Immunotherapy: unleashing immune system to attack cancer
MD Anderson Cancer
Lisa Garvin: Welcome to Cancer Newsline, a podcast series from the University of Texas MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention providing the latest information on reducing your family's cancer risk. I'm your host, Lisa Garvin, and today we'll be talking about one of our Moon Shot Programs, one of our more successful ones. Our two guests today are Dr. Jim Allison. He is the Chairman of Immunology here at MD Anderson and Dr. Pam Sharma, who is an Associate Professor in GU Medical Oncology and also the Scientific Director of Immunotherapy Platform. We'll start with you Dr. Allison. As some of you may know, Dr. Allison's work that he brought to MD Anderson is really helping us make great strides in immunotherapy in this instance for melanoma. Dr. Allison, talk to us about your work with CTLA 4, which was kind of the receptor or protein on the T-cell surface.
Dr. Jim Allison: I've got to go back to the start.
Lisa Garvin: Sure.
Dr. Jim Allison: Immunotherapy has been compelling to many of us as a way of treating cancer for several reasons. They make it really completely distinct from other approaches to treating cancer. One of them is the specificity of T-cells. They recognize peptides, little bits of protein in cells that are there either because the cells are factored by a virus or because there are mutations that are associated with protease process that causes cancer. So in a way T-cells of the immune system targets the cancerous process itself. The second thing is it provides memory and once you've got memory you've got it for the rest of your life just as you get a vaccines when you're a kid the immunity stays with you and the third one is adaptability. We all know from things in the press and from observations in the clinic that tumor cells are incredibly adaptable and they can change as the population to escape almost anything you throw at them. Well, one of the things we know, that I know as an immunologist, is that the immune system is even more adaptable than the tumor cell because the immune system has to be able to change and deal with any virus or anything that nature throws at you to protect you from it and so it's perfectly capable of dealing up with changes in the immune system, but for many years despite the fact that we've known T-cells can do this, we know what the targets are in some cases and people have tried to make vaccines to use therapeutically not prophylactically and prevent the cancer from actually treat the cancer and with very few exceptions these have really not been very successful at all and it was because people didn't really understand that much about how T-cells are regulated. So that's an area I've been studying for almost three decades now. It's not cancer per se but it's how T-cells are regulated and what we learned in the last decade or so is that it's really regulated by three structures on the T-cells surface. One of them is the antigen receptor. This is like the ignition switch in a car that recognizes something different about a cell that it's had a mutation and it's a cancer cell or it's a virus infection, whatever. The second one that we found was a molecule called CD28. It's sort of like the accelerator pedal, you know, you've got to give it the gas after you turn on the ignition and nothing happens. There was another component called C24 molecule that we showed, a colleague at the University of Chicago, Jeff Bluestone, showed was the brakes and actually stops the immune system and it has to stop it because the way the immune system works. These cells expand incredibly fast to allow the immune system to keep up with bad things coming on and what we thought was all the attempts that people make to vaccinate with these bits of tumors was they were trying to give the on signal. What they didn't realize was the wiring of the immune system every time you do that it's followed by the off signal and so after a while you're just giving the off signal. So, anyway when we realized this in the mid 90s I thought that this would be a wonderful thing to think about in treating cancer because for one thing you're not treating the cancer cell, you're treating the immune system. So this is completely different in all of the approaches of cancer therapy or even the cancer vaccines or at the end of the day focused on a bit of a cancer cell where if we block that, suspend the brakes temporarily the immune system can take care of the tumor itself. The second thing was this all works at the level of initiation of immune response what we call priming, which requires tumor cell death and so I felt this sort of approach with NFC24. If it worked by itself, that was great, but if it didn't, you could combine it with radiation or with the new genomically targeted therapies or freezing or some way of killing the tumor cells.
