Full Show: Dr. Benson describes how immunotherapy and NK cells work, and why most cancers are genetic or molecular diseases and not anatomical diseases
Originally posted on mPatient Myeloma Radio
The mPatient Radio Podcasts are now available in iTunes. Listen at home or in your car to learn what is happening in myeloma clinical trials and how your participation can drive to a cure. In iTunes under Podcasts, search on "mpatient." Dr. Don Benson, MD, PhD, The James Cancer Center, The Ohio State University Interview date: August 16, 2013 Summary On this week's show, Dr. Don Benson shares how nk (natural killer) cells combat myeloma and how this and other immunotherapy treatments work to use your own immune system to attack the myeloma cells. He shares how his current KIR antibody (an immune therapy) clinical trial works and his patient, Joel Wharton, shares his experience participating in this latest trial (results expected in December 2013). Dr. Benson describes how PD-1 works, why it looks promising and describes his upcoming PD-1 clinical trial next month. He says that we have to stop thinking about myeloma and other cancers as anatomical diseases and think of them as genetic or molecular diseases. If we think about myeloma in this way, we can separate it into sub-types by mutation and then potentially cross-reference those mutations with other cancers that share that mutation. The live mPatient Radio podcast with Dr. Benson
Jenny: Thank you for joining us on today's interview for the Innovation in Myeloma Series on mPatient Radio. Our goal for this series is to connect patients with myeloma specialists. In their research, myeloma doctors are identifying hurdles we need to overcome to find a cure. By participating in clinical trials, we as patients can determine how fast they run towards that goal. We are joined today by one of the many great researchers who is helping to discover the next target - Dr. Don Benson. We're also joined today by one of his patients, Joel Wharton who will introduce Dr. Benson and later share with us his experience in joining a clinical trial. Welcome, Dr. Benson and Joel. Okay, Joel, why don't you go ahead and introduce Dr. Benson?
Joel: Sure. Thanks, Jenny. It's a privilege for me to introduce my own doctor today. Dr. Don Benson is an Assistant Professor of Clinical Internal Medicine at the Arthur James Cancer Hospital and Richard Solove Research Institute at the Ohio State University. His specialty and clinical interests include multiple myeloma, amyloidosis, and blood and marrow transplantation. In addition to his clinical practice, Dr. Benson is an avid researcher in the arena of natural killer cell biology and immunotherapy. He was voted 2012 Professor of the Year at the Ohio State University College of Medicine. He is a well-educated and well-published expert in multiple myeloma. He's also a committed advocate. Just last weekend he and his wife rode bikes 180 miles over two days in the Pelotonia while raising millions of dollars to fund novel cancer research. On a personal note, I feel most blessed to be under his care. Four years ago, Dr. Benson's first question to me was, "What's important to you?" His treatment philosophy gives my life such dignity. He sees me first as a man with life goals and dreams that happens to have myeloma. His advocacy is very personal. I found a myeloma specialist that is both highly competent as a physician and thoroughly concerned about my life as a husband, a father, a counselor, a man of faith and a fellow human. I really appreciate his personal approach to my treatment and it's good to welcome him to today's conversation.
Dr. Benson: Thanks, Joel. It was very kind of you. Thank you.
Joel: You're welcome.
Dr. Benson: Where should we start, Jenny? Do you want to start talking about immunotherapy in general and the approach that we've been studying here?
Jenny: I would love for you to do that.
Dr. Benson: Okay. Our research is a little bit unique here, where we focus. Most of your listeners I'm sure know that research in myeloma is a very active area right now. Just in the last year, there have been two new treatments FDA approved for myeloma, Kyprolis and Pomalyst. The pace of research in myeloma is very fast and it's actually accelerating even faster. As a field, we're moving away from cytotoxic chemotherapies, from drugs that work like poisons and we're moving quickly into this new area of designer treatments or targeted treatments for myeloma that can kill myeloma cells without collateral damage to the patient or to other healthy cells in the body. Our research is, I suppose, a little complementary to traditional therapies though because we focus mainly on how to harness the body's immune system to fight the cancer. We started with the observation that a donor's stem cell transplant may be a curative therapy for myeloma. To go back a little bit further, we know that for other types of blood cancer, a donor stem cell transplant may cure those cancers -- leukemias, lymphomas, and so forth. Really for 20 years or so, there has been a lot of research into donor transplants for multiple myeloma as a potentially curative therapy but compared to the success that's been seen in other blood cancers, donor transplants for myeloma have remained, relatively speaking, an investigational approach still. The reason for that is that while it appears that some patients may be cured with this approach, the risk is very high. The risk of dying from the transplant itself or suffering significant toxicities and side effects is very great. So donor transplant has not become a standard of care yet for myeloma, and the bulk of the research that we've done in our laboratory and in our clinical trials has been to look at the principles of how benefits are obtained from donor transplant and try to exhibit those favorable benefits using the patient's own immune system so as to circumvent the great risks of a donor transplant in this kind of setting. If people aren't familiar with a donor transplant, it's a process where we find a healthy source of cells. Sometimes it's a brother or a sister; sometimes it's a volunteer donor. These days we can even get blood stem cells from umbilical cords and we give those cells, those stem cells from the donor to the patient. In doing that, what we're actually doing is transplanting the immune system from the donor into the patient, and in this kind of approach the curative intent from that type of treatment comes from the donor's immune system. It doesn't come from the chemo or the radiation or the other treatments we give. It's actually an effect that's mediated from the donor's immune system. For whatever reason, the donor's immune system can recognize the myeloma as being cancer and kill those cells off once and for all. The problem with that approach, much of the risk with that approach, comes when the donor's immune system recognizes the patient's body as being foreign too and while it attacks the myeloma, it also attacks the patient's body and people die from that. That's really the barrier that's kept that as an investigational, experimental treatment still. What we do in our laboratory and what we've done in our clinical trials is to try to dissect or try to divorce those two effects. In other words, we've tried to develop treatments where we can harness the body's immune system to kill myeloma cells but prevent the body's immune system from attacking itself. That's kind of a general overview of what we do.
Jenny: That's great. We know that you are specializing in certain types of immunotherapy. Can you kind of describe for us the different types of immunotherapy that are available?
Dr. Benson: Sure. The history of immunotherapy is very interesting. It actually goes back over a hundred years, back in the late 1800s. There were doctors who were making observations that the immune system may be able to recognize and kill cancer cells. In fact, when a cell in the human body goes bad, when a cell develops a mutation, when a cell doesn't divide properly, one of the reasons we have our immune system is to take care of that cell that many times, the majority of the time, the body's immune system is able to recognize that, that abnormal process, and kill that cell long before it could ever cause cancer or cause any problems that would come to attention. The body's immune system has two arms, basically. There's an innate arm which I like to think of as an early responder arm and then there's a more evolved arm, there's an adoptive arm of the immune system that is charged with other responsibilities like remembering a stimulus. If you think about certain viruses or certain infections that people can get, there's an arm of the immune system that responds right away and there's an arm that puts the rest of the fire out and keeps it from happening again. Traditionally, in immune therapy, ever since its inception what people have done thematically is try to stimulate an immune response. In other words, they try to rev up the body's immune system. Think about race carts. It's as if people are trying to step on the gas to try to really rev up the immune system and generate an immunoresponse against the cancer. People have done this with vaccines, with cancer vaccines. People have done this with cytokines which are hormones to try to stimulate an immune response. People have done this with certain types of bone marrow and stem cell transplants. But thematically, since the infancy of immune therapy, the goal has been to try to stimulate the immune system, to turn it on, to get the cells angry, to get them fired up and get them out there killing tumor cells. In the last ten years or so, what people have started to realize is just like a race car, if you step on the gas but the brakes are still on, it's hard to get your car moving. And so in the last ten years, a new area of immune therapy has started and it's basically, conceptually, it's an effort to try to take the brakes off the immune system. And so that's thematically most of the work that we're doing. In other words, we're trying to figure out how cancer cells can hide from the immune system, why isn't the immune system able to recognize this cancer as being abnormal and then what are ways that we can take the brakes off, what are ways that we can release the immune system from inhibition and use it to kill cancer cells successfully.
Jenny: And would you like to describe the different kind of subcategories of immunotherapy?
Dr. Benson: Sure. Most people who work in immune therapy study cells called T-cells. These are cells that are in the adoptive arm. They're in the second arm of the immune system. One of the attractive things about T-cells is that they have a memory for their target. In other words, if you could teach a T-cell how to kill a cancer cell, those T-cells can remember what that cancer looks like and down the road they can prevent the cancer from coming back. People that study cancer vaccines, for example, focus their energies on T-cells because in theory these cells could eradicate the cancer and then keep a memory in the immune system for what the cancer looks like. The effect would be not only to put the cancer in remission but then to have a memory in the immune system for what it looked like. If the cancer ever tried to come back, the immune system could take care of it again. The type of cells we study in our laboratory are called natural killer cells or NK cells. These are also lymphocytes. They are also cells in the body - their lot in life is to circulate around in the bloodstream and look for trouble. These are innate immune cells, which means they're part of that first responder arm. With any kind of injury in the body, with any kind of trauma or infection, the natural killer cells are among the first on the scene. They are the ones that arrive right away and assess the situation and try to figure out what needs to be done and the natural killer cells can make cytokines. They can send signals to other cells in the immune system to say, "We need your help here." But the natural killer cells are kind of in the trenches, on the front line trying to keep us healthy every day. Since the mid-1970s when natural killer cells were first discovered, people have realized that these cells can kill cancer cells. Natural killer cells actually got their name in the first publications in the mid-1970s because unlike T-cells, they didn't need to be told to kill a cancer cell. In other words, if a natural killer cell is able to realize that a cell is cancer, it will kill it right away. No questions asked. One of the limitations of a T-cell is that it needs at least two signals to be told to kill a cancer cell whereas if an NK cell recognizes a cancer cell as foreign, it will kill it right away. The other interesting thing about a natural killer cell is once it's killed, it can immediately kill again. Once it has its target acquired, it makes a decision whether this is friend or foe and then it goes about its business. We've been attracted to NK cells in particular because of those properties; that they have an innate role, they have an early responder role. And in our laboratory and in other laboratories around the country, people have shown in test tubes and petri dishes and in mice and so forth that natural killer cells can certainly kill myeloma cells. How that happens, how a natural killer cell can kill cancer was something nobody really understood until about ten years ago, maybe 15 years ago. It just wasn't clear, the biology wasn't clear why an NK cell would kill one cancer and not another. We've begun to unravel that and more importantly, we've begun to translate that into a clinic with new treatments. In fact, the clinical trial that Joel is participating in right now is one of these trials to actually augment natural killer cell function. Basically, the way it works -- and I apologize if I slip into a scientific foreign language. Catch me. I'm trying to stay away from science terms as much as I can. Basically, what we think is that cancer cells develop an ability to hide from the immune system. The way that they do that oftentimes is that they preferentially express proteins on their surface that look like you. They tell the immune system, "Hey, we're part of the good guys here. Hey, we belong here. Leave us alone," so that when a natural killer cell comes by, it can't recognize that it's cancer. The cancer cell looks like a normal cell to the immune system and so they are left untouched. The cancer cells also make cytokines. They make signals and send them to the immune system to blunt its effect or to cause immune cells to die. Cancer cells use all kinds of strategies to hide and prevent the immune system from seeing them as it were, or seeing them as foreign anyway. A lot of the treatments that we've been working on are ways or strategies to uncouple that effect. The first example is the work that we've done with a receptor system called KIR. KIR are a family of proteins that are used by natural killer cells to detect self from non-self. KIR are on the surface of natural killer cells and they use these receptors to feel the surfaces of neighboring cells. If the KIR receptor finds a self protein on the target, the candidate target, it won't kill that cell. If it comes up to a cell and does not find any self protein on it, the natural killer cell will kill that cell right away. No questions asked. These natural killer cells also have activating receptors on them and so they make these decisions based on how much inhibition they're receiving and how much activation they're receiving. Basically, if they are receiving any inhibition at all, they won't kill. Even in the presence of an activating signal, they won't kill if there's inhibition present. It's kind of like having a safety on a gun that you'd prefer to be safe first rather than sorry. The inhibition signals always override the activating signals. In other words, for example, if a cancer cell has an activating protein on it, the natural killer cell can't kill that cell unless there's no inhibition present. One of the first treatments that we developed was an antibody to block inhibitory KIR on natural killer cells. This was work that started over ten years ago and we have done probably five or six clinical trials now in different settings for people with multiple myeloma. The most recent trial that we've done, Joel is actually participating on, and basically the way this works is, like I mentioned earlier, it's a strategy to try to take the brakes off the immune system, to release the NK cells from inhibition and let them attack these targets, let them attack these cancer cells. It's a principle that we learned in the setting of donor transplant in some of these trials where they've done donor transplants. They've looked at the donor's KIR proteins and how they interact with the cancer cells, and if the KIR proteins are mismatched with the cancer proteins the NK cells can kill those tumors readily. So we're trying to reproduce that effect with the patient's own immune system, with the KIR antibody.
Jenny: And what stage of study is this?
