Dr. Figlin: Welcome. This is Bob Figlin, and I’m the Steven Spielberg Family Chair at Cedars Sinai Cancer, and I’m delighted to have Jedd Wolchok joining me today at ASCO ’22. In person!
Dr. Wolchok: Thank you very much Bob, it’s a privilege to be here.
Dr. Figlin: Pretty much amazing. So Jedd is the chief of immuno-oncology service at MSK, and most importantly the Karnofsky Award awardee for this ASCO, which is a wonderful contribution, and thank you for all of your hard work.
Dr. Wolchok: It's a privilege and I deeply appreciate the committee's nomination for this award. And of course, that name means so much to all of us.
Dr. Figlin: Exactly. So let’s just dive in. I mean, we’ve been around the block, so to speak. We were here when immunotherapy was a twinkle in our eye, and here we are decades later where immunotherapy is curing people, producing quality and quantity of life. And I think the questions that many of our community oncologists have are, what’s next? Have we accomplished everything that we can with immuno-oncology? Are there strategies that we need to be thinking about? And how do we take care of these people that don’t seem to benefit from the immuno-oncology approaches that we’re giving?
Dr. Wolchok: Those are really important points. And I think the short answer is that we’ve done some good work, but we’re not finished by any stretch of the imagination. There are some people for whom the currently available checkpoint blocking antibodies and the CAR T cells are very effective. But there are many more people for whom they’re not. And so I think that the future is really about understanding how to combine these therapies with other forms of anti-cancer treatment. We see hints of that in some of the combination strategies in lung cancer with chemotherapy and checkpoint blockade, but I think that there’s a lot more that we could do to exploit these sort of orthogonal means of controlling cancer.
Dr. Figlin: So, you know, growing up in the chemotherapy era, we always talk about chemotherapy resistance. Then we went to the targeted therapy era, and we’re talking about targeted therapy resistance. Tell us what your concepts are for immuno-oncology resistance.
Dr. Wolchok: Well, thankfully, resistance in terms of secondary resistance – not primary refractoriness, because that's a very different challenge for immunotherapy – but secondary resistance people have, you know, sometimes a dramatic response and then years later, all of a sudden, a resistant clone will grow. Those are difficult to address. Sometimes what we’ve seen through sequencing of those resistant tumors is a loss of the ability to present antigen to the immune system, so an inability to express the MHC proteins and that’s really a dead end for T cells. So then we have to start thinking about antibody-directed therapies or CAR T cells. So, in addition, now, we are seeing sort of a renaissance of interest in natural killer cell-based therapies. And of course, natural killer cells, the basic immunologists will remind us, are particularly equipped to recognize target cells that do not have MHC expression.
Dr. Figlin: Exactly. So, you talked about bringing targeted therapy, chemotherapy, into the immuno-oncology arena. There’s also evidence that sublethal radiation can take tumors that were otherwise cold and possibly make them hot? Are there other things that we need to be thinking about to convert those tumors that may be resistant for other mechanisms into something that’s more immunotherapy responsive?
Dr. Wolchok: That’s a major point. And I think that we’ve seen some things tried in terms of oncolytic viruses. And I think some of the problems with the ways in which those clinical trials were carried out was they cast a very wide net. They tried to say, well, if we give oncolytic virus plus PD-1 blockade to people and compare that with a randomized group that got PD-1 blockade alone? We expect to see a big difference. Well, you may not, because PD-1 blockade has a pretty good impact by itself, and so you may miss the primary endpoint. I think that what we really need to do is rethink clinical trials to not cast a very wide net, but go into clinical trials that address this resistance. So introduce the concept of combination therapies into patients who have not shown a beneficial response to the checkpoint inhibitor by itself. Now you know, I think that’s a smaller group of people, it may take longer to get there. But I think that those are the people who need the treatment most. And we can imagine that with oncolytic viruses, and now there are numerous injectable TLR agonists that are being explored, and you know, perhaps those need to be developed, again, in the resistance setting.
Dr. Figlin: So it’s almost like a basket trial for the resistant population.
Dr. Wolchok: Exactly. And the patient is their own control, because a patient has shown you that they have a disease that does not respond. And so those are very powerful observations when you can have a patient who has resistance, and all of a sudden now show with the addition of an additional agent that you have sensitivity.
Dr. Figlin: One of the areas of expertise obviously is in melanoma and we know from the recent reports that immunotherapy followed by targeted therapy for BRAF-mutated melanoma is better than targeted therapy followed by immunotherapy. Should we generalize that observation to other diseases, or do you think that’s a melanoma-specific observation?
Dr. Wolchok: I don't think it’s melanoma-specific. I actually give great credit to Mike Atkins for sticking with it, a very challenging trial to accrue that is really a gem for the cooperative group system as well. But I think that those lessons should be carried forward into other diseases as well.
