As part of our coverage of the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, we discuss some of the immunotherapy treatment options for urological cancers.
Today we are speaking with Dr. Charles Drake, MD, PhD, associate professor of oncology, urology and immunology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, about advances in immunotherapy approaches for prostate, bladder, and kidney cancers, as well as to highlight upcoming data presentations at the 2014 American Society of Clinical Oncology (ASCO) Annual meeting, which is being held May 30th to June 3rd in Chicago.
-Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: There are certain tumor types that historically have been known to be immunogenic, that is, these tumor types can respond well or better to immune-modulating therapies than others? What are some of these tumor types and what are the characteristics that make them amenable to immune modulation, and allowing for a patient to experience an anti-tumor immune response?
Dr. Drake: That’s a great question. The cancers that we typically think of as immunogenic are melanoma and kidney cancer. More recently, we have seen objective responses to immune checkpoint blockades in patients with lung cancer, so I think lung cancer is joining in the group of tumors that are now thought to be responsive to immunotherapy. And quite honestly, from a scientific point of view, it’s not particularly clear why some tumors respond to immunotherapy and others don’t. One idea is that tumors that are likely to respond to immunotherapy may have a higher density of mutations and the idea is that these mutations give rise to antigens, new antigens that can be recognized by the immune system. For melanoma, this looks like it is the case. Melanoma has a high rate of mutations. Bioinformatics analysis by several groups suggests that this gives rise to new MHC (major histocompatibility complex) binding proteins and new antigens. So for melanoma, it may be immunogenic because it has a high mutation rate, but when the sequencing data started to come out on kidney cancer, it was exactly the opposite case. Kidney cancer, if you look at the mutation rate in the TCGA (The Cancer Genome Atlas) dataset, there are not that many mutations. So simply, it’s not just mutation rate, actually. The one characteristic that could justify the response, although we don’t know the mechanism, is that tumors that respond to immunotherapy tend to be the ones that are already infiltrated with lymphocytes. Particularly CD8+ lymphocytes and activated lymphocytes. So melanomas and kidney cancers are frequently infiltrated with lymphocytes. But this still doesn’t explain everything because colorectal cancer is also infiltrated with lymphocytes and so far has not responded quite so well to immune checkpoint blockades or vaccines. The bottom line, I would say is that mutation rate helps, that a pre-existing immune response is probably a good thing, but really this is one of the mysteries of the field and one of the areas of active research--why some tumors respond and some don’t.
OncoTherapy Network: You study immunotherapy approaches for prostate cancer among other tumor types. What do we now know about immunotherapies for prostate cancer? What have we learned in the last several years?
Dr. Drake: It’s interesting because prostate cancer is probably more challenging than either melanoma or kidney cancer. For prostate cancer, there is an FDA-approved immunotherapy, a vaccine called sipuleucel-T. In fact, this was one of the first immunotherapies approved based on a positive Phase 3 trial. Based on that, there is a lot of enthusiasm that other immunotherapy approaches like checkpoint blockade, particularly with anti-CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) would be successful, but we recently published data showing that in patients who have failed chemotherapy, anti-CTLA4 didn’t really achieve its primary endpoint of overall survival benefit. This is the opposite of what happened in melanoma where this agent is FDA-approved and has nice activity in melanoma. What we are learning about prostate cancer is that it is probably immunologically sensitive, but it is going to wind up being more challenging than some of the other tumor types. The other thing I would say is that we presented the data (from the anti-CTLA4 prostate cancer study) and it doesn’t come out quite so clearly in the paper, but we presented the data at the ASCO GU (Genitourinary) meeting from this 043 phase 3 trial looking at anti-CTLA4 in men with metastatic castrate-resistant prostate cancer who had progressed on chemotherapy. In this trial, men were randomized one to one to either immunotherapy with anti-CTLA4 or placebo. Both arms got a dose of radiation and the idea was to prime the immune system. In that trial, the overall trial again was negative--it did not reach its overall survival endpoint, but it did meet its secondary endpoint of progression-free survival. But what was really interesting from that trial is when we went back and grouped the patients according to whether they had visceral metastases or bone disease, and it was really stunning. I think this is actually a very clear and important message for prostate cancer: what was seen was that patients who had soft tissue disease but not in the bones-and again this was retrospective, hypothesis-generating analysis-in those patients there was absolutely no evidence that there was going to be a benefit. But, on the other hand, in the patients who had bone only disease, it really looked like there was likelihood that if only those types of patients were enrolled, the trial may have had a better chance of reaching its primary endpoint. So the other thing we have learned about prostate cancer is that not only is that it is a bit more challenging, but bone-only disease versus visceral metastases may be two entirely different diseases or populations of patients, and really needs to be taken into account when moving forward with future trials.
