Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Akash Patnaik, who was an Assistant Professor of Medicine at the University of Chicago and a GU Medical Oncologist. Thank you so much for talking with me.

Akash Patnaik: Thanks for having me.

Alicia Morgans: Of course. We have talked so many times over the last few years, and we participated in a spore together, so I have that great honor, too... but have been just fascinated with all of your work and expertise in immunotherapy in prostate cancer, which I would say is still a field in its infancy, but is sometimes marked by exceptional responses that certainly inspire me, and I think others, to keep pushing to find out how we can best