Dr. Benson: The study is a Phase I/II study. I'll give you some background on that. The last time we spoke we talked about clinical trials and the different stages of development. In our first trial with the KIR antibody, we did a Phase I trial and this was the first time we had ever given it to patients so we didn't know a lot at all about the right dose, the right duration, and so forth. In the Phase I trial that we did several years ago, we treated 32 patients in that study. All of them basically had myeloma that had no other treatment options left, just like any typical Phase I trial. In that study, about a third of the patients actually had their disease stabilize. We didn't have antibody in that study where the myeloma went away completely or where they had durable remissions, but we did have a third of those patients where the progression arrested and their symptoms got better. So at least a signal, we learned about dosing and we learned about how to use the antibody, they gave us some hope as we went forward. The current trial is a Phase I/II trial. The reason it's Phase I/II is we're actually giving the KIR antibody with Revlimid in this trial. The reason for that is as it turns out, drugs like Thalidomide and Revlimid and a new drug, Pomalidomide, these drugs as a class can kill myeloma cells directly but indirectly they can also modulate NK cells. In other words, these drugs as a class may actually cause NK cells to become activated and actually cause them to expand as well to proliferate. So our thinking with this trial was if we use Revlimid to activate cells, in other words, to step on the gas, we can use the KIR antibody to release the brakes at the same time. In the trial Joel is participating in, patients are getting Revlimid and the KIR antibody together as a dual form of immunotherapy, one to turn on the gas and one to take the brakes off.
Jenny: How long has the trial been active, and how long will it take for you to have results?
Dr. Benson: The trial went online almost three years ago. It's done now. The last patient has been enrolled and is still getting treated currently but at the upcoming American Society of Hematology meeting in December, we'll be presenting the final results publicly from this trial. I can tell you today that it's working; that we've had patients respond to this treatment. We've had some patients do quite well. In fact, the first patient who went on the study is still in remission today. He is a gentleman in his mid-50s who was diagnosed several years ago and received conventional treatment, had a stem cell transplant with his own cells, relapsed a couple of years after that and went on the study and is still in remission today and doing great. We've had a number of other patients both here and at other institutions where the trial is open who have had similar responses. I don't know, Joel, if you want to talk about your experience on the trial if that would be helpful.
Jenny: I think it would be. Go ahead, Joel.
Joel: Sure. A little history, I was diagnosed in August of 2009 at the age of 36 and, as Dr. Benson just said, I participated in conventional treatment. I was on a Revlimid-Dexamethasone combo leading up to an autologous (my own cell) transplant in January of 2010. And then I was in a very stable remission for about 18 months. And then as my monoclonal protein began to just gradually rise, I made the decision to go on this trial. It's now been 20 months ago that I started this trial. As I recall, there were eight monthly doses of the anti-KIR treatment that was administered through IV and those were daylong experiences but virtually no side effects from that drug at all. It was an antibody treatment, isn't that correct, Dr. Benson?
Dr. Benson: Right.
Joel: I think the biggest side effect was just being tired of sitting in one place for eight hours, but otherwise that actual treatment had those side effects. Then Revlimid, I was at the highest dose, 25 mg of Revlimid, and the result has been a very stable, partial remission status for me. There's still a measurable monoclonal but I've experienced a very distinct remission that's been very stable.
Jenny: That's wonderful. Thank you, Joel, for sharing your experience and I think you could help us greatly ask questions at the end.
Joel: Please. That's fine.
Jenny: Dr. Benson, do you want to continue with your work in immunotherapy because I know you have several areas?
Dr. Benson: Along the same lines, we've been working on another protein called PD-1, Programmed Death Receptor 1. PD-1 is a protein that is also a checkpoint or a break in the immune system, and the role of PD-1 normally is to keep your immune system from getting out of control in the setting of an infection. What this protein does is once an immune response is made, the role of PD-1 is to keep things under control, in other words, to prevent the immune system from going crazy and causing a lot of continued fevers and so forth and so on, a lot of inflammation. What we have shown in myeloma and what at least two other groups have shown now too is that myeloma cells are aware of this protein, and they actually can subvert PD-1 signaling as a way to evade the immune system. In other words, when an immune cell does recognize myeloma, the myeloma cell actually has proteins on its surface to stimulate PD-1 on the immune cells to prevent their response. What happens then is that even if a cell is recognized, the immune cell can't attack because it's being told to shut down. In a similar way, there are a number of antibodies now that target PD-1 and people have been using these in clinical trials -- colon cancer, in melanoma, in kidney cancer and so forth. There are early phase trials looking at PD-1 as a target in multiple myeloma. We're going to start our own study here probably next month, in September, with another antibody that blocks PD-1 signaling. The attractive thing about PD-1 is that it's also on T-cells, and so it would be a way to potentially -- we don't know that's why we need to do the trial -- but it would be a way potentially to involve both arms of the immune system so not just NK cells, not just innate immunity but also T-cells as well. It's something we're very excited about because of some of the observations made in the