OncoTherapy Network: What about immunotherapy in development for bladder cancer?
Dr. Drake: Bladder cancer is a bit underdeveloped at this point. As this audience probably knows, bladder cancer is one of the original immune-sensitive cancers in early stage disease. Non-muscle invasive disease is treated with immunotherapy routinely by urologists who give BCG (Bacillus Calmette-Guerin), into the bladder and this induces an immune response that is local and inflammatory, and eventually a systemic response that can cure somewhere between 30% and 40% of these patients in the long run. So bladder, especially early-stage disease, is clearly immunologically sensitive, maybe one of the most immune sensitive and many patients are cured. This has really not been heavily explored in the metastatic setting, which has really focused for many years on optimizing and testing different chemotherapy regimens and trying to subset patients into the ones who are likely to respond to chemotherapy. I think that the field is ready to move back into immunotherapy. The Mayo Group, a few years ago in the early 2000s stained bladder cancer and showed that bladder cancer quite frequently expresses a molecule called PD-L1 (programmed death-ligand 1). In other diseases, PD-L1 has been shown to be a marker of being more likely to respond to checkpoint blockade with PD-1 (antibodies]. So, I think that bladder cancer is likely to be a good target disease for immune checkpoint blockade using agents that either block PD-1 or PD-L1, and I think that we are looking forward to some of the trials in these patients going forward.
OncoTherapy Network: Lastly, there will be many new study results and updates on immunological agents, some of which you mentioned like the PD-L1 and PD-1 antibodies, for various cancers at the upcoming annual ASCO meeting. Could you highlight several studies you are looking forward to seeing the results of?
Dr. Drake: Absolutely. There are three in particular that I really want to see presented publically. One is an abstract on using the Genentech anti-PD-L1 antibody, MPDL3280A in bladder cancer. This is a small group of patients, pre-selected to be PD-L1 positive and the abstract reports a really beautiful response rate in the second line and further, of around 50% or so. So what I am looking forward to is seeing those data, to see exactly what the character of those responses are, and how long it looks like those responses could persist. And also, what kind of side effects seen in this sort of patient population. This agent, MPDL3280A, has generally been pretty well tolerated, but it will be nice to see those data. The second one is data from a large dose-finding study with the BMS (Bristol Myers Squibb) PD-1 antibody, nivolumab in kidney cancer. Dr. Motzer from Memorial Sloan Kettering will be presenting this data. It is a pretty big group of patients, about 150, and the patients were randomized to receive three different doses of the PD-1 antibody. This is probably the largest single-agent, single disease experience in kidney cancer before the Phase 3 comes out, so it will be nice to see the data of the response rates. We reported last year, in the Phase 1b trial with the agent that the response rate looked pretty good, around 29% or 30%, but my guess is that in a larger group of patients that may not be exactly the same. I am really looking forward to seeing, number one, the dose response, and two, what is the response rate to PD-1 monotherapy in second-line kidney cancer in a larger patient group. The last one, the one I am looking forward to the most, is, in our lab and in other others, groups have tried combining different checkpoint blocking antibodies together, often with rather stunning results. For example, we published blocking PD-1 plus LAG-3 and the results were really exciting in mice, but obviously that does not really count as much as what happens in humans. Jedd Wolchok and colleagues published a paper last year showing that in melanoma, combining anti-CTLA4 and anti-PD-1, you have a really tremendous response rate. The responses are fast and they are also very durable, so that is very cool. What we are looking forward to (at ASCO) is a presentation by my colleague, Dr. Hans Hammers from Johns Hopkins, will be presenting data looking at the combination of PD-1 plus CTLA4 in kidney cancer. It’s not a huge group of patients, about 50 or so. I am really looking forward to seeing if that looks like it does in terms of response rate and toxicity compared to the melanoma data. Because if it does, if that combination has a nice response rate as it did in melanoma in the range of 40% to 50%, this may be the way to go forward for checkpoint blockade in kidney cancer.
OncoTherapy Network: Thank you so much for joining us today, Dr. Drake.
Dr. Drake: My pleasure, thank you very much!
Upcoming immunotherapy ASCO abstracts highlighted in this podcast: