MD Anderson Cancer Center
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Lisa Garvin: Welcome to Cancer Newsline, a weekly 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. Today, we have big news not only in the treatment of advanced melanoma but also in cancer treatment over all. A paper is about to be release in the June 2nd New England Journal of Medicine that will talk about the first vaccine study in melanoma treatment and one of the first in cancer over all. Our guest today are Patrick Hwu. He is the Chair of Melanoma Medical Oncology at MD Anderson Cancer Center. Our guest, joining us by phone, is Douglas Schwartzentruber. He is Medical Director of Indiana University Health Goshen Center for Cancer Care. Dr. Hwu and Dr. Schwartzentruber were co-authors on this study. Dr. Schwartzentruber, this is really big news. We've talked about vaccines for cancer treatment for years. Tell us about your study. It's been 10 years in the making.
Dr. Douglas Schwartzentruber: It is big news and there has been much anticipation because this is the first study that demonstrates that vaccines do have a role in the treatment of patients with metastatic melanoma. This study is helpful I think to all of us that are looking for new treatments for melanoma and is a proof of principle that the immune system can indeed be manipulated to result in cancer regression.
Lisa Garvin: Let's talk about immune--I guess this is considered immunotherapy or at least that's what they used to call it 10 years ago when you started.
Dr. Douglas Schwartzentruber: Immune therapy or immunotherapy or biologic therapy.
Lisa Garvin: Now, where did you start ten years ago? What was the idea that you had back then and what was the research that you took into this trial 10 years ago.
Dr. Douglas Schwartzentruber: More--slightly over 10 years ago when Dr. Hwu and I were members of the Surgery Branch at the National Cancer Institute, we conducted--the team there led by Dr. Steven Rosenberg conducted a trial in patients with metastatic melanoma who received a vaccine, in this case the same vaccine, gp100 along with a systematic treatment, high dose Interleukin-2 and noted that patients appeared to be responding at a higher rate when receiving that combination.
Lisa Garvin: Let's talk about what a peptide vaccine is. The name of it you said is gp100 peptide vaccine. What is it and what is its action on the cancer?
Dr. Douglas Schwartzentruber: A peptide is a short fragment of a protein and this particular peptide or protein is present on cell surface and in this case, a cancer cell. It happens to also be on some normal pigment cells that are present in the skin but in particular, it is present on most melanoma cancer cells.
Lisa Garvin: So basically it works to stimulate the body's immune system to attack the cancer cells?
Dr. Douglas Schwartzentruber: So yes by taking this same protein or portion of a protein and injecting it let's say in this case the thigh, just underneath the skin, along with another immune stimulant, we start or initiate an immune reaction, in other words, we train the body's lymphocytes, a type of white cell, to recognize the cancer and hopefully attack it. The principle here then is to generate the immune system and grow these lymphocytes with a drug called Interleukin-2. Interleukin-2 is a growth factor for lymphocytes. So they multiply in large numbers and hopefully then go throughout the body and find wherever there are any cancer cells, any melanoma cancer cells and destroy them.
Lisa Garvin: Over the last the 10 years, you had 185 enrollees in the trial?
Dr. Douglas Schwartzentruber: Yes, that is correct and the trial was designed as a randomized to trial which means arbitrarily the treatments are divided. One half of the group received just Interleukin-2 alone which is an FDA approved treatment, the other half received the experimental arm which is the vaccine plus Interleukin-2 and so the main difference between the two treatment arms is just the vaccine which was given as the experimental treatment.
Lisa Garvin: Let's talk about overall response rates to the trial. It says that you had a 16.5 percent response rate among those who received the vaccine.
Dr. Douglas Schwartzentruber: Correct. So in the treatment arm that received the vaccine and the Interleukin-2, their response rate was about 16.5 percent. That means that tumors either shrank in half or completely, and then the other arm of treatment which was just Interleukin-2 alone, experienced less than half of that response rate. So in other words, about 6.5 percent had a response to treatment. So there was more than a doubling of responses with this experimental agent.
Lisa Garvin: And I think that's important to note because I think just looking at the raw figures, people may not see that that's big progress but it actually really is.
Dr. Douglas Schwartzentruber: Well, it illustrates a couple of points. So first of all, response rates are low but that is true of any treatment that we have currently for metastatic melanoma and it emphasizes the need to continue to research and to look for new treatment so that we hopefully continue with every new trial. If we can double and then double again, we will make a major impact on this disease.