Lisa Garvin: Well, we were talking beforehand immunotherapy as an approach in cancer has waxed and waned over the years. I mean it seemed like there would be discoveries that didn't bear fruit and now with discovering that CTLA4 is a brake rather than a gas pedal seems to have blown the whole field wide open.
Dr. Jim Allison: Yes, it really has. Our first experiments in mice were almost magical. It made me very skeptical and I actually did some experiments myself, but we give mice transplantable tumors and then inject with this antibody we made to the mouse CTLA4 molecule and the tumors would grow for a while but then just disappear. The mice would be permanently immune to rechallenge. They had lifelong immunity and when we saw this, we started doing different tumor lines and just as we had predicted from the mechanism the tumors were pretty much irrelevant. Not completely but, you know, we were treating the immune system again not the tumor cell.
Dr. Pam Sharma: But if I can interject just slightly I just want to point out that CTLA4 as an inhibitory molecule, yes, that was something new from the basic science and basic immunology, but I think Jim's idea which really shifted how we did things was to point that in the clinic we were so used to thinking of giving the on signals to get the immune system going instead of paradigm shifting idea actually was that let's not give the on signals, let's block an off signal and that was why anti-CTLA4 I think was such a new way of thinking of things, there was a whole new concept. I mean the idea that CTLA4 was an inhibitory molecule I think, you know, fuel labs including Jim's lab, sort of looked at that and saw that but the concept of blocking an inhibitory pathway to now turn the immune system on instead of how we were doing it before was really the big paradigm shift and that led to the clinical responses that we're now seeing.
Lisa Garvin: So, the first batch of studies in the late 90s, early 2000s, kind of led to the development of ipilimumab, which is also called Yervoy commercially, it must have been really exciting to see this theory actually come to fruition in the trials.
Dr. Jim Allison: Yes, it was quite exciting to hear about the early days. There was a trial, Phase I trial, which is normally considered from where you test the safety of the drug and, of course, there have been extensive testing in animal models and they've been saved but there are animal toxicity studies, but still the question was what would happen in the first trial and there were 14 patients in the first trial that got a single injection of the antibody and 3 of them actually had objective responses, which is basically unheard of in drug development to get a clinic signal in Phase I.
Lisa Garvin: And these were melanoma patients?
Dr. Jim Allison: Yes. The other studies have shown, other studies just after this showed responses as we would have predicted in a lot of other kinds of cancer including kidney, prostate, lung, ovarian cancer, several others, small trials just anecdotal things but later on Bristol Myers Squibb decided to go for registration of melanomas they concentrated there, but I didn't really learn about it until actually in 2011 when I was visiting UCLA to give a seminar I met one of the people that was in that first trial. Her name was Sharon who had gotten melanoma, she played a lot of tennis in Santa Monica, and her doctor a good friend of mine, Tony Revis, and he told me that she was there the day I visited because he told her I was going to be there and anyway he had told her 10 years before that there was this new drug and it was first demand and the usual stuff, said it might be dangerous. She said I'll do anything. She had failed everything, she said I'll do anything I just want to live long enough to see my son graduate from high school and so I was meeting her 10 years later and she had had no recurrences, no further therapy and they showed me her CAT scans, which looked exactly like a CAT scan six months after treatment only it was 10 years and now it's been almost 4 years additionally and she's 14 years out now from therapy after getting only a single treatment of the antibody. So that was really, sunk home to me that this was, you know, doing good things. It became something more than just, you know, of a number or fraction.
Lisa Garvin: And it was the proverbial ah-ha moment.
Dr. Jim Allison: Well, I had had an ah-ha moment before that a little bit but it certainly still touches me to think about that.
Lisa Garvin: Especially when you see the human face of your work that must be interesting.
Dr. Jim Allison: So I met another woman who about she was in her early 20s and she had just gotten married and just finished college and, again, failed everything in 2005 I think it was I was asked to come to the clinic and she was a year out from being declared totally tumor free and since then I've gotten two emails from her with photographs of her babies, she now has 2 babies. She's about 10 years out now.
