Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Aaron Rapoport, MD University of Maryland Greenbaum Cancer Center Interview date: March 28, 2014 

Dr. Aaron Rapoport shares the progress being made on T cell and vaccine immunotherapy. T cell therapy is a way to use a patient's own immune system cells to target and eliminate myeloma cells, either by waking up and empowering T cells through engineering (called CAR T cells)  or using a vaccine to stimulate the T cells to do their job. He shares how transplant is being used to eliminate the myeloma cells and T cells are being used to build back up the immune system to prevent future infections, like pneumonia. Although T cells are being used traditionally in combination with transplant, he shares how this is being used even without transplant in a newly opened study at the University of Maryland and City of Hope clinics. He shares how he and others are carefully moving forward with T cell approaches in order to create targets that just hit the myeloma cells while sparing healthy cells. He describes how you can join a T cell study by knowing your HLA tissue typing, an easy test to obtain that is performed by major labs. This test tissue typing is typically used if a patient is trying to find a donor transplant match.     The live mPatient Myeloma Radio podcast with Dr. Aaron Rapoport 

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. Learning from these brilliant men and women is an important part of receiving outstanding care. They are working hard to move the field forward to help find a cure for myeloma. By participating in their clinical trials, we, as patients, can help that happen at a faster pace. If you'd like to receive a weekly email about the past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter, and please share these interviews with your myeloma friends. We also have a new site called myelomacrowd.org that is the first all-inclusive site for myeloma. We invite you to join The Myeloma Crowd to learn about the very best resources for myeloma. We also invite you to contribute what you've learned during your myeloma journey. On the "Become a Contributor" link, you can see the many options to share what you know to help other myeloma patients. Finally, there are links to the best new sources, support groups, diagnostic information, and everything about myeloma in a single place. Now, we are very privileged today to have with us Dr. Aaron Rapoport. Dr. Rapoport is a professor of medicine and Assistant Director of the BMT program at the University of Maryland Greenebaum Cancer Center. He's a board-certified hematologist and stem cell transplant physician with over 25 years of experience caring for patients with blood disorders. Dr. Rapoport conducts research that focuses on using T cells and vaccines to enhance immune recovery after stem cell transplant and was in the lead to direct major clinical trials using this T cell therapy that have now enrolled over 150 patients. He has written numerous papers and received many awards, including The Leukemia & Lymphoma Society Clinical Scholars Award, the LLS Stohlman Scholar Award, the MMRF Senior Research Award for three years in a row, and was appointed to a Gary Jobson Professorship in Medical Oncology. Dr. Rapoport has several open NIH-funded studies on T cell research and has laid the groundwork for the development of effective cellular immunotherapy for myeloma. Dr. Rapoport, welcome!

Dr. Rapoport: Thank you very much. I'm very glad to be here.

Jenny: Thank you so much for joining us. This is the first time we've heard about T cells and vaccines, so as an immunotherapy, can you give us in maybe layman's terms an explanation of engineered T cells and how they work?

Dr. Rapoport: Sure. Well, let me just start by talking a little bit about the role of T cells or immune cells in cancer therapy. There are several lines of evidence that T cells are very important in controlling and curing cancers, especially blood cancers. One of the lines of evidence is, first of all, in HIV, in the AIDS realm where the HIV or AIDS virus actually results in depletion of T cell populations and these patients are at increased risk for developing cancers including blood cancers like lymphoma as a result of the immune deficiency that results. Clearly, in this case, the T cells are protective against cancer. Also, in patients who get organ transplants, kidneys, hearts, livers who are on long-term immune suppression, they also are at risk for developing a variety of cancers especially blood cancers as a result of the deficiency of the immune system from the drugs. So clearly, if you deplete T cells and T cell function, reduce T cell function, then cancers can develop. It seems clear that healthy T cell populations and immune cell populations are protective against cancer. Furthermore, in the realm of bone marrow or stem cell transplantation, we recognize that T cells from donors are very important in producing cures of blood cancers, including myeloma, leukemia, lymphoma, all types of blood cancers because we know that the T cells and the immune cells that come from the donor come into the patient and we're able to recognize an attack, leftover blood cancer cells, and help to destroy them and eradicate them and that is a very important part of the curative mechanism of donor transplants. If you take out those T cells and you deplete them, then the likelihood of cure is much less. So through many of these lines of evidence, we realized that T cells are very important not only in protection against blood cancers, but also the treatment and cure of blood cancers. The challenge has been how to get a patient's own immune system to get into the act and to wake up and be able to recognize the patient's own cancer and be able to attack that. That's sort of been one of the holy grails of cancer therapy, is figuring out how to get the body's immune system to get back into the act. When blood cancers and really all types of cancers develop, they have to evade the body's immune system. The body's immune system is geared toward protecting us from cancer and foreign invaders, as I mentioned. So in order for a cancer to develop, it has to figure out how to evade or bypass or suppress the immune system so that it can grow out. One of our challenges as oncologists and as cancer immunotherapists is trying to get the body's immune system to wake up and to become reactivated and reengaged in the process of going after the cancer.

