M. D. Anderson Cancer Center
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Dr. Ed Camp:
Welcome to Cancer Newsline, [background music] a podcast series from the University of Texas, M.D. 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, Dr. Ed Camp. Today we're talking with Dr. Patrick Hwu, Chair, Department of Melanoma Medical Oncology and Dr. Beth Mittendorf, assistant professor in the department of Surgical Oncology. Today we're going to talk about immunotherapy and some new data that has come out regarding breast cancer, but we know this field has really covered many different tumor types. And I know patients come and see me, and they asked, "Well, what can we have as far as vaccines. Don't those make the most sense, don't those cover us and help prevent and not only treat cancers." And disappointingly, I have to tell them many times, you know, we don't have anything right now in the clinic, that applicable at least in lung cancer, but it's a fascinating area, we know that bodies immune system is something that can help us fight. This data that's going to be presented on upcoming meeting, Dr. Mittendorf seems very promising. I wonder if you can give us an overview of that.
Dr. Mittendorf :
Sure. So the data that will be presenting at the upcoming ASCO meeting is preliminary data from an ongoing Phase 2 trial that's looking at a vaccine administered the breast cancer patients. And the thing that's noticeable about this is it's been administer in the adjuvant setting. So after our patients whose completed all of their standard of care therapy, and rendered free of all their disease, we're giving them the vaccine and the hopes that by educating their immune system, we could delay any recurrent events or perhaps even prevent disease recurrence. And so the trial has enrolled patients who have node-positive or what would we define as high-risk, node-negative breast cancer. And they can have any degree of HER2 expression on their tumor. And this is an important distinction because when we think about HER2 positive breast cancer, we considered patients who are going to benefit from the drug trastuzumab. And in order to benefit from trastuzumab, patients have to have a lot of the HER2 on their cell surface. About 25 percent of breast cancer patients meet that criteria, but for this vaccine approach, patients can have any degree of HER2 expression. So that's expands the number of patients who may benefit from vaccination to about 70 percent. So, patients were administered the vaccines, it is given just under the skin, once a month for six months. After they complete that series, they didn't get a booster inoculation, much like, we would see in an infectious disease model, like a tetanus booster, once every six months for 3 years. And then we're following the patients to look for disease recurrence. And the data that we're going to presenting is looking after a followup period of 22 months. And it shows that there is a decrease in the rate of recurrence for those who receive the vaccine compare to patients who received the placebo inoculation.
Dr. Ed Camp: And this setting of patients where the--they are cured and were told, "My gosh, you know, you're doing well." Usually to discussion of which hormone therapy and which pill they're going to take, is this something that causes a lot of side effects or is it pretty to take?
Dr. Mittendorf :
It's very well tolerated and I think that's why the patients have a lot of enthusiasm for it. And actually as an investigator, that's why I initially had enthusiasm for it. This is something that we're administering after completion of standard of care therapy, so we're not suggesting the vaccine where we place chemotherapy or we place radiation. When patients get the shot, most of them do have a little bit of redness at the injection site. The majority of them have a very short live period in which they have flu like symptoms, feel little bit achy, it seems to be resolved with Tylenol. But other than that, it's been incredibly well tolerated. And so, the thought is that if you can get benefit with such little toxicity, that is something that's appealing to both myself as the investigator and the patients. But with respect to your comment about endocrine therapy, clearly, in breast cancer, that's a very important component of their care. So patients on our trial, who have the estrogen or progesterone receptor on their tumors, do continue to receive their hormonal therapy pill as a standard practice throughout the duration of the vaccine series.
Dr. Ed Camp: So Patrick, you know, melanoma is probably one of the tumors that has really seen the gamete of immune modulation and has really tested this. From your vast experience, studying this for decades and now seeing where we are today, how this is compared with the early treatments for melanoma and now to what we have, you've seen in this type of data.
