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Feb 15, 2020

TRANSCRIPT:

Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll. Joining me today to discuss key takeaways from the ASCO-SITC Immuno-Oncology Symposium in Orlando is the meeting's co-chair, Dr. James Gulley. Dr. Gulley is chief of the Genitourinary Malignancies Branch at the National Cancer Institute at NIH where he also leads the immunotherapy group. Dr. Gulley, welcome to the Daily News Podcast.

Dr. James Gulley: Thank you so much, Geraldine. I'm delighted to be on here with you.

ASCO Daily News: Dr. Gulley, do you have any conflicts of interest that you'd like to disclose that are relevant to our conversation?

Dr. James Gulley: The National Cancer Institute does have some cooperative research and development agreements with several companies, including Bavarian Nordic and EMD Serono that supply institutional funding for some of the projects that I work with.

ASCO Daily News: OK. Well, the 5th and final Immuno-Oncology Symposium, co-sponsored by ASCO, that is dedicated to immunotherapy revealed some significant advances in the field. What are the key scientific takeaways from the meeting?

Dr. James Gulley: So Geraldine, this is an amazing meeting. There were 18 oral sessions, and there's so much going on here. I just want to share a few highlights that were my key takeaways.

Dr. James Gulley: First story comes about earlier use of immunotherapy may be better. Jen Wargo from MD Anderson gave a really nice talk on neoadjuvant studies in melanoma, really highlighting the fact that this can be a correlative goldmine for addressing the impact of immunotherapy on the tumor microenvironment. In addition, Dr. Sara Tolaney talked about breast cancer and the consistent improvement in pathologic complete response rates with immunotherapy in combination with chemotherapy versus chemotherapy alone of about 15%. As you know, pathologic complete response rate are a registration pathway for agents.

Dr. James Gulley: What was interesting is that this is seen both in PD-L1 positive and PD-L1 negative patients. In addition, both Dr. Jamie Chaft as well as Dr. Ford talked about lung cancer and the use of neoadjuvant immunotherapy studies in lung cancer, showing major pathologic response rates of about 50%-- up to 50%. In a study that was published in the New England Journal of Medicine, the first studies showed nine out of 20 patients having this major pathologic response rate. And this has led to four ongoing phase II slash phase III studies with PD-1 or PD-L1 inhibitors in the neoadjuvant setting.

Dr. James Gulley: Now, in addition to the earlier is better story that we heard, we also heard about that it's not just about T cells. So there was a couple of abstracts of clinical trial data. One of them was by Dr. Christopher Cole from Dr. Annunziata's group at the National Cancer Institute, talking about autologous monocytes with interferon given to patients with ovarian cancer. And they saw some nice, interesting responses in this relatively small phase II study of 18 patients. With two out of 11 patients with a valuable disease having a partial response, and an additional patient that didn't have a valuable disease having a response by CA125 markers. In addition, six out of 11 patients had stable disease.

Dr. James Gulley: There was another interesting study or a small randomized phase II study of 88 patients that was presented by Dr. Lindskog talking about monocytic dendritic cell approach with sunitinib versus sunitinib alone in patients with renal cell carcinoma. Now this is still relatively early on in this study to look at overall survival and progression free survival. Survival curves looked similar, although there was a late separation in the curves.

Dr. James Gulley: However, the objective response rate in those patients receiving the dendritic cell approach was 42% versus 24%. The complete response rate was 6.7% versus 0%, and the duration of responses was 7.1 months versus 2.9 months, suggesting there may be some activity there. So it's an interesting story to continue to follow up on down the road.

Dr. James Gulley: The final take away point is that biomarkers are becoming more sophisticated. There was a great biomarker session, and I just want to highlight some of the contributions from Dr. Larry Fong. He really put it nicely when he said that we started out with simple T cell enumeration, looking in the peripheral blood at things like neutrophil, the lymphocyte ratio. That does make a difference, and you can divide patients up into a higher versus lower and look at the outcomes as well as looking at T cell enumeration within the tumor.

Dr. James Gulley: More recently, we've looked at T cell specificity by TCR sequencing. But what we're now able to do is to look at-- not only at T cell specificity, but to couple that with a functional state looking at single cell RNA seq. And this may provide new insights that can really help propel the field forward.

ASCO Daily News: Well, you've described some amazing new insights. What were the advances reported at the meeting that are likely to support new standards of care moving forward?

Dr. James Gulley: That's a really good question. And I think that what I take away from the meeting is there are a couple of very interesting emerging stories that I'd like to share with you. So first of all, we have the alveolar small part sarcoma story, and this is a very rare malignancy. Less than 1% of all soft tissue sarcomas are alveolar soft part sarcomas.

Dr. James Gulley: This is a relatively indolent slow growing disease, but 80% of the patients develop metastasis and it's unresponsive to traditional treatment. Like most sarcomas, this has low tumor mutation burden and it's driven by effusion. So what we are seeing now from emerging data is that it actually has a good response rate to immune checkpoint inhibitor therapy.

Dr. James Gulley: There's a study looking at atezolizumab where the response rate is 37.5%. Another study with pembrolizumab and axitinib where six out of 11 patients have had partial response. So these studies that were presented by Dr. Miriam from Dana Farber, I think, really provide an interesting story in what might be emerging. I think with a very rare tumor like this, it is likely that only single arm studies will need to be done to get approval or compendium listening.