Jenny: Can you give us just some biology basics because I know myeloma is a B cell malignancy, correct? Can you explain the difference between a T cell and a B cell?

Dr. Rapoport: Yes. There are several different arms of the body's immune system and that one of the arms of the immune system is called the adaptive immune system where our body adapts to foreign invaders and helps to get rid of them, and the B cells, B lymphocytes and T lymphocytes are part of the adaptive immune system. B cells are chiefly involved in producing antibodies, which are proteins that can recognize foreign invaders and bind to them and help to clear them from the body. So when you get a flu vaccine, your body develops antibodies to parts of the flu vaccine, and those antibodies or proteins then can attack the flu virus and help to clear it from the body or prevent it from attacking the body. Plasma cells, which is where myeloma cells are derived from, are actually sort of the final step or one of the final steps in B cell development. The plasma cells are the antibody factories of the immune system. Each small clone or population of plasma cells is capable of producing essentially one type of antibody against one particular germ or one particular target. And in our bodies, we have tens and hundreds of thousands of these families of plasma cells, each producing a different antibody, but for reasons that are not entirely clear, as a result perhaps of changes in the genetic makeup of the cell population or things like that, one particular clone or sub-family of plasma cells can grow out excessively and sort of take over the neighborhood. And all of these cells, because they're all derived from the same family or clone, produce the same antibody. When you have an outgrowth of a clone of plasma cells all producing the same antibody, you have a buildup of a protein called the M protein or the paraprotein, which is one of the defining features of myeloma. Now, the paraprotein itself can have side effects, but the cells that are producing this particular paraprotein or M-spike, this expanded clone of plasma cells, also has side effects and it can release factors that cause damage to bones and could cause suppression of other cell populations resulting in low blood counts like anemia and suppression of normal plasma cells and other antibody-producing cells. That's the genesis of myeloma. Now, T cells are another arm of the immune system where instead of the antibody or the protein attacking the foreign invader, in the case of T cells, a cell population actually attacks the foreign invader. It's a cell, so it's sort of cell-based immunity as opposed to protein or antibody-based immunity. In the case of T cells, the cells themselves are doing the attacking and that's more adept, more able to attack foreign cellular invaders, for example. So if you have a cancer or a foreign cell invader, T cells are going to be more adept at attacking those invaders because the T cells actually attach to these abnormal cells, cancer cells, or engrafted tissue if one tries to do some transplant of sorts. These T cells can then engage these foreign cells and actually kill them through various mechanisms.

Jenny: Thank you for giving us some of the basics because I think we need that before we have this discussion with you today. Now, do you think you could give a little history about the T cell area of research and maybe in cancers in general and then in myeloma?

Dr. Rapoport: Yes, sure. In the past, as I mentioned, one of the challenges has been how you get these patients' own T cells to recognize their own cancers and target them. As I mentioned, when cancers develop, they have developed the ability to evade the immune system. If they couldn't evade the immune system, they would not be able to develop, so they have developed mechanisms for suppressing the body's immune system and shielding themselves from the immune system. How does one get the T cell population and the immune system reengaged? In the past, historically several strategies were used. One strategy was to take T cells out of the patient's body and grow them or expand them outside the body in a laboratory environment so as to remove the T cells from the cancer and from the tumor environment, and hopefully by doing that, the T cells would be able to wake up because they would be away from the inhibitory or suppressive effects of the cancer. Another strategy has been to use vaccines to take cancer cells or proteins that are expressed in cancer cells and to inject those into the body with the idea that one would then be able to reawaken or activate the T cells within the body against that vaccine. And then that activity, that activation of the cells, could then transfer over to the cancer cells. So if you take a protein or a marker that's present on the cancer cells and you make a vaccine out of it, then you inject that into the patient, the hope is that the body's immune cells would see that injected material, react to it, and then the reactivated or activated cells would then carry over to the cancer itself, the myeloma itself, that is expressing that same marker. Those strategies have had some measure of success, but overall, they've been somewhat disappointing. The impact on the disease, on myeloma and other forms of cancer in which it's been used has not been as strong as was hoped. I think that part of the reason is that the cancer's ability to suppress the body's immune system is really very strong, and the numbers of T cells within the body at any one time that are able to recognize and attack the cancer is relatively small. It's just been very challenging. It's been very difficult to use vaccines and merely expanded cell populations to overcome the inhibitory and suppressive effects of the cancer and to attack the cancer. So a number of years ago, some very clever immunologists, including a particular researcher in Israel named Zelig Eshhar came up with the idea that one could potentially engineer T cells, genetically engineer and modify T cells in a way that one could introduce a new specificity or a new capability for the T cell that it didn't have before, and then introduce those cells back into the body in the hope that they would be able to then attack the cancer, which had a marker that the T cell could now recognize. This is the basis for the CAR T cells, the chimeric antigen receptor T cells, where you essentially have on the cancer a certain marker, say, a marker called CD19, which is present on B lymphocytes or B cell lymphomas, and also on some myelomas, and you have a genetic construct that encodes a protein that on the outside has a binding site that recognizes CD19, and on the inside has a molecular complex that stimulates the T cells. So you introduce this construct into the T cell and the T cell then goes around. The antibody portion on the outside of the T cells sees the CD19 marker on the B cell, the B cell lymphoma, and then it starts to activate the T cell as a result of that engagement or that binding. The T cell then proliferates and expands and multiplies many, many times. And as a result, it can then go and kill all the cells that have that CD19 marker, so you're essentially introducing these T cells that didn't previously have this functional ability to recognize this marker, but you've genetically modified the cells so that they can do that. And now, it's not like picking a needle out of a haystack anymore. You're already introducing a little army of cells that already are capable of recognizing the cancer cells. And then once they see the cancer cells, they start to react and proliferate and expand exponentially many, many fold and they're able to go after all the cells that have that marker that they now can recognize as a result of that genetic engineering. This has been used with dramatic success in patients with certain types of leukemia called CLL, chronic lymphocytic leukemia, and even ALL, acute lymphoblastic or lymphocytic leukemia. Your listeners may be aware of a young girl named Emma who had a terribly resistant form of acute leukemia that had relapsed after many treatments, including bone marrow transplant, and got her own T cells that were genetically engineered to recognize this CD19 marker. And although she had a relatively rough course, she came out of it in complete remission and then is now in remission for several years. It's just a remarkable story. This has been played out a number of different times for a number of different patients, but it really did highlight the tremendous power of these engineered T cells, and in this case, the CAR T cells.

Jenny: Can I ask you a couple of questions about that? When her cells were taken out and they were genetically reengineered, what's the process to do that? How long does that take? Is that something that just happens in the lab and then she was given back the cells? Because I know CD 19 -- I don't know if it's common in myeloma or not, but I know certain proteins like CD38 and CD138 are more common in myeloma. Maybe you can tell us how that might work also and if it's possible to do that same thing.