Lisa Garvin: And I understand there are a couple of challenges here. First of all, the administration of IL-2 is difficult and must be performed in a hospital setting and also this vaccine is only good for people with certain tissue types. Is that correct?
Dr. Douglas Schwartzentruber: Correct. So back to an immunology lesson here. It turns out that the immune system can utilize lymphocytes in this case to recognize cancers in a very specific way but not only do they recognize the tumor antigen, in this case gp100, but they also must do that in the context of a very specific tissue type and so you need both components. So about half of the Caucasian population has the tissue type that is relevant, in this case, that would be able to be recognized by the immune system with this particular vaccine.
Lisa Garvin: Dr. Hwu, you and Dr. Schwartzentruber have been working on this for the last 10 years you've been doing a lot of work in the clinical setting. What are the implications of the study for the treatment of advanced melanoma?
Dr. Patrick Hwu: I think it's an important principle that we've uncovered that vaccines can be helpful in the treatment of patients with metastatic cancer. It's the first demonstration that tumors shrinkage or clinical response can increase when we combine a vaccine with other agents but I think another main point of this work is that this was not a vaccine given itself that worked. We've learned more and more that individual agents given alone are largely ineffective in our therapies against metastatic cancer and in this study, it was a combination, a rational combination of two stimulants, a vaccine along with the standard Cytokine Interleukin-2 which stimulates T-cell proliferation and I think that is where the future is, is that we're gonna continue to rationally combine agents. We know a lot of agents now that turn on the immune system. We know a lot that turn off the immune system and we manipulate now the immune system using multiple agents to improve these responses to get further 'cause clearly we have to do a better job. We've double the response rate but still that means that 84 percent of patients did not respond, so there's a long way to go still.
Lisa Garvin: And your treatment toolbox for advanced melanoma is pretty small at is point, isn't it?
Dr. Patrick Hwu: It's getting much larger very rapidly and it's actually getting quite exciting. I used to tell patients, you know, 10 years ago my toolbox had, you know, one screwdriver in it and that was about it. Now we got a screwdriver, a hammer and a drill and it's starting to get much more exciting. For example, the targeted agents are coming to the floor and starting to work in melanoma. So in half of all melanoma patients, they have a specific mutation in a protein called B-Raf and this is like when the patients have this mutation in their tumor, it's like turning on a light switch and the tumor starts to grow and proliferate. There are a couple of agents now that are in investigation that are just pills that turn off these mutations and patients tumor shrink quite readily with these B-Raf inhibitors. The issue is that happens in, you know, a large majority of patients but they're very transient in terms of the responses. So responses only last for a few months and then the tumors grow back again. So we're hoping that rational combinations of agents such as the B-Raf inhibitors along with vaccines and cytokines and antibodies, we can put them all together in a rational way and we can get high response rates as well as long and durable responses.
Lisa Garvin: Over the years, have we been able to budge the survival rate for advanced melanoma patients very much?
Dr. Patrick Hwu: In a small percentage of patients we have and those are largely been driven by the immune therapies. So Interleukin-2 as cytokine, it's FDA approved for the treatment of metastatic melanoma in a small percentage of patients under 10 percent, they have long and durable responses over 10 years in some patients. But we have to improve that and this vaccine will potentially improve that long and durable response in a small subset of patients. Another drug that was just approved by the Food and Drug Administration for the treatment of melanoma, ipilimumab, it targets--it's an antibody that target a protein called CTLA4. It takes then breaks off immune cells thus stimulating the immune system. Also in a small percentage of patients, they have long and durable responses. Dr. Schwartzentruber and I gave some of the first patients this throughout [inaudible] the NIH over eight years ago and some of them are still doing well today and so, those are the kinds of agents that we now have to start putting together to try to rationally combine agents in order to increase the number of patients that live five, ten years having had metastatic melanoma because in the end, that's what patients want. They want to have long and durable responses and I think by rationally combining these agents we can get there.
Lisa Garvin: Now this study was phase three trial which is usually the last step before FDA approval. What's down the road for gp100?
