is an awful disease. And even the patients who do best with it, usually are sick with it when they first get it and potentially with some irreparable organ damage so it would great to be able to take patients who we know have a high risk of developing myeloma and if there were a safe therapy that were effective, sure I don’t see why not but I think we’re a long way from that point for sure.
Caller: Thank you so much for your very clear answers.
Dr. Garfall: No problem, thank you for your questions.
Jenny: Thank you Jack for your question and thank you for your answer Dr. Garfall.
Caller: Thank you, Dr. Garfall. This is Paul. Thank you for taking your time on the show with us today.
Dr. Garfall: My pleasure. Thank you for listening.
Caller: Maybe you answered this but I didn’t hear it. A follow-up question to the last one, do this trial also included transplant?
Dr. Garfall: Which trial I’m sorry?
Jenny: I think the BCMA trial.
Dr. Garfall: So it will not include a transplant and that’s largely because the reason we’re including a transplant in the trial targeting CD19 is because we think for CD19 directed therapy to work, we need some other therapy to get rid or at least reduce substantially the number of malignant plasma cells that don’t express the target, the CD19 in order to see any benefit from targeting CD19. And of course the jury is still out over whether that strategy is going to work in the long term. We have some early evidence that’s promising in a small trial but the ultimately test will be in larger, more definitive studies. But for targets where we expected to be on most or all the plasma cells, there is not that same need for transplant. There is some need we think for some that we call lympho- depleting chemotherapy which is a little bit of a pre-conditioning to suppress the immune system a little bit to let the CAR T-cells grow inside the body. And almost all CAR T-cell trials do incorporate a medium dose, not high dose melphalan that you give with the transplant but some kind of medium dose of chemotherapy to allow the patient’s immune system to receive the cells and allow the cells to grow. And there’s various reasons why you have to do that but it seems to be a theme that a little bit of chemotherapy beforehand is important for allowing to CAR T-cell to thrive after they are infused.
Caller: All right. And follow question to that, when does the trial open and how many patients will be involved in this trial?
Dr. Garfall: So I can’t provide too many details about that just because we’re very restricted about how we recruit patients to clinical trials and this sort of form isn’t a suitable place to recruit patients to clinical trials but all clinical trials once they are open are listed on clinicaltrials.gov. And patients can go to the Abramson Cancer Center website, where we have on our website all active clinical trials for all the diseases we treat. We don’t have firm date for opening a trial yet, as you may know these things tend to move around a little bit so we hope to have the trial open in the next couple of months. And again that trial will be led by my colleague Dr. Adam Cohen and we hope to post something on clinicaltrials.gov and Abramson Cancer Center website as soon as it is open.
Caller: You just open up another host of questions like clinicaltrial.gov is not a place to go to apply for a clinical trial, that’s not how it works.
Dr. Garfall: No. You’ll be able to find on clinicaltrial.gov the contact information to inquire about availability of slots things like that.
Caller: There’s no sense of timing right now?
Dr. Garfall: I don’t have detailed timing information that I can disclose in this forum. I’m sorry.
Caller: All right, Thank you.
Dr. Garfall: It should be in the next couple months.
Caller: All right, Thank you. Jenny: And will be watching for it. Okay. So my final question for you is how can patients help accelerate this very exciting work that you’re doing?
Dr. Garfall: So that’s a great question and I should take this opportunity to thank you Jenny for creating such a fantastic forum for patients to hear about clinical research. I mean, with this website and these interviews you’ve really I think been able to have some really fantastic investigators come and talk about their research and I’m really honored to be among them. But I think it’s becoming easier and easier for patients to gain access to information about clinical research. In some sense it’s overwhelming and I think clinicaltrials.gov is a great example and is hard for patients to navigate this. But I think what patients can do is ask their physicians about clinical research even if there not at a center where clinical research is being conducted. Nearly all oncologist these days think of clinical research as part of clinical care. And even centers that aren’t actively participating in research collaborate closely with centers that are participating in research and can point you, given the medical details of your particular case, towards the center that has clinical research options available to you if you are so inclined to participate. I’m always amazed by and humbled by the work our patients do just to just live with this disease let alone participate in clinical trials, which are often difficult on patients in terms of the time commitment. And I’m extremely grateful for all the efforts of our patients in our trial and the myeloma community in general which is this incredibly lively community of engaged patients. So I think there’s a number of great patient resources, your website among them Jenny, where patients can learn about cutting edge research in myeloma. But ultimately the best person to help guide a patient to clinical trials is their physician, even if patients are treated at sites that are not actively participating in clinical research, their physicians can guide them towards places were clinical research is happening if it’s appropriate for them.
Jenny: All right. Perfect, from a patient’s standpoint were very excited to help accelerate your work. So, I always suggest that patients look at clinical trials and come up speed themselves so they can at least ask the doctor intelligent questions about what would be most appropriate for them. If we doubled participation in clinical trials you could do your work so much faster.
Dr. Garfall: I agree. One of the most gratifying things is being to offer participation in clinical trial to a patient who is enthusiastic about it. I mean it’s a satisfying thing to see nowadays where the therapies that are even in Phase One trials are often very, very promising. It’s gratifying to see science advance before your eyes often to the benefit of the patients involved in the research. So I agree, as the clinical investigators we thrive on the enthusiasm of our patient for advancesin the disease and the treatment of the disease and I think continued enthusiasm from myeloma patients is a huge, huge driver of progress in this field.
Jenny: Well we are thrilled and we’re so grateful that you took the time today to describe it for us. You just did a great job explaining it and we’re excited to see where it leads. So thank you so much.
Dr. Garfall: I like to thank you also for the opportunity and I want once again thank all of my colleagues with the University of Pennsylvania, who are part of a very, very large program driving these therapies forward. I’m just very one small piece of it and we’re all very fortunate to work in this field and to interact with our patients who received these therapies and we’re very, very optimistic about the potential of CAR T-cells and other exciting and innovations in multiple myeloma research to improve the care of patients with this very difficult disease.
Jenny: Well thank you again. And we just so appreciate you being on the show.
Dr. Garfall: My pleasure, Jenny. Thank you.
Jenny: Thank you for listening to Myeloma Crowd Radio. We believe that patients can help support the discovery of a cure and we encourage you to become involved.
about the author
Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical research. Founder of Myeloma Crowd by HealthTree and the HealthTree Foundation.
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