Lisa Garvin: So what made you come to MD Anderson? You've only been with us for a couple of years. What made you bring your work here? Was it out Moon Shot Program for melanoma?
Dr. Jim Allison: In part, in part, but when the early work was going on, I was at the University of California at Berkeley, it was a wonderful school for basic science, and I became more and more convinced that anti- CTLA4 was going to go to the clinic and I wanted to help it go there. So, I left Berkeley in 2004 and went to the number two cancer center in the world, Memorial Sloan Kettering. So with the goal of getting more acquainted with the clinic and, again, I'm a scientist and I wanted to understand just to say how it works isn't good enough, you know, by then it was known there are additional of these checkpoints we call them and so we needed to know the mechanisms, the detail of molecular and mechanisms by which these things work so that we can understand how to put them together. So, I came here. That wasn't really going on to the extent that I liked at Sloan Kettering. So, I came here in part because Dr. Sharma had developed a way of doing clinical studies that are really designed to learn that basic information, these small pre-surgical trials that she pioneered where you really design the trial to help the patient, if possible, but mostly just to get information, mechanistic data and so I knew this was going to be the place to go. So that was really attractive because that's what needed to be done and then Ron told me about the moon shots and we could together the two of us could develop this platform to really bring these drugs forward. I should maybe point out that after these almost miraculous responses in the first trial, the ipilimumab is a model therapy was found to give durable responses in about 20% of metastatic melanoma patients. So about 20% of patients that are alive 3 years after therapy die of something else basically anybody that makes it for 3 years and that's about 20% never reoccur, never need more treatment and die of something else. There's another drug called PD1 that has a different mechanism that has the same sort of properties in general, it works very differently, but it has kidney cancer, non-small cell lung cancer melanoma as well and if you put them together since you have different mechanisms they're additive and so 50% of patients respond there and the survival we'll know soon, but I just mentioned that because now we're at the point for the first time immunotherapy certainly maybe cancer therapy in general where a big fraction of the patients can have durable responses that can last for decades and so that example I think illustrates why we need to know mechanism and so maybe Pam Sharma can tell you about her attitude towards what we're trying to do in the platform.
Lisa Garvin: Dr. Sharma, as the Director of the Immunotherapy Platform, obviously you're building the basis for trials and studies and then the translational research into the clinic, tell us more about your flexible clinical trial design. How important was that in dovetailing with Dr. Allison's work?
Dr. Pam Sharma: So I think we all wanted to understand what were the immune responses and the patients. So if you took the brakes off, if you block CTLA4 and you enhance T-cell responses, what did that look like? What does that mean? How are the T-cells now changed so that they can start to attack the cancer cells? Because the basic thinking is that the immune system exists within all of us. We all have the same immune system. The immune system can protect us from viral or bacterial antigens, also from cancer antigens as Jim was mentioning. So why does the cancer then grow if we have this immune system and this immune response there? So really we could understand that the immune system was becoming not capable of functioning in the same way because the tumors learn how to evade the immune response. Also the immune system was not really having the effect that we needed it to have because it had all of these brakes, these inhibitory signals like CTLA4 and PD1 affecting it. So if you gave an antibody to block, then you could take off those signals, but once you remove the inhibitory signals, what did the T-cells really do? Why was it that only some patients could respond to the therapy and not others? If we learned something from the ones who are responding, could we then apply it to the patients who are not responding initially and then get them to respond to the therapy as well? That way you can have more and more patients. That's how they, you know, thinking about the combination therapies because we don't think it's monotherapy, it's going to be combination therapy that's going to lead to more and more patients responding, but we need to know what combinations, we need to know what was happening in the patients themselves. So we needed to do the immune monitoring studies not because we had all these great mouse models, we needed to do immune monitoring studies because we had all these great patients now who are responding and those who are not responding. You can learn from both groups, but a lot of times the immune monitoring was usually done in peripheral blood. That's what decades of immune monitoring consisted of peripheral blood. So we understood by this point though the peripheral blood was not sufficient because in order to understand what the immune system was doing against the cancer cells, we needed to get the tumor tissues