Dr. Patrick Hwu: Well, we've talked to some--this was done by the academic community. So we weren't really a drug company doing this and we have had some interest in some pharmaceutical companies and I'm continuing to talk to some to see if they want to try to take this to the population because I think it would be useful today in clinic because we're still giving patients high dose Interleukin-2 and we just don't have this vaccine available because a pharmaceutical company is not producing it. So it would be nice if it was picked up and we're hoping that that it will be. But the future will be to try to broaden the number of patients that can receive the vaccine as you said and pointed out, only 50 percent of the patients can receive this vaccine due to their tissue type but there are ways--and we do have peptides that bind to other tissues types so we could cover almost the entire population. So we need to start mixing peptides together so we can cover more patients. That's one of our goals. Another goal is to mix these peptides with better helpers or adjuvants. So we have a number of trials doing that and then a third goal is to try to make even better vaccine formulations. So those are all ongoing and in fact, at MD Anderson we have a trial of a MAGE vaccine trial or with the new adjuvants plus Interleukin -2 are the followup to this study.
Lisa Garvin: And Dr. Schwartzentruber, what are your next steps with this research?
Dr. Douglas Schwartzentruber: As Dr. Hwu has mentioned, that we believe that developing either a more potent vaccine or a vaccine that is more broadly applicable to patients with other tissue types is probably the next step before we have a vaccine that is more useful to the general population, so working with a number of other scientists including Dr. Hwu to develop that next vaccine which will also require another clinical trial then to demonstrate its efficacy as well.
Lisa Garvin: Do you think that this study, because it's one of the first shows of efficacy for vaccines and cancer overall, does this kind of kick open the door for vaccines not only for melanoma but other cancers as well?
Dr. Douglas Schwartzentruber: I would say so and actually just recently, a prostate cancer vaccine has been approved but it is a very, very costly vaccine and in contrast to this melanoma vaccine, it would be very cheap to produce and so, we hope that the financial constraints would also be a obviated by this type of an approach.
Lisa Garvin: What about patients who are hearing this and perhaps they have metastatic melanoma or knows somebody who does, is the trial still open? Can they get the vaccine in a clinical trial setting?
Dr. Patrick Hwu: Yeah and so, at MD Anderson we do have a couple of trials available with this vaccine but it's in an earlier stage. For stage 3 patients, patients who have had tumors in their lymph nodes but are free of disease, they are all at risk of having the tumor come back. So we do have patients able to get that vaccine in combination. We have one study open in combination with interferon-alpha which is another cytokine immune stimulant that we found to be very helpful in combination with vaccines and we have another trial of the gp100 vaccine with an adjuvant called resiquimod which is another stimulant of the immune system.
Dr. Douglas Schwartzentruber: And the other thing to emphasize too is that this is still being designed for patients that have metastatic disease and when you think of a vaccine, you think of a preventive vaccine like it is commonly used for infectious diseases but we're not there yet with cancer. At this point in this stage of development, vaccines for cancer tend to be tested more in the context of metastatic disease.
Dr. Patrick Hwu: And then at MD Anderson for metastatic melanoma, we also have a vaccine--another vaccine, a MAGE vaccine in combination with high dose Intelukeun-2 and that's a phase two trial but if that looks promising, then we will work with Dr. Schwartzentruber and the others in this consortium to try to do another randomized study with this improved vaccine.
Lisa Garvin: Great. Thank you both. This is very exciting news. Is this going to be talked about at the next ASCO Conference which is coming up?
Dr. Douglas Schwartzentruber: It's not on the ASCO agenda per se because we discussed this at the ASCO two years ago. However, the fact that it's being published at the time of ASCO with the June 2nd issue, we anticipate there will be a lot of talk. There will be also talk about the other agents that Dr. Hwu mentioned ipilimumab and the B-Raf kinase inhibitors that will--there's presentations that are expected at the meeting that will, I think, also generate a lot of excitement for treatment of metastatic melanoma.
Dr. Patrick Hwu: I think though that--they all talk about similar principles and that's. With ipilimumab and this vaccine study, we now know that the immune system is important to try to stimulate and that we can have positive effects in cancer patient if we stimulate the immune response. We know that the targeted therapies are very helpful but unlike the immune therapies, the responses aren't really transient so hopefully in the end we'll put all of these agents together and have much better responses.
Lisa Garvin: Sounds like you both have your work cut out for you.
Dr. Douglas Schwartzentruber: We do. Thank you so much for talking with us and for your very good questions.
Lisa Garvin: Thank you both.
Dr. Patrick Hwu: Thank you, Lisa.
Lisa Garvin: If you have questions about anything you've heard today on Cancer Newsline contact Ask M. D. Anderson at 1-877-MDA-6789 or online at www.mdanderson.org/ask. Thank you for listening to this episode of Cancer Newsline. [Music] Tune in next week for the next podcast in our series.
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