Charles Ryan: Hello from APCCC 2019. I'm with my friend and colleague, Chuck Drake from Columbia University. Chuck is probably the leading voice of immunology and castration-resistant prostate cancer or prostate cancer. It's a field that is evolving so rapidly in oncology in general, but I wonder where we are with regards to immunotherapy in prostate cancer, certainly within the disease, but also relative to the other solid tumors.

Charles Drake: In prostate cancer, I think that there are multiple trials that now really confirm that immunotherapy, monotherapy is not going to be as effective in prostate cancer as it is in multiple other tumors, including bladder, kidney, lung, and on and on actually. I think that's firmly established. I think what's not established is what's the best combination therapy. We have some data that chemotherapy adds to immunotherapy, that PARP inhibitors add, and there's some data too that hormonal therapy can add to immunotherapy. What's the optimal combination going to be, and will any of those combinations beat monotherapy? We don't really know right now.

Charles Ryan: Yeah. I would argue, I think it's an area for some debate. If immunotherapy has not shown any monotherapy benefits in advanced prostate cancer, why would we think it would work in combinations?

Charles Drake: There are multiple mechanisms, my friend. One idea, actually, for the combination of chemotherapy is that chemotherapy kills tumor cells in a way that activates the immune system. The tumor antigens go to the lymph nodes like a vaccine and can prime the immune system when it was formerly silent. This process is called immunogenic cell death, and there are animal data suggesting that docetaxel, in fact, does cause immunogenic cell death. That's one scientific rationale to think that the combination might be different than chemotherapy alone. Hormonal therapy as well can cause a tumor cell death. How immunogenic this is, we don't know. Data from my group and others suggest interesting that it's initially immunogenic, and then, later on, it actually becomes tolerogenic. When you combine hormonal therapy with immunotherapy, the timing might be absolutely critical.

Charles Ryan: Right, right. The therapy that you're giving with the immunotherapy is doing what? Is it altering the tumor to make it more antigenic, so to speak? Is it altering the tumor microenvironment to allow the immune cells to penetrate in combination with immunotherapy? Or is it, I don't think it is, but potentially potentiating the immune system directly?

Charles Drake: Three things. You're absolutely right. One thing, we all know that a greater a tumor burden is more immunosuppressive. Just killing tumor cells, that's probably good for the point of the immune system. The second thing is the tumor cells themselves when they die and are taken up by antigen-presenting cells, that can prime the immune system. Finally, though, the thing that you mentioned that was actually quite intelligent, and many people miss actually-

Charles Ryan: It happens from time to time.

Charles Drake: I know. Is that, in fact, the whole tumor microenvironment can be altered. It's not just the tumor cells and the T cells, it's also the other cells in the microenvironment. For example, the data that we have suggests that when the tumor cells die, eventually this population of suppressive cells comes up, these myeloid suppressor cells, so that's why it's a little bit complicated.

Charles Ryan: You get tumor cell death, you get subsequent death of suppressor cells or activation of the suppressor cells?

Charles Drake: It's more like the suppressor cell seems to come in, actually. Things dying are a signal to the immune system to try to put out the fire, keep inflammation down.

Charles Ryan: Right. I see, I see.

Charles Drake: It's the tumor cell death, probably, that primes the influx of these suppressors cells.

Charles Ryan: Given all that, if you could design, and maybe you are designing the perfect clinical trial in let's say CRPC that's going to integrate immunotherapy as a combination, what is that trial? There can be more than one answer.

Charles Drake: Yeah. In the castration-resistant setting, I think that we need to use multiple modalities to maximize the chances that we kill tumor cells, and that'll be immuno-activating. I think that the combination of hormonal therapy plus chemotherapy, adding that to immunotherapy, then you have two ways to have cell death.

Charles Ryan: Got it.

Charles Drake: Both of which might be immunogenic. We're working on a trial for oligoprogressive patients, in which we combine both chemotherapy plus immunotherapy.

Charles Ryan: Okay. Docetaxel with and without immunotherapy.

Charles Drake: And radiation therapy actually, to kill the oligometastatic cells in another immunogenic way.

Charles Ryan: Great, great. We should also just speak briefly about MSI-high, a disease which is a clear exception to the general rule that monotherapy immunological treatment in prostate cancer's not effective. There, we clearly have a pathway, we have FDA approved drugs for that, and it's something that clinicians who are watching this should know that they should be testing their patients for MSI status. You want to comment on whether we can exploit that observation at all for any greater amount of benefit?

Charles Drake: Yeah, you took the words right out of my mouth. Patients with metastatic prostate cancer, actually just metastatic in general, if we're getting a biopsy, we should be absolutely sure that it's tested for MSI. One way to test is with a genetic test. Most of the genetic tests will read out MSI. Another concept is to confirm that with an IHC test, particularly for MSH2, but those tests overlapping this very, very few patients, and that's really important because some of these patients go into a remission, sometimes a complete remission, sometimes for many years. That's something we absolutely should not miss. I have to tell you honestly, I've had patients come into my clinic with genetic testing that says MSI-high, and they weren't treated appropriately, actually.

Charles Ryan: Yeah. No, I think that's a really key point. It's one of those situations where if you're going to treat a prostate cancer patient, you absolutely need to know this because of the tremendous implications of the therapy. Are we ever going to be able to take a non-MSI-high, MSI-low tumor and make it MSI-high? Are we ever going to be able to turn those cold tumors hot, in that regard?

Charles Drake: I got to tell you, you're one of the few people that asked that question. We have, at Columbia, some preliminary data that there's some drugs that can vastly change the spectrum of antigens that are being presented in tumors, actually. We're actively investigating this in prostate cancer cell lines. The concept is exactly as you alluded to, that is to increase both the number and the spectrum of antigens that are presented, and at least in some sense make the tumors that are MSS, microsatellite stable, look more like they're microsatellite high.

Charles Ryan: Yeah. There's hope for immunotherapy in prostate cancer after all? I'm joking.

Charles Drake: I think the combination's actually, in most of the tumor types when chemotherapy is combined with immunotherapy, the result is almost always at least additive. I believe that there's a strong possibility that the chemo plus immuno trials have a good chance of at least weekly positive-

Charles Ryan: Those are interesting, interesting designs.

Charles Drake: Exactly, but going to the next step of actually getting deep remissions that are long-lasting probably will take a little more time, and a little bit more creativity.

Charles Ryan: Okay, very good. Well, we're looking forward to you solving the problem for us, so keep talking.

Charles Drake: Well, I appreciate it very much.

Charles Ryan: Okay, Chuck, nice chatting with you.

Charles Drake: Thank you, Chuck.