Dr. Rapoport: Yes. So the production of these cells doesn't happen overnight. It does require some time, usually several weeks. The cells have to be collected through a procedure called apheresis where the patient usually has a catheter hooked up to a machine and then for several hours, their blood is processed through the machine and the T cells are extracted, and then these T cells have to be genetically modified. Usually, this involves using a vector derived actually from HIV, but it doesn't cause HIV. It just has some of the same abilities of HIV to get into the cell, cross the cell membrane, and deliver genetic material. So these T cells are then sort of incubated with this vector that then carries in the gene, the DNA that encodes this CAR, this chimeric antigen receptor. And then once it's inside the cell, then the DNA is converted to RNA and then into protein, and then the cell puts this protein construct on its cell surface and it essentially takes on a whole new personality as a result of this new protein. And so, whatever the T cell was recognizing before, it now recognizes the thing that the genetic construct tells it to recognize, which in past studies has been CD19, but these cells have to be expanded. They have to be cultured for a period of time for the genetic transfer to take place, and then the cells usually have to be expanded, grown out for a week or two. And then they have to go through a very rigorous testing to make sure that they are sterile and that there's no contamination of germs or other things that could cause harm to the patient. And then only after that are they released back to the patient, so it is a process. It does take three to four weeks to be done. And during that time, patients may require some treatment to keep their disease in check while waiting for the cells to be produced. As you say, the CD19 is not commonly expressed in myeloma, although it is sometimes expressed in myeloma and there is a notion that the myeloma stem cells may actually express CD19. So even though myeloma cells do not, the precursor cells of myeloma may. That's sort of an area that's under investigation. So it's possible that the CD19 CAR T cell could actually maybe not attack the myeloma itself, but could attack the myeloma stem cell perhaps, and that could have benefit obviously if it attacks the cells that were maintaining the myeloma population. But as you point out, this technology really has an ability to be expanded in multiple directions and really, in a way, the sky is the limit. If you make a chimeric antigen receptor that can recognize a different marker such as CD38 or CD138, then you'd have a myeloma CAR as opposed to a lymphoma CAR. It's not quite as easy as I mention because not all CARs work the same. Not all antibodies are suitable for being turned into CARs. One does have to be careful about how one targets these CARs. These genetically modified T cells are very potent and powerful cells, and if this marker that they're attacking is present on, say, a vital organ in the body, it could cause serious damage to that vital organ. For example -- and this is not the case -- but if CD19 were on the liver, then the cells would attack the liver and cause liver failure. That doesn't happen because CD19 is really only on B cells, but one has to recognize that there's both a great deal of potential, but there are also pitfalls to this technology and there are some dangers. Another approach that has been taken in terms of engineered T cells has been to use what are called affinity-enhanced T cell receptors. So the T cell receptor is what gives the T cell its specificity. It's what allows it to recognize specific targets. So rather than using a CAR, which is an artificial protein construct, one could actually take an isolated T cell receptor that is able to recognize a protein that is expressed on myelomas. For example, a cancer tests this antigen called LAGE-1 or MAGE-A3. These are antigens that are expressed on a proportion of aggressive myelomas. If one isolates the T cell receptor that is able to recognize LAGE-1 and then one does some fancy molecular biology to make that receptor even more potent, enable it to bind to that target even stronger, one could then introduce that, what we call affinity-enhanced T cell receptor, into T cells and then generate a population of T cells that can attack that myeloma target through its enhanced or its more potent T cell receptor, so it's another type of genetic engineering of T cells. Those studies are actually in progress in myeloma. I've been privileged to be one of the principal investigators of several studies that take a myeloma patient's own T cells and then we genetically engineer them to express a T cell receptor that endows those T cells with, again, a new functionality, a new specificity, a new personality, which then allows the cells to go after myeloma cells that express the marker that those T cells now recognize Right now, we're limited to certain markers or certain proteins that myeloma cells can express that not all myeloma cells express, but many of what the more advanced myeloma do express. And again, these are the so-called cancer/testis antigens like LAGE-1 and MAGE-A3. And so, this is a very exciting area.

Jenny: I also understood that you are among the first to show -- and you're going to have to translate this, maybe -- that combo immunotherapy with vaccine-primed and ex-vivo costimulated autologous T cells could give a good response after transplant. First, can you explain a little bit about that, and then maybe how it's being used with or without transplant, and then we can talk about your open studies because you have a few different approaches  using T cells and vaccines.

Dr. Rapoport: Yes. As I mentioned, our earlier approach had been to take a large number of T cells from patients with myeloma, and then expand these in the laboratory and then give them back to patients after transplant. The background is that transplant, autologous transplant, high dose chemotherapy, and then stem cell transplantation, is a very important part of the treatment armamentarium for myeloma. Lots and lots of patients have gone through that type of procedure and will continue to do so. This has proved to be a highly effective therapy, but it does not result in a high percentage of cures. It's probably a small percentage of cures that come after autologous transplant. Our hope was to build on that transplant foundation or platform and try to improve upon the responses and the durability of the responses and hopefully increase the frequency of cures. What we're trying to do was to enhance the recovery of the immune system after stem cell transplant. After your high dose chemotherapy, oftentimes the immune system remains quite suppressed for long periods of time because the high dose chemotherapy, in addition to attacking the myeloma, killing the myeloma, can also damage the immune system. So our notion was to do the transplant in a standard fashion, but in addition to giving the stem cells, which build up the blood counts, we would give immune cells or T cells to build up the immune system. We did show that this was effective at enhancing and improving the immune system resulting in better protection from infections like pneumonia and things like that. And we're also able to show that if we used a cancer vaccine, a vaccine that was derived from or related to myeloma, that we could generate immune responses to that cancer vaccine in a significant proportion of patients after transplant. In our most recent study, we looked at a cancer vaccine based on MAGE-A3, which is a protein that is expressed in about 50% of myeloma patients, myeloma cells, and we use that as a vaccine as part of our transplant and immunotherapy study. We introduced some additional immune enhancements and that resulted in a high frequency of cancer-directed immune responses, so we were able to show that almost three quarters of patients who went through a transplant got vaccines, got T cells. About three quarters of those patients would develop immune responses in their T cells that were directed against the cancer vaccine, and the hope was and the hope would be that that enhanced immune function would then protect the patient from myeloma cells that express that MAGE-A3 marker.