Dr. Figlin: And lastly, two things, but in the adjuvant setting. We’re starting to see some really impressive, in my area, in GU oncology and kidney cancer, to see pembrolizumab have an effect in the high-risk resected kidney cancer population is really a result that was unexpected. So clearly, immunotherapy even in the micrometastatic setting seems to be helpful. Do you think that’s generalizable?
Dr. Wolchok: I mean, I think that the concept is generalizable. However, I think that the adjuvant setting with immunotherapy presents a very difficult challenge, and now in melanoma, we’re even treating people with stage II disease after surgery. Because we are, by default, by definition, really treating people who are potentially cured after surgery alone. And we are offering them therapies that have a small but real potential of harm, and lifelong harm in the form of Type 1 diabetes or thyroid or pituitary failure. And so, thankfully, it’s not the majority of people, but I think we, as a field, need to think about adjuvant therapy in a much deeper way. When I’ve been discussing this, we need to find ways of differentiating “minimal residual disease” from “no evidence of disease,” and perhaps some of the cell-free DNA technologies will allow us to move from very well-established clinical risk stratification systems to molecular stratification systems, where we will be able to say to a patient, you don’t have detectable disease right now, by the most sensitive means that we know, and so we would not necessarily be offering everybody with stage X disease adjuvant therapy.
Dr. Figlin: Yeah, and I think that’s critical for us, because I know that adjuvant therapy, the goal should be cure, right? I mean, it’s not disease-free recurrence, it’s cure. And if it’s cure with a side effect that lasts you a lifetime, that is very different than if you have the cure without that side effect. I think, thinking about adjuvant trials in the setting of selected populations, that maybe through ctDNA, chooses the people that we should otherwise be treating might be a way of approaching that.
Dr. Wolchok: Yes, I agree with you completely. And in fact, you know, the same drugs that we are offering as adjuvant therapies are being offered for treatment of metastatic disease. So to use the example of the PD-1-blocking drugs in melanoma, these medicines have a 40% to 45% response rate as a single agents in metastatic disease, that yes, they reduce the likelihood of recurrence, but the question that we need to ask ourselves is, does it matter when a patient gets that treatment?
Dr. Figlin: Exactly. Two final questions, this is just a great conversation. As we’re moving I/O therapies early, we often get patients where they receive therapy, they have some benefit, and then they relapse. Do you think those patients have different immunologies in terms of our ability to give them I/O therapies, post-previous I/O therapies?
Dr. Wolchok: Yeah, this is going to be an open question. And we may have to start looking at those tumors that appear after adjuvant therapy molecularly to understand, have they lost MHC expression while they were at the minimal residual disease stage?
Dr. Figlin: Exactly. And finally, Jedd, you’re leading the Parker Institute efforts at MSK. Tell us about how that’s going and what's happening around the country with that.
Dr. Wolchok: So the Parker Institute has been a really outstanding effort to tie together some of the major institutions around the U.S. that are interested in immunotherapy through the generous support of Sean and Alexandra Parker, and we have really benefited from the collaboration and collegiality of our partner institutions, and the Parker Institute itself in San Francisco, to catalyze collaborative research, both in the laboratory and in clinical trials. There are several high-profile clinical studies that Parker has conducted by itself.
One of the things that I’ve really appreciated about the support that we’ve gotten from the Parker Institute is that there were no rules given to the individual center directors as to how this funding needed to be used. There were two general mantras that were handed out to us, which was “collaborate like heck” and “do kick-butt science”. But what we did at MSK, and it’s Marcel van den Brink who is the co-director with me, we basically said we’re going to spread this money out to create a community of immuno-oncology researchers, spanning from basic scientists through clinicians, and include outreach efforts to communities of need in the New York area that don’t have access to sophisticated clinical trials yet, and raise awareness about this, to educational endeavors, and to clinical trial support.
One of the things that we really hoped to do, which I think we’ve accomplished, is to bring into our community of immuno-oncology researchers people who would not have identified themselves as being immunotherapists before. So I think, you know, we had a pilot grant program that we designed for rapid turnaround, modest awards for high-risk, high-reward ideas. And one of those awards that we presented was to Scott Lowe, who is of course a world-renowned cell biologist. So, to be able to say that Scott Lowe is being funded by an immunotherapy organization, that was a proud moment for us to really open the tent, because I think we are not so narrow-minded as to think that immunotherapy is the panacea for every disease. We need to embrace all of the other fields of research and come up with thoughtful combinations.
Dr. Figlin: And I think that's true for all of oncology. I mean, we have to embrace other parts of science, because we’ll be better for it. Thanks so much for taking the time and speaking with us.
Dr. Wolchok: Of course, thank you, Bob.