Dr. James Gulley: There's another interesting emerging story with adoptive cellular therapy and multiple myeloma. And Dr. Garfold had a really nice presentation about B Cell maturation antigen, or BCMA CAR T Cells. So these chimeric antigen receptor T cells are associated with the response rates in multiple myeloma of between 65% and 90%, depending on the studies, and a very good PR or CR rate of 35% to 80%.

Dr. James Gulley: There were four studies that were looked at. The one thing that I would point out is that these responses were not as durable as hoped. And so new strategies are emerging to use this earlier on in the disease course in multiple myeloma, and perhaps co-target CD19. Another very interesting target for adaptive cellular therapy CAR T's is mesothelin. And Dr. Adusumilli talked about the use of these mesothelin targeted CAR T's in mesothelioma.

Dr. James Gulley: One interesting thing about this is with mesothelioma, for instance, plural mesothelioma, you can just give these CAR T's directly into the pleura and therefore get a higher amount of these cells directly to the tumor than you could if you gave this intravenously. In addition, he showed data that suggested an improved outcome with PD-1 inhibition. And these studies are ongoing.

Dr. James Gulley: The final study that I think is very interesting and could change standard of care is a story that is emerging about the ability of doctors to use immunotherapy in patients with solid organ transplants. It turns out that there's been a threefold increase in solid organ transplants since 1988, and cancer is the third most common cause of death in organ transplant recipients. Unfortunately, because of the requirement of the patients to use immune suppression to prevent the rejection of the organ graft, and because the anti PD-1 or anti PD-L1 agents could promote the rejection of the organ transplants, these have been traditionally excluded from clinical trials.

Dr. James Gulley: There's now an effort going on combining nivolumab with tacrolimus and prednisone for patients with kidney transplant. The nice thing about this study is that there is a backup of dialysis if there are problems with the organ transplants. So this should allow us to get substantial data in the solid organ transplant setting. This trial is open now and is enrolling patients with melanoma, merkel cell carcinoma, basal cell carcinoma, cutaneous squamous cell carcinoma, and MSI high colorectal cancer.

ASCO Daily News: Dr. Gulley, are there new treatment approaches emerging or agents in development that seem really promising?

Dr. James Gulley: So Geraldine, there are some fantastic new approaches and some new agents that I think are worth keeping an eye on. First of all, I want to highlight the really excellent talk given by Dr. McQuaid on the microbiome. There were multiple excellent talks, but I just want to highlight this one talk because it really hit home for me how important the diversity of the microbiome is.

Dr. James Gulley: So it turns out that when we have a diverse gut microbiome, we have better outcomes. And actually things that we might think that could improve that, such as taking probiotics, actually narrow the repertoire of the diversity in the microbiome and are associated with worse outcomes. Antibiotics obviously can also decrease that. In another talk, Brian Chu from UPenn showed that the use of antibiotics was associated with decreased overall survival and increased colitis in patients with melanoma that was required steroid. But in Dr. McQuaid's talk, she talked about how we could potentially improve the good microbiome. So it's not just enough for us to have the right bacteria. You really need to also be able to feed them.

Dr. James Gulley: And what she showed was that if you had a high fiber diet, you could get fermentation by the bacteria, which would lead to increased short chain fatty acids, which would lead to increased immunity. And the fiber should be from multiple sources. And then also you need to not kill those bacteria with antibiotics if at all possible.

Dr. James Gulley: In addition, there was some really interesting data on anti-semapohrin 4D. So semaphorin 4D is associated with myeloid derived suppressor cells with M2 polarized tumor-associated macrophages and with T regulatory cells. An agent, ipnimab targets semaphorin 4D. This allows for increased infiltration of effector cells within the tumor. In addition, there was a clinical trial showing that there was activity in non-small cell lung cancer in combination with avelumab.

Dr. James Gulley: Another interesting story was the fact that real world evidence and real world data are going to be playing an increasingly important role in helping us understand issues in medicine in general, but also may be important in immunotherapy. This was highlighted in a session that was looking at real world evidence, not just from big data sets like electronic medical records, but also in a very interesting talk by Dr. Heather Jim from the Moffitt. Wearables or devices like cell phones or smart watches have accelerometers in them, and they can be used to help gather data on the activity of patients and whether they're up and about more. I think we're going to see a lot more of this type of approach in understanding what's going on in between clinic visits for patients, so stay tuned for this approach in the near future.

Dr. James Gulley: Finally, we had three excellent keynote speakers. I just want to highlight one of them from-- one aspect of one of them from Dr. Dario Vignali from the University of Pittsburgh. And he talked about several things, including neuropilin-1 and how this may be targeted to help destabilize T regulatory cells within the tumor microenvironment. I would stay tuned for that emerging story from Dr. Vignali's lab.

ASCO Daily News: Well, I want to thank you, Dr. Gulley, for sharing these amazing developments in immunotherapy. I look forward to continuing this conversation with you in our next episode, to reflect on the enormous impact that the IO Symposium has had on cancer research, education, and patient care over the past five years.

Dr. James Gulley: Thank you so much.

ASCO Daily News: Thank you to our listeners for tuning in to the ASCO Daily News Podcast. If you're enjoying the content, please rate and review us on Apple Podcasts.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

The following represents disclosure information provided by the guest(s) of this podcast.

Dr. James Gulley

The National Cancer Institute has cooperative research and development agreements with several companies, including Bavarian Nordic and EMD Serono that supply institutional funding for some of Dr. James Gulley's projects.