Dr. Patrick Hwu: Well, the melanoma is interesting and that it's already trying stimulate the new systems. So it's very immunogenic. So we've study a lot of immune therapies with melanoma. However, we're finding now that other cancer types are immunogenic as well. And I think that immunology will be helpful to almost any kind of cancers. So, this is a nice example of how vaccines maybe helpful with breast cancer. We've had performed a vaccines like this in melanoma patients and we're trying to optimize these vaccines all the time. There are many ways to stimulate the body's immune system. Vaccines are one method. Other methods are antibodies to take the breaks off the immune system. And others are using cytokines. Our feeling in the melanoma field right now is that combining these areas and combining these different approaches maybe be optimal. For example, we had a study that was published last year looking at vaccines in melanoma plus inner looking to a cytokines that helps to stimulate T-cell proliferation compared to the inner look into by itself and the combination increase the response rate in a randomized study. So I think, I would predict that this is a really nice result that--that Dr. Mittendorf has and that it all even be strengthen further with the combination with other kinds of therapeutic such as cytokines or antibodies that take to break off immune system. This is been a very important field, this new field of checkpoint blockade. Let me explain that to you. Our immune systems can be quite dangerous to us. The immune cells are like little tanks circulating through out the body meant to kill bacteria and viruses and we're of course trying to stimulate and we kill tumors. But left unchecked, we get a lot of disease such as autoimmune disease. So the body has natural breaking mechanisms on all of our immune cells. And we're starting to learn what those breaks are, and developing antibodies to block those breaks. One of these is called CTLA-4, a break that turns immune cells off. This was research done by Dr. Jim Allison. And if you take that break off, you then allow the immune cells to kill cancer better and that antibody was approved last year for metastatic melanoma. And we use it everyday in the clinic now. Other antibodies along these lines include anti-PD-1 and anti-PD-L1 antibodies, and these are have been effective not only in melanoma but other kinds of cancers as well such as lung cancer. So, we're really excited now that we think that the immune response is going to be important not just for melanoma but also for breast cancer, lung cancer, colon cancer and other cancers.
Dr. Ed Camp: It's certainly an area that seems to be better utilized and more recently, I know questions that viewers who are listening would have is they are used to hearing about anti-HER2 therapy in breast and it's been long documented how effective it is. You discussed that this would not interfere or even replace any current therapies that would be use in the curative setting. Couldn't they be used on top to help synergize or compliment, you know, is more better in this situation?
Dr. Mittendorf : Yeah, that's an outstanding question in an area of active investigation for our group. Very briefly, we think that our data is showing that patients with the lower expression, the one plus, two plus, who don't benefit from the trastuzumab are seeing benefit from the vaccine alone. And in fact, in the Phase 2 trial that we've recently finished looking at in a different HER2 derived peptide vaccine, something now called NuVax. We again show that the patients with the low expression did well with the vaccine. And that's the population that is it's currently being studied in the Phase 3 trial. But we had generated some data in the laboratory that suggest that for patients who have the highest expression of HER2, if you use the combination as you suggested. So give them the trastuzumab and the vaccine that will actually augment the response. And so, when we went back and looked patients who didn't enrolled in our trials and these were data that we presented out last year's ASCO meeting and we found small numbers but 30 patients who had received trastuzumab, a standard of care therapy because they were HER2, 3 plus. None of those patients got the vaccine and the recurrence rate was exactly what we would have anticipated about 12 and a half percent. We had 32 patients who were HER2, 3 plus who got trastuzumab standard of care and then received the vaccine and no recurrence is in that group. One year later, still no recurrences in that growth. So at M.D. Anderson, we're currently conducting a Phase 1 trial. Looking at the combination, we have completed enrollment in the highest dose cohort and now, we needed to enroll 6 additional patients in an expansion cohort. And we've already designed Phase 2 trial that's going to be supported by Genentech looking at this question of the benefit of combination immunotherapy.
Dr. Ed Camp: I mean and I think what we've learned from the melanoma side is that these combinations can certainly be beneficial and used to augment other effects, as well as complementary to the curative therapy, so Patrick?
Dr. Patrick Hwu:
Yeah, so it makes a lot of sense that an antibody plus a vaccine that's trying to trigger T-cells would complement to each other very highly. It makes a lot of theoretical sense. And so, I would predict that, that would work better.