with the immune response ongoing in there after we gave the treatment so we could see what the immune response was doing within the tumor micro-environment basically. To design those kinds of studies we had to think about our cancer patients in general and cancer patients it's usually the stage 4 metastatic disease patients who get involved in these clinical trials and it's not that the patients failed every therapy it's that the therapy failed the patient, right? So a lot of these poor patients, unfortunately, those therapies that we have out there right now didn't work for them and so then you're putting them on a clinical trial. So then you're trying to understand what's going on and it's hard to get tumor tissues in that setting because they have metastatic disease and it's not easy to give biopsies and it's not easy to grow enough T-cells out of the small biopsies. So we designed a clinical trial where patients with localized disease, these are patients with early stage disease who are scheduled for surgery. So when you schedule for surgery, you usually have somewhere between an 8-10 week window before the actual surgery happens and so in bladder cancer patients where we first designed the first trial, we asked these patients if they would want to participate in the protocol where they would get 2 doses of the drug before they go to surgery. Now a lot of people say this is a neoadjuvant trial that's what they call it because you're giving treatment before surgery. Well, I don't want to call it a neoadjuvant trial because neoadjuvant implies that we're giving clinical benefit, okay, because a neoadjuvant trial means you're giving maximum amount of therapy to illicit clinical benefit. That's not the purpose of these trials. They're really trials designed to understand mechanism of the drug. So, for example, if ipilimumab is approved as 4 doses of the drug of 3 milligrams per kilogram, now what we were doing is giving 2 doses of the drug. So obviously we're not giving the maximum amount of drug that's approved for treatment. We're giving just 2 doses so to try and see what is the mechanism associated with the drug? So these patients participate in what we term the pre-surgical clinical trials in that they got some of the drug, they went to surgery and we were able to now take all of their tumor tissues at the time of surgery to ask what are the T-cells doing in these tumors? How are they different from patients who didn't get the drug? So it's important because we had another cohort of patients who went directly to surgery as they normally would without participating on the protocol and that was the comparison group to see how did the untreated versus treated look in terms of a immune response that's occurring within the tumor and by that way we can start to identify potential mechanisms or markers and in this setting we identified a marker known as i-clos, where we were able to say this is probably an important player in why these immune responses are occurring and then Jim and I collaborated to actually show that was true in mouse models and now hopefully we can start to think of how to bring target of i-clos back to the clinic for patients again. So it was a 12-patient clinical trial that first pre-surgical trial in bladder cancer patients and from 12 patients we could learn a lot because we had the tumor tissues and the blood and so it really provided us with mechanistic details that I don't think that in 800-patient trials where all you're getting is blood gives you the same kind of understanding. So we're big proponents with immunotherapy platform of trying to not only think of your Phase I, Phase II and Phase III clinical trials, which we're all used to, but also thinking of these small mechanism based trials, these 10-20 patient trials to really understand how do these drugs work either as monotherapy or in combination with other things.
Lisa Garvin: So it sounds like as we move forward on immunotherapy study and research that we kind of have to drop the whole standardized notion of how clinical trials are designed and people participate.
Dr. Pam Sharma: I think we have to incorporate the new thinking. The Phase I, II and III absolutely work for understanding clinical efficacy and safety, but we have to start to incorporate this other way of looking at the clinical trials for mechanism based understanding because a lot of times we just give the drug but we don't really know whether it's working or not and we can't afford to keep doing that for 800 patients and then going, oh, the drug is not having the impact we want it to have, it's not having a biologic impact. We understand we need it to have clinical efficacy, but before clinical efficacy we should at least show that it's having biologic impact. So, for example, when we give anti CTLA4, we can see in the control patients who did not receive the drug very few T-cells were in those tumors. After CTLA4 and patients who received that lots of T-cells infiltrating. There you go. We have a biologic way of showing now the drug is having its impact. Now maybe you can start to look more at those mechanisms but understand that also the clinical efficacy is important to look at in the larger trials. Unfortunately, a lot of times we don't even have a biologic readout that the drug is having an impact and we're just waiting for clinical efficacy and when you don't see clinical efficacy you don't understand why not because you didn't do the mechanism based studies.