Jenny: And this is a study that you currently have open, right?

Dr. Rapoport: No, that's a study we finished and we published.

Jenny: Okay.

Dr. Rapoport: Our current trials involve -- we have one trial that we are actually almost finished with that involves transplant followed by the genetically modified or genetically engineered T cells that have the high affinity T cell receptor against the LAGE-1 marker, which is expressed on a proportion of myeloma patients. And then we also have a trial that is actually a non-transplant trial for patients who've either been through transplant or are not able or willing to go through transplant, and we give them just the chemotherapy followed by these genetically modified T cells, so relying more on the immune cells than the transplant to attack to myeloma, and that trial is relatively newly opened. We've just enrolled two patients. This trial is open both at the University of Maryland in Baltimore, and also at the City of Hope in Duarte, California.

Jenny: Is that the one that's titled "CT antigen TCR-engineered T cells"? Is that that study or is that a different study?

Dr. Rapoport: Yes, I think that would be that one, yes.

Jenny: I'm just trying to keep them straight because this is the first time that we've talked about this approach before. It sounds like you're using a combination approach with the T cells and the vaccine. When do you use the T cells alone or when do you decide to use those alone and when do you decide to use it combined with a vaccine?

Dr. Rapoport: Well, in the past, we've used the vaccines in combination with what we call polyclonal T cells, so these are the non-engineered T cells. What you're trying to do is you're trying to generate specificity and you're trying to educate the T cells to recognize and attack the myeloma. When you're using vaccines, you're using the vaccine to do that redirection or that education step. So typically, vaccines are used in combination with T cells of multiple specificities and you're using the vaccine to try and pull out or selectively expand the populations of cells that recognize that particular vaccine out of a mixture of T cells of different functionalities and specificities. The alternative is the genetically engineered approach where you're actually taking the T cells and you're forcing them through genetic modification, forcing them to recognize the particular target on the cancer cells, so those are alternative approaches. Now, it's possible that in the future, we may find that it's actually important to do things in combination and that maybe genetically modifying T cells is an important step, but maybe it would be a more optimal approach if one also introduced a vaccine or perhaps other drugs that could enhance or perpetuate the T cell function in the future. One of the challenges of using any form of genetically modified T cells is how long do those T cells last in the body? We do know from our own studies that genetically modified T cells can persist for years. In fact, we have one patient who has detectible gene modified T cells for more than two years after transfer, so we know they can last, but in other patients, they don't last nearly that long and part of the reason may be that the myeloma itself may be aggressive enough and resistant enough and hearty enough to persist in the body and continue to create problems even for those genetically modified T cells. They work to inactivate them or suppress them or result in their disappearance from the body. It may be necessary to give additional infusions of genetically modified T cells or it may be possible through some pharmacologic interventions and using certain antibodies, for example, to perpetuate or enhance the survival of those T cells after they are infused. We're still very much in the early stages and we have a lot to learn and a lot of questions to be answered and a lot of optimization improvements to be made.

Jenny: Can you give us an idea of how long you've been researching the T cell/vaccine area for myeloma?

Dr. Rapoport: I've been actually involved in this work for over 15 years. I've been working very closely with -- I've initially started working with Dr. Carl June, who's now at the University of Pennsylvania. Dr. June and I did an early study in CML or chronic myelogenous leukemia using T cell transfers, and then we turned to myeloma actually in early 2000. We started our first study in 2000 and we have since done actually six trials of using T cells in myeloma. We've gone from just taking the patient's T cells before transplant, expanding them, and then giving them back after transplant along with a pneumonia vaccine where we showed that we could generate a high frequency of protection from pneumonia after transplant, so using a series of different vaccines that were relevant to myeloma. And now, we're doing these engineered T cells, genetically engineered T cells in our current study. So this has been a work that's been going on for over 15 years and specifically in myeloma for about 14 years. I think we're really starting to see the light at the end of the tunnel and seeing some very exciting developments, and I'm very, very optimistic for the future of cellular immunotherapy for myeloma, as well as a variety of blood cancers.

Jenny: I think the idea of having your own immune system attack the myeloma cells in any form, whether it's these T cells or monoclonal antibodies or vaccines, so maybe we can go back for a minute. I have a question. How are cancer vaccines discovered?