laboratory with this approach. For instance, blocking this receptor system, blocking PD-1 seems to have a vaccination effect in some of the mouse models that have been used. In other words, treating mice with a PD-1 antibody will cause cancer to go away but it will also prevent that mouse from getting that cancer again. It's something that we're really excited about on the immune front. We've done a fair amount of work with a drug called Elotuzumab, and this is a drug that's in Phase III trials now for myeloma. There are two big Phase III trials. One of them is done close to accrual. The other one should be done by December. Elotuzumab is an antibody that targets a protein on the myeloma cells and acts like a flag. In other words, it marks the myeloma cells as being targets for the immune system. A patient is given Elotuzumab and when the Elotuzumab binds to the myeloma cell, it doesn't necessarily kill the cell but what it does is it flags the cell for the attention of the immune system and then the natural killer cells can come in. They may not recognize the myeloma cell per se, but they recognize Elotuzumab on the cell and realize that that's a signal to get rid of that cell. Like I said, that one is in Phase III trials now. We were involved in some of the early work with that and I've done some work in our laboratory with that agent and had patients in some of the early trials that have been published now for a long time but had patients with Elotuzumab who had similar experiences to Joel or patients who had years of remission using that approach too. There are a number of other immune therapies out there. It's interesting now that learn more about how drugs like Revlimid and Pomalyst and Thalidomide wor as well as Velcade too, that all of these drugs in parts seem to have some beneficial effect in modulating the immune system in addition to their primary effects. I really believe we're just on the doorstep of a new era in cancer therapy, being able to harness the immune system the way that we're talking about today.
Jenny: I think it's a whole new world.
Dr. Benson: I teach in the medical school here and I tell the medical students that surgery for cancer has been around for thousands of years. They can find remains that are thousands of years old where it's apparent that somebody tried surgery on a cancer. We've had radiation for over a hundred years and we've had chemotherapy for over 60 years and we're still fighting cancer today. I can remember in my training in the 1990s when I was in medical school and so forth that one of the attractions to immunotherapy for me was that we have all these other approaches and yet we still have cancer. There's got to be a better way to do this. There's got to be a more effective way than cutting the cells out or burning them out or poisoning them. Really, it's been in the last ten years or the last five years where we've seen the most incredible breakthroughs in immunotherapy across the board, not only in myeloma but in other forms of cancer too. It's an exciting time and I think this is just only going to get bigger and more widely applied in the next couple of years.
Jenny: Well, it is an exciting time. I just want to go back to PD-1 because you and I had a conversation about that and you started telling me about how effective it was in other types of cancers. Do you want to speak to that?
Dr. Benson: Yes. PD-1 is being studied in a number of cancers particularly in melanoma right now which is a form of skin cancer. Melanoma is a terrible cancer. There are no good cancers but melanoma is particularly aggressive form of skin cancer where once it metastasizes, once it's spread from the skin, historically people experience very poor survival and it's cancer that's difficult to do surgery, it's a cancer that is not particularly sensitive to radiation, and it's not a cancer that's particularly responsive to chemotherapy either. Melanoma has been a cancer that has been a topic of immune therapy for many years just because there really isn't anything else that has had a good track record. Melanoma was one of the tumors that I worked on principally when I was in medical school and so forth, that it was something that at least for some patients showed promise with immune-based treatments. Several years ago, there was a study done with a drug called Ipilimumab, and Ipilimumab is an antibody. It's in the same class as KIR and the other things that we've talked about so far. It's the same idea too. Ipilimumab works by releasing the brakes of the immune system. It targets a protein called CTLA-4. What they found in this clinical trial, they had patients with metastatic melanoma who at the time had a life expectancy that was measured in weeks. At the time the study was done, the average survival for someone with metastatic melanoma was around 12 weeks. In this study, the people who got Ipilimumab actually did quite well. Importantly to note, not everybody responded to the treatment. In fact, it was the minority of patients, only 20% or 30% of people the drug worked. But when it worked, it worked quite well. In fact, the responses were quite durable. Again, none of these drugs do anything to the tumor directly. They all act on the immune system. Because of that trial, Ipilimumab was approved and it was actually the first treatment that had ever shown a survival benefit for metastatic melanoma in all the time that anything has ever been studied. The current studies have looked to build on that and that's where PD-1 comes in. PD-1 is expressed more broadly in the immune system than CTLA-4 and therefore is maybe a more attractive target for an approach like this. At the ASCO meetings in Chicago back in early June, we saw our first public presentation of the data from some of these early trials where over half of the patients with metastatic melanoma were responding to PD-1 antibodies. It's the same idea again. If you can figure out a way to release the immune system from its inhibitory effects, from the powerful inhibition that it has, you may be able to make a big difference in the efficacy of the treatment. Jenny: When you initially told me that and I said, "Wow," you said that is a severe understatement. Can you describe the significance of that, because to me it's shocking?