Dr. Jim Allison: So, I mean Pam said it well a 10-12 patient study in her case identified a new pharmacodynamic marker of the drug actually hitting its target which tells you it's working or it's having biological effects. The second thing was that small child identified a new, target, looks like a potential additional target that we could use to develop new drugs and we're working on that but that's outside the Phase I, II and III system, which is that older system is still useful except it has got to change too because we know now from the early data on a few hundred patients with anti CTLA4 and PD1 together there's a 50% objective response rate do you have to have an 800-patient randomized trial before you understand that that's doing something? Do you have to have a 5-year trial to show that that works? Suppose this new thing we have proved do we need 5 years of studies on that before it could be approved in another 5 years? This whole process has got to be shorter. It used to be that you needed those large trials because the effects were so small you wanted to see a median increase, the increase of survival of 50% of the patients increasing by a few months because that's all the drugs did. Now these drugs give you, they do that they move to survival, median survival over but they also give you a tail on the curve where people are apparently cured and no other drugs have done that before at the level these immunotherapies do and we've got to concentrate on that not moving the median survival to the right a little bit, we don't need those 800 patient trials. We should be concentrating on raising that tail and taking it to more patients where we can get it from 20% to 40% to 60% and then go outside of melanoma. We can't take 5 years for every incremental step to do that.
Lisa Garvin: Will the FDA go along with this?
Dr. Jim Allison: They're becoming more receptive. It's hard to come up, it's going to take a lot of thought and a lot of collaboration and cooperation, but I think they're becoming more receptive to surrogate end points.
Lisa Garvin: But it sounds like the research that you all have done with anti-CTLA4 has kind of maybe softened their outlook because we've seen something that can rapidly move into the clinic ostensibly.
Dr. Pam Sharma: Yeah, we think cancer immunotherapy is definitely at a point now where it's a pillar, it's a pillar of treatment for sure. Radiation, surgery, chemotherapy, these are all pillars for our patients and cancer immunotherapy is one of them. The immunotherapy drugs out there that are showing these kinds of promise. One of the things that we feel is that the FDA, the NCI, they all have to get behind this and seeing the cancer immunotherapy agents through making sure we have an easy path for getting these drugs to our patients understanding, of course, safety has to be established, but I look back to the HIV era and the advocacy programs that are out there to really move these drugs quickly and in combination quickly so that we can help our patients who have nothing else. That was an amazing time to watch how the whole structure, the infrastructure between the government, the patient advocates, the patients themselves, all of these organizations coming together to make that work out we need to do the same thing right now for cancer patients with these immunotherapy drugs.
Lisa Garvin: I feel like Gleevec kind of kicked the door open just a little bit because that was a very successful leukemia drug that they actually ended the trial early as I recall because so many people were benefiting.
Dr. Pam Sharma: That's right.
Lisa Garvin: So, as we move forward, I know that you said there were some other immune checkpoint blockades that you guys have identified. So --
Dr. Jim Allison: -- not just us but there's a lot more people working in this area now.
Lisa Garvin: So as it pertains to the Melanoma Moon Shot here at MD Anderson, where are we going now from here?