Dr. Rapoport: Well, in different ways. Some of the early work involves identifying novel or new proteins that are expressed on myeloma cells that are not expressed on normal plasma cells, and the cancer/testis antigens that I mentioned are one such family of proteins that are expressed in myeloma cells selectively and not in normal plasma cells, but there are a variety of other proteins that are also expressed in myeloma cells. Some of those can be used to develop vaccines or gene modified T cells that are able to recognize those myeloma-specific proteins. But as the experience with CD19 shows, it doesn't necessarily have to be a target that is only expressed in myeloma. It could be a target that's expressed in all plasma cells. For example, CD19 is a marker that's present on B cell lymphomas and B cell leukemias, ALL and CLL, but it's also expressed on normal B cells. And in fact, patients who get these CD19 CARs, their healthy B cells are often eliminated as well and the body can survive that. The body can handle that. And so, potentially if there was a good target that's identified only on plasma cells, say, CD138 for example, one could potentially develop a CAR against that that could eliminate all the myeloma cells, but also all the healthy plasma cells, but patients can actually live without plasma cells nowadays because we can give them Immunoglobulin G or IgG and be fairly well protected from infection. One doesn't have to only rely on proteins and markers that are only expressed on myeloma cells. There could also be things that are selectively expressed on that class of cells, but as I mentioned, it's important that the targeted protein not be expressed on the vital organ. In fact, the T cell immunotherapy literature does have a number of papers describing where genetically engineered T cells have gone awry and attacked not only the cancer, but also attacked the healthy cells that were important for patient health and viability. We actually did have an experience like that using T cells that were directed toward the MAGE-A3, the cancer/testis antigen. This has been published where a couple of patients developed a fatal cardiac disease as a result of the T cells and a protein in the heart that also was very similar to the MAGE-A3 protein that was being attacked on the myeloma cells, so the myeloma cells were eliminated, but unfortunately, the heart was damaged irreversibly as well.

Jenny: You have to be careful.

Dr. Rapoport: Yes. This is a very powerful, very potent technology, but it definitely has to be pursued very carefully and cautiously and with a lot of attention to safety, and doing the studies to ensure that the T cells are going after only the things you want them to go after. It's a very powerful technology, but there are definitely pitfalls to it.

Jenny: And some follow-up questions, is there a difference that you've seen in responses for patients with different genomic myeloma types like t(4;14) or t(11;14) or del(17p), or have you seen that these T cell and vaccine approaches work just the same across the board?

Dr. Rapoport: Well, that's a good question. I think that we really don't know that yet. I think the numbers of patients who've been treated doesn't really allow us to say that.

Jenny: Subdivided.

Dr. Rapoport: Yes. However, I would say that the patients that are eligible for our immunotherapy trials, especially the gene modified T cells that are directed against the LAGE or NY-ESO-1 cancer/testis antigens, is already a sort of selected group of patients with a more aggressive myeloma and a large proportion of those patients have those high risk cytogenetics t(4;14), del(17p), relapses after prior therapy and often after prior transplants. We're in fact treating many of those patients, but to say this this approach works as well against to those patients with high risk features as it does with patients with lower risk features, I think we can't really comment on that, but we're already de facto treating those patients because those are the ones that tend to express those cancer/testis antigens. The cancer/testis antigens tend to be expressed in patients with relapsed, aggressive, more proliferative, extramedullary myelomas.

Jenny: And so, has this approach been considered in smoldering or MGUS to maybe prevent this disease progression at all, or you're using it more with the aggressive and going for that group first until it's a little more developed?

Dr. Rapoport: I would say that we're definitely focused on the patients who have active symptomatic disease and usually patients who've had relapsed after multiple prior therapies, not to say that it couldn't have a role in the future for preventing certain patients with high risk smoldering myeloma from progressing, but right now we're definitely focused on patients with symptomatic, advanced, or high risk disease.

Jenny: And so, you have a trial open that is for advanced myeloma with the LAGE-1, right? And then you have an approach that includes no transplant, and then you have another approach that is the T cells and the vaccine with transplant, correct?

Dr. Rapoport: So the vaccine, transplant, and T cell trial, that's now closed. We've completed that. That was recently published in the Clinical Cancer Research on March 1st, so we've published that and that trial was closed. Having said that, we are developing some plans to test this particular MAGE-A3 vaccine further in a future study. That study is not yet open. In fact, it's worth pointing out that certain markers like the MAGE-A3 may have to be approached with a vaccine rather than with a redirected or engineered T cell because as I've mentioned, the redirected T cells against MAGE-A3 had a deleterious effect on the heart, so we may have to rely on the vaccines for certain proteins and use genetically modified T cells to target other markers and other types of myeloma. But yes, we do have currently opened one trial using transplant plus gene modified T cells and just low dose chemotherapy plus the gene modified T cells without transplant, and the latter trial is open at the University of Maryland here in Baltimore, as well as the City of Hope in Duarte, California.