Dr. Benson: It is. I mean, I can remember taking care of patients with metastatic melanoma as a student and there was really nothing that you could do to slow the disease down, that people would come to our clinic and they would have one shot at a treatment. For many of them it was a clinical trial because the odds of something else working were just dismal. Thinking back 15 years, if we had a treatment that had a 50% response rate, if you had proposed such a thing, you would have been thrown out of the hospital. It was considered science fiction. I don't know how else to say it. It's kind of the same idea of saying, 15 years ago, somebody would have said there's a pill you can take for myeloma and you'll go into remission. I mean you wouldn't have been left out of the meeting and yet those are kind of commonplace things today. The significance of these approaches is, I think, can't be overstated. Again, I think it's important to note that these treatments don't work for everyone and we're still trying to figure out why that is. But when they do work, they tend to be very durable in their activity.
Jenny: Can I ask a follow-up question about that? There's been so much that's been talked about - profiling myeloma genetically and having specific, unique profiling and then targeting therapies for those profiles. Do you think that the people that these might working for, it might be a genetic mutation that they have that it's affecting?
Dr. Benson: That's something that we're really interested in our laboratory. We've talked about this before too that myeloma is not one disease; that myeloma is probably a family of cancers and the treatments that may work for one may not work at all for another. I believe, I suspect, I hypothesize, that there are sub-types of myeloma that may be especially susceptible to immunotherapy and whether we can learn that by genetic profiling or whether we can do that through amino phenotyping or flow cytometry or I think the more we know about the tumor cell, the better we can personalize therapy. I think to step back and think about cancer therapy with broad brush strokes, this is an era that we're entering now as well. Traditionally, we speak of cancer with reference to anatomy. We say, "Oh, she had breast cancer," or "He had colon cancer," or "She had a blood cancer," and we talk about cancer as being an anatomic disease and it's not. Cancer is a molecular disease; it's a genetic disease. I think we're just now entering this era too where once we understand the genetics and the molecular biology, we can develop treatments that target those problems specifically. I've shared this analogy with you before too. It's kind of like when your computer crashes, you can get your baseball bat out and hit it. It might make you feel better, but it's not going to make the computer work again. The other thing you can do is you can call an IT guy to come and find the bugs in the software program and fix the bugs and then the computer will run again. I think that analogy is kind of right where we are now in cancer research and cancer therapy, that traditionally we've hit these tumors with a bat, these cancers with a bat because that's all we've had. Sometimes it works and sometimes it doesn't. But we're entering this era where we have the technology, we have the capability of finding bugs in the software program, in other words, finding mutations in the DNA; and then we can literally customize therapies for a particular cancer to fix the bugs in that software program or we can profile the tumors and find an immune therapy that will be particularly promising for that cancer.
Jenny: And is that today or is that six months from now or a year from now? When do you think it will start happening or is it already happening now?
Dr. Benson: It's already happening now. It's already happening now. For instance, in the KIR trial, before Joel or before any of the patients enrolled in the KIR trial, we did laboratory testing to make sure that their proteins would bind the antibody and we made sure that their tumor had the inhibitory liganes expressed and that was a criteria for enrolment on the trial. It's something we're seeing more and more now. We have another antibody, a CD38 antibody study opening here where we're doing that kind of testing before a patient is enrolled to make sure that this is a treatment that has a good chance of working for them.
Jenny: I think it's how it should be done, just from a patient's perspective.
Dr. Benson: It's going to really redefine I think our whole clinical trial program. It's going to redefine how we develop treatments. We talked about this in the last episode too; the whole Phase I, Phase II, Phase III drug development was developed in a time where we didn't have this kind of technology. Inevitably, in those older trials, a lot of patients got drugs that didn't work and nobody understood why but that's where the science was at that time and now things are a lot farther along than that. I think that we're getting to a point now where -- I don't know if we're there yet across the board - but we're getting there now where we can think about myeloma as a family of diseases, for example, not just one disease and maybe not all therapies, it's not one size fits all when it comes to therapy, but there are certain subtypes that are especially responsive to one form and not another. I think there's an important role in there for immune therapy.
Jenny: Thank you so much, Dr. Benson. I would like to open it up to caller questions and give people an opportunity to ask you some questions. Joel, if you would like to ask any questions, we would like to have you as well.
Caller: Thank you very much. I have just a question. You talked about how we can look at this cancer as a family and looking at multiple approaches to making changes. What is the process in getting solutions maybe on other areas just as you have? You took cancer that was working with melanoma patients and now are bringing it to myeloma. What is the process to take other solutions that may be can be there as a combined attack on a family of cancers as you described it?
Dr. Benson: What is the process? Thank you for the call and the question. The question is what is the process behind this kind of thinking?
Jenny: Well, I think her question is about how do you take existing drugs that might already target a particular mutation or particular issue and find them for myeloma?
Dr. Benson: Oh, okay. I think that this is where collaboration comes in. I think this is where team science is very important. I think historically, traditionally, people in research, people in academics focus in one area specifically. I do that. I do natural killer cell biology and immune therapy for myeloma. I think as we learn more about what makes cancer cells tick and what makes these cells work, there are principles and there are lessons that we can translate between them. Actually, earlier this week, there was a paper that came out in the journal Nature where they looked at 30 different cancer subtypes or 30 different cancers and they found specific genetic signatures, significant genetic mutation patterns that were reproducible across all of these cancers in something like 95% of the cases. The significance of the work I think is important because it implies kind of the same thing we talked about a couple of minutes ago. It implies that there's some final common pathway or there's some commonality in the genetic events that happen in a cell going from a normal cell to a cancer cell. If we learn these signatures, if we learn their similarities and differences, then we can really move away from describing cancers anatomically and we can start to talk about cancers molecularly. It doesn't matter if it started in someone's bone marrow or in their liver. We can conceptualize that cancer on a molecular level rather on an anatomic level. I think one of the keys is collaboration and that's something that's being emphasized at our institution and I think nationally now with the way that the NCI is and with the way that philanthropic groups are, I think that collaboration is key and working across disease specificities is important. Just earlier this afternoon, literally I got an email from a friend of mine who works in kidney cancer and they have characterized the mutation in kidney cancer cells and they're developing a treatment that targets this enzyme. It so happens that there are a couple of publications that this mutation might be important in myeloma too. So he invited me to participate in the trial where some of the patients would have kidney cancer and some would have myeloma. But to be eligible for this study, you had to have this particular mutation. I think that's an example of where things are headed. We're moving away from anatomic definitions and more towards molecular and genetic descriptions.
Jenny: I agree. There was an article in the Wall Street Journal yesterday, that was the front page, that talked about lung cancer and specific genetic mutations in lung cancer and how that is being treated. So I think that's part of the future as well. We had an emailed question from a caller named Byron and his question is how would someone go by getting into the PD-1 trial?
Dr. Benson: Oh, that’s a good question. It's all written and done. It's at our Ethics Committee now at IRB, and I'm hoping it's going to open at September. When it opens it will be online on our cancer center website and it will also be on the national website.
Jenny: Joel, I would like to hear about your clinical trial.
Joel: Absolutely. What would you like to know?
Jenny: Well first, why did you decide to join this trial?
Joel: As I think back this was fall in 2011. This trial lasts 2 years. At the time, I was post-transplant about 18 months and my monoclonal protein began to rise gradually. Dr. Benson just introduced the idea to me and understanding that he was the principal investigator on this trial gave me a lot of confidence in him. Rather than just going on with conventional treatment, I decided that the clinical trial seemed valuable to me. One, as just a patient in order to give back. Secondly, I was able to get a clear sense from him that the risks associated with the experimental trial were really no greater or less than conventional treatment. I made the decision to go ahead and join the trial.
Jenny: What did you think a trial would be like? Did you have any preconceived notions?
Joel: I sure did. In fact at first diagnosis in 2009 I actually had another oncologist I was working with at the time. Dr. Benson was actually a second opinion for me. Once I had experienced his care, I made a very quick switch. At that time I was introduced to a clinical trial at first diagnosis and there was a lot of fear involved. Some of the fears were – I guess I assumed that clinical trials seemed to be what were like last-ditch efforts and that scared me. I was just recently diagnosed and really what I came to find out is that clinical trials aren’t last-ditch efforts at all. In fact, this is how new treatments come to market. That was a fear. I guess another fear was just not understanding what conventional treatment was vs. what a clinical trial was. When I found out that clinical trials are as closely if not more monitored, that my treatment would be so closely monitored, that debunked my fear.
Jenny: Because you’ve had both a conventional approach and a clinical trial approach, was there a difference in the care that you received or the attention that you received?