Dr. Ed Camp: What about some of these other tumor types? I know everyone seems geared toward testing in breast cancer and what we do know that HER2 exist specially at some lower levels in other tumor types such as the lung cancer even or salivary gland cancers or others, have there been any investigations to expand those types of populations?
Dr. Mittendorf : So, some of the earliest trials with one of the HER2 derived peptide vaccines were conducted actually in ovarian cancer patients. The most studied HER2 derived peptide was actually first found in ovarian cancer. There's been an early study and show--looking in bladder cancer but those were again just early phase trials. There is an active interest in an international trial looking at a HER2 derived peptide vaccine in gastric cancer. So there is a growing interest in perhaps using HER2 peptide vaccines in other disease sites.
Dr. Ed Camp: There's no reason why we don't work on any kind of cancer that has HER2 expression.
Dr. Mittendorf : Right.
Dr. Patrick Hwu: But plus, I think the low level of expression can be recognized by immune cells. So I think that T-cells can recognize very low levels of antigen expression. So even that may explain why you got good results with patients even with low levels of HER2 expression.
Dr. Mittendorf : And that also speaks to the fact that some of these other disease sites that you've then identified which haven't responded to Herceptin may respond to a vaccine.
Dr. Patrick Hwu: The other is--there's a lot of evidence now in experimental models that if you just start the immune response against one antigen, it can then spread against many other antigens, so we call that antigen spreading. So, it's possible that you'll be able to get an immune response started again to HER2 but then spread that response against many other antigens. And some of those antigens looked like they maybe mutated peptides. So we know that cancer cells have many mutations in them. That's what drives the cancer cell to be a cancer. Those mutations maybe the most immunogenic antigens of all, they maybe the best vaccines in the end and so by stimulating a immune response against HER2, you may be stimulating a subsequent immune responses against some of this mutated peptides from the genes that are mutated in breast cancers and other cancers.
Dr. Ed Camp: Well you took my last question and that was Patrick, it was going to be, is this really targeted therapy or are we really defining something different that the public can relate too and that patients can relate to that is not really a target specific, but is now more of a system specific modulation occurring?
Dr. Patrick Hwu: I think we just have to get the fire started. We have to get the immunology fire started and if you started that with a HER2 vaccine or a gp100 vaccine in melanoma or vaccine against any particular antigen, you can just get the immune system kicked off to recognize all of the other proteins that are abnormal in the cancer cells. So, I think it will potentially have relevance for almost any kind of cancer vaccines and these are these immunomodulatory antibodies. And I think we're talking about combined immunotherapy, that's really important. But the other combination that's important is now with all the targeted therapies. If we have to learn how to rationally combine the targeted therapies with the immunotherapies, these are traditionally two separate silos of science and we now need to try to bring those together to bring these two therapeutics and I think we'll get optimal patient benefit with that.
Dr. Ed Camp: And I'll completely agree and the last talk that Dr. Mittendorf, what does this mean to the breast cancer patient now who's listening to this or somebody who has a friend or relative who's diagnosed with breast cancer, what should I do with this information?
Dr. Mittendorf : All right, what I would recommend to the patients, in fact, do recommend to my patients is that they consider enrolling on to clinical trials in general. But specifically, for the patients who have a fairly good prognosis of breast cancer who are looking for something to do other than the watching weight to see if something comes back that consideration for enrollment on a vaccine trial may provide them an opportunity to get a non-toxic therapy that may have some clinical benefit.
Dr. Ed Camp: Yeah and I think those are the types of therapies that really patients and the physicians are looking for is that something that's easy to take, that will help one be proactive in managing their disease or at least preventing their disease and we know that these are young women who are being affected. And so, I know many of them who are listening are going to be very proactive about this. And I think it's very exciting. So, I thank you both for being here today to discuss this topic. I think it's a timely topic and certainly, there'll be more information coming out and look forward to that at the ASCO meeting. If you have any 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. [Background music] Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.
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