Jenny: Well, that's wonderful. I know patients will be very interested in that. I don't want to take too much time because I have some email questions and we have some caller questions. Let me open it up to that right now, if that's okay with you.

Dr. Rapoport: Sure, absolutely.

Jenny: Okay. If you have any questions for Dr. Rapoport, please call 347-637-2631 and press 1 on your keypad. Please go ahead.

Caller: Hi! You say that you're optimistic about this type of approach for the future as far as treating multiple myeloma in patients. How far in the future would you consider that to be?

Dr. Rapoport: A very good question. I think that in terms of the engineered T cells, clearly we already have studies looking at the high affinity approach, but in terms of the developing CARs or chimeric antigen receptor modified T cells, I think that we're going to see first the studies using that approach, I'm thinking within the next year, so definitely be on the lookout for that.

Caller: Excellent! I have another question as well. Are you still there?

Dr. Rapoport: Yes.

Caller: Many of these therapies or many of the existing therapies are really tough on the patients. I mean, it takes quite a bit out of us. And so, how difficult would you say on a scale of one to ten would you say it is on our body? And then also, is this a kind of therapy that we can repeat again and again and again if necessary?

Dr. Rapoport: Good questions. Well, I think that in terms of the cell-based therapies, it depends very much on the particular cell product that's being used. We've actually found that with the affinity enhanced T cells, the side effects are quite minimal. The studies on the chimeric antigen receptor modified T cells do show more in the way of fusion-related side effects. Most of the side effects occur within the first couple of weeks of therapy. I think the other part of the question, can it be repeated, I would say potentially, yes. In fact, we've done that with our own trial using transplant plus gene modified T cells. We have actually given second infusions of T cells to a handful of patients and those have been well-tolerated, and we've seen some interesting effects in terms of myeloma.

Caller: Excellent! Thank you very much.

Dr. Rapoport: You're welcome.

Jenny:  We have another caller. Go ahead with your question.

Caller: Thank you very much. I appreciate your time and the doctor's time, very interesting research and clinical applications. One, Dr. Rapoport, would you be able to comment on the success of recent clinical trials? It seems as though I've read something that Dr. June did with maybe a very limited clinical trial patient population, maybe 15 or maybe even just 10 or 12 patients that seemed to do well Also, would you be able to comment on the options for non-transplant application of gene therapy, how well that's progressing compared to perhaps maybe the stem cell transplant, plus the gene therapy is more effective at this point in time, but how you see that effectiveness of just the gene therapy without the transplant?

Dr. Rapoport: I think there really is a potential for doing cellular immunotherapy without transplant. Certainly, the studies from Dr. June's group have related -- you were talking about before. Those have been people and patients with CLL, chronic lymphocytic leukemia, and ALL, acute lymphoblastic leukemia, and those were done without transplant or patients may have had transplant before, but transplant wasn't part of the cell-based approach. And yet there was obviously significant clinical efficacy and a majority of the CLL patients and the ALL patients have had excellent responses, and a number of those responses are now lasting for more than three years. I think that one of the notions in immunotherapy has been that immunotherapy is best used and most effective for patients who have minimal disease. And so, the idea was to do the transplant, get the myeloma down to a low level, and then attack it with immunotherapy. That's been one of the dogmas, but that may not be necessary especially with some of the more potent and longer surviving cell-based approaches, so more to follow on that, for sure.

Caller: Okay. And just real briefly, with regards specifically to myeloma, I thought I saw something that Dr. June had done or maybe under the umbrella of his lab, but can you comment on recent efficacy of any trials for myeloma?

Dr. Rapoport: Well, I think that most of the immunotherapy trials for myeloma have been single-arm trials. There's been one randomized trial and one double-arm trial. Nobody has yet compared standard therapy with standard therapy plus a vaccine or immunotherapy for myeloma. However, there is a trial that is actually under development that the CTN, the Clinical Trials Network for a center for stem cell bone marrow transplantation, will be addressing that, that will be using a cellular vaccine based on taking a patient's own myeloma cells and using that to make a vaccine, and patients will be randomly assigned to get either a a standard transplant or a transplant followed by the vaccine and comparing the outcome. So I think that would be one of the first trials that will address that in a randomized, comparative fashion.

Caller: Thank you very much. I appreciate your time.

Dr. Rapoport: You're welcome, my pleasure.

Jenny: Thank you so much. We also have another question by Byron that says, "How would I go about joining your T cell trials or know if I qualify?"

Dr. Rapoport: Well, first of all, all T cell trials are listed on the NIH website at clinicaltrials.gov. He can certainly email me directly, arapoport@umm.edu. The main thing for eligibility is that patients need to have a certain HLA or tissue marker called HLA-A201, which is the most common A-marker. It's present in about 50% of Caucasians and about 30% of African-Americans and Hispanics, so it's relatively common, but not everybody has it, so that's the first thing. They have to have the A201 marker. Then we have to check their myeloma cells to see if they have the LAGE-1 or NY-ESO-1 marker, which requires a bone marrow test, so those are the main eligibility criteria. I'd be happy to fill any inquiries and there's more information in the clinicaltrials.gov website also.

Jenny: And then we have one more email question by Judy and she says, "I've heard a study vaccinating for shingles with possible anti-myeloma effect. What might your thoughts be on other types of vaccinations that might affect myeloma?"

Dr. Rapoport: I have not heard that particular linkage between the shingles vaccine and myeloma. In fact, usually the shingles vaccines that's out there is a live, attenuated virus vaccine and usually not recommended for patients who have active cancer or who have gone through transplant. There is actually a killed vaccine that's under development, but I don't think that's yet commercially available. We've actually done a lot of studies with the pneumococcal conjugate vaccine as many of our early studies used a pneumonia vaccine called the pneumococcal conjugate vaccine. Certainly, I would say that these vaccines, the ones that can be safely given to patients with myeloma transplant I think do lead to enhanced protection from the germ, but I don't think there's any data that I'm aware of that that's protection from the infection, which is beneficial. I mean, patients can develop a very serious viral infection, flus and pneumonias after transplant and after therapy from myeloma, so protection from infection is not a trivial thing, but I'm not aware of that protection actually transferring over to the myeloma itself.

Jenny: Well, thank you for the clarification. I thought we had one more caller. Well, thank you, Dr. Rapoport. We've gone overtime, but we do have one more caller. They came on and came off, and came on again. All right, go ahead with your question.

Caller: Thanks for taking the call. Sorry, I was having problems with the buttons there.

Jenny: That's okay.

Caller: Dr. Rapoport, thanks for taking the question. When you mentioned patients participating in medical trials, you mentioned that they had certain markers. How do you know if you have those or not? Because my wife, the markers that you've identified, she's had a lot of testing, but she hasn't been -- as far as we know, we don't know if those markers are present or not present. Those are new markers that we haven't heard of before. So if the traditional tests that the doctors are doing aren't identifying these specific markers, how would you even know if you could qualify for a trial or to reach out? I went to the website you mentioned. It's pretty confusing. I wouldn't even know how to go about understanding what they're talking about on the government website.

Dr. Rapoport: I guess we know the government websites are sometimes problematic, but with regard to the tissue marker, it's not routinely done. It's not like a CBC or chemistry panel. It's not part of that. It has to be ordered specifically. It would be ordered as part of -- if a patient was being considered for a donor transplant, for example, and one needed to do tissue -- it's a tissue-typing test basically, so it would have to be specifically ordered. It's easy to obtain. It can be done by any major lab. Any major hospital can do that type of test, but it does have to be specifically ordered, HLA-A typing. These are very commonly done and any patient, as I mentioned, who may be a candidate for a donor transplant would have a full panel of tissue typing and HLA antigen typing done. If your wife has not had any testing for possible donor transplant, she may well not have had that done, but it is easy to obtain.

Caller: All right. Thank you.

Dr. Rapoport: You're welcome. Feel free to email me if you have further questions or if I can help in any further way.

Caller: All right. You mentioned your email earlier. Thank you.

Dr. Rapoport: You're welcome. Good luck!

Jenny: Well, Dr. Rapoport, thank you so much for joining us today. This area of research is so exciting. And so, we hope you just keep going and continue your excellent, excellent work. Thank you for your dedication to myeloma patients. We know that your work will contribute to finding a cure for this disease, so thank you for all that you do for us.

Dr. Rapoport: Well, I thank you, but I want to really reflect that to all the patients out there, patients and families who've really been the driving force for this and all types of research in every way. And the patient's courage and determination and energy that drive this work make it all possible, so really that's where the credit is due to all the patients out there and families, so we thank them.

Jenny: Well, we thank you for taking care of us. Thank you and we hope that at some future time, you'll join us again and give us another update.

Dr. Rapoport: It would be a pleasure. Thank you so much for allowing me to talk this morning and I hope it's been helpful. Thank you.

Jenny: Extremely helpful. Thank you so much. Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we as patients can help support a drive for cure for myeloma by joining clinical trials.