Dr. Pam Sharma: So there are combination treatments now in the Melanoma Moon Shot with the anti-PD1 plus anti-CTLA4, for example, there are other agents so not just blocking the inhibitory pathways such as CTLA4 and PD1 those are well-established inhibitory pathways that are now co-stimulatory pathways where you want to turn some of these pathways on such as OX 40, 41BB, i-clos, all of these other pathways where we think maybe, you know, putting an antibody that blocks an inhibitory pathway but an antibody that turns on a co-stimulatory pathway even those things might be meaningful. So these are all different combinations that are coming through the pipeline and also combining targeting agents. So, for example, the braf mutated melanoma, the braf inhibitors are out there working very well but even though you have these dramatic responses they tend not to be long-lived responses. They're very short lived. So giving the braf inhibitors in combination with things like anti-CTLA4, anti PD1, to get the immune response also involves so you can get more long-lived responses against the tumors.
Lisa Garvin: So, Dr. Alison, do you think, and I am using a term that our president used, Dr. DePinho, do you feel like we're circling the moon on melanoma?
Dr. Jim Allison: We're getting close, yeah, I think that's going to be the first Moon Shot that's going to be there, but I think the way things are going I think lung cancer and women's cancers particularly breast cancer are going to be soon to follow.
Dr. Pam Sharma: Prostate cancer as well.
Dr. Jim Allison: Prostate as well.
Lisa Garvin: Dr. Sharma, how exciting is this for you? I mean this is probably something you've been noodling around in your mind for a while now before Dr. Allison's arrival. So this must be like a whole new day for you.
Dr. Pam Sharma: It's an exciting time I have to say. I did my PhD in immunology and, of course, my MD in medical oncology so I've been seeing patients for a long time and I've been conducting a lot of clinical trials before anti-CTLA4 and anti-PD1 came along. We did the older clinical trials where we gave patients vaccines, peptide vaccines or protein vaccines trying to get their immune system turned on to eradicate the tumors and those were not very successful. We had anecdotal responses at best and now to have agents where you really have a larger proportion of patients who are doing so well is absolutely wonderful. I mean we all knew the day would come it's just great to see it finally here and to see immunotherapy take off in this direction.
Lisa Garvin: And, Dr. Allison, obviously we're glad to have you at MD Anderson, but it sounds like you found your home as well.
Dr. Jim Allison: I think so. Pretty happy here.
Lisa Garvin: So what do you see coming in the next year? Now is ipilimumab, I know it's been FDA approved is it commercially --
Dr. Jim Allison: -- yes, it's been FDA approved for metastatic melanoma I would think that probably every melanoma patient in the country that's at a major cancer centers is getting it, the community I'm not sure. I think that the next thing to happen probably is maybe the approval of the anti-PD1 antibody in lung cancer and pretty soon we're going to see I hope, I'm optimistic, really sound results with ipilimumab in prostate cancer.
Dr. Pam Sharma: I would just say that patients should definitely think about seeking immunotherapy clinical trials and there are lots of them out there and please feel free to start talking to your doctors about them.
Lisa Garvin: So, Dr. Allison, do you think that immunotherapy finally gets the credibility that's been lacking for so long?
Dr. Jim Allison: I think you definitely did. The December Science magazine voted immunotherapy as their scientific breakthrough of the year. That's all sciences including astrophysics, the Higgs boson won the year before and so it's a scientific achievement immunotherapy is there.
Lisa Garvin: I do have one last question. I think that those of us who remember Judah Folkman and anti-angiogenesis I think that, you know, of course, time triumphed cure for cancer and everyone got excited and then it didn't really bear fruit, but it sounds like we've got a different story this time.
Dr. Pam Sharma: I would absolutely think so. I mean the word cure is certainly on the tip of all of our tongues as we're treating patients with immunotherapy agents and the thing is that's not for everyone that it's working and so we need to figure out why not and how to make it work for everyone.
Lisa Garvin: Great. Thank you both very much and good luck in your continued research.
Dr. Pam Sharma: Thank you.
Lisa Garvin: If you have questions about anything you've heard today on Cancer Newsline, contact Ask MD Anderson at 1-877-MDA-6789 or online at mdanderson.org/ask. Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.
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