Joel: I guess I would say that the quality of my care was no different, whether it was conventional care or the experimental treatment that I’ve been on. The experimental protocols tend to demand a bit more lab work. I find myself giving a little more blood, at my monthly checkups. It didn’t require an additional bone marrow biopsy in this case – they were able to use everything they had gained at first diagnosis. I guess that’s the one major difference. The amount of time they spend with me asking detailed questions about how I’m doing, side effects, they are very careful to understand all of those variables. The only other thing that happened on the first day of the trial I was actually admitted to the hospital for a 24-hour period just to monitor for side effects of which I had none. They basically infused me with the antibody treatment and sent me home the next day. It was a monthly infusion of the experimental drug for 8 months. I never had an adverse reaction to the medication. Revlimid was the other drug that was administered for a 21-day cycle every month, 7 days off which continues to this day.
Jenny: Now Dr. Benson said earlier that this trial was targeting a specific sub-type or genetic mutation possibly. How did he come to determine that?
Joel: That’s a good question. I recall that during my diagnosis process and then right before the autologous transplant, which was about four months after my diagnosis, I did have bone marrow biopsies done a total of two times, both the biopsy and the aspirate. They did do a cytogenetic test at that time though you are asking a great question. I don’t know my exact sub-type, however, as you already heard Dr. Benson share, just having a myeloma specialist has been so critical in my care as a diagnosed person with myeloma. Knowing that he understands that and is looking for that to tailor my treatment to the cytogenetics that I have in the subtype of myeloma that I have. That’s been kind of nice just to have confidence in his ability to measure that and to be aware of the treatment options that are going to be the best for me.
Jenny: Because you’ve had both an oncologist and a myeloma specialist help you with your care, what do you see as the difference now?
Joel: I suppose it’s primarily the confidence with which I am able to entrust Dr. Benson with. When I think about any kind of physical issue, there is always the greater comfort with the specialist over the general practitioner. I know that he is reading the research, he is doing the research, he is aware of all of the drugs that are currently being researched, are new to market, as opposed to having to keep track of hundreds if not thousands of drugs for every kind of cancer that exists. That’s been incredibly important, in fact most of our conversations during our visits have to do with what’s new in the research journals because he is on top of everything that is coming down the pike.
Jenny: And participating.
Joel: That’s exactly right.
Jenny: About your clinical trial: How long did the trial last?
Joel: The trial was a total of two years. The two years will be completed this December which is right around the time that Dr. Benson mentioned that he is going to be sharing results of this at the Hematology conference. So I’m kind of excited about that.
Jenny: I look forward to hearing the results. Now that you’ve participated in a clinical trial, what do you think now that you are finished?
Joel: Well, absolutely I would do it again and will if the opportunity presents itself. In fact Dr. Benson had previously spoken to me about clinical trials and I don’t know what research he was quoting here, but he used a statistic that was pretty impressive. He said 80% of patients who participate in a clinical trial would do it again and I really found that to be true of my experience that again because the side effects have been so manageable. In fact most of my side effects have been those that people experience on Revlimid. I’ve been working full time the entire two years. I’m fully engaged as a parent and a husband. It hasn’t robbed me of my life. I’ve been able to be fully participatory in my life. I feel like at this point that it would be a very easy decision to continue on a clinical trial if the opportunity arose.
Jenny: Let’s talk about that for a second in terms of risks. Sometimes people view clinical trials as a risky option vs. the conventional therapy. Can you speak to what your experience was?
Joel: The first clinical trial that was presented to me at diagnosis was a drug combination of four drugs. I suspect that that experience would have been a little different. The side effects between the interaction of the drugs and just the number of drugs being combined perhaps would have created a situation where I would have been a little more tired, a bit more unable to continue on with my daily life, but my experience on this one personally has been so minimal. The worst part of a clinical trial was having an IV inserted every month and sitting there for 8-10 hours during the day of the infusion. That was it. There really were no side effects that caused GI problems. There were no GI problems, there was no exhaustion associated with this. Some of that is because the experimental drug was, as Dr. Benson has already described, was used to harness my own immune response and so it’s not introducing a toxic substance into my system. It was introducing something that was going to alter how my immune system responded to myeloma.
Jenny: I think we are all hopeful that immunotherapy can cure this disease.
Jenny: Joel, we are so glad you are on today’s call. We would like to thank you and Dr. Benson for participating today. Dr. Benson is listed in our doctor directory so if you're interested in sending a message to him directly, you can go to the www.mpatient.org website, click on the doctor directory and find his profile. We are very excited to hear about the outcome of his work, and we thank him so much for his persistence and dedication to finding a cure in new and advanced areas. Thanks for listening to another episode of Innovation in Myeloma. Join us next week for another interview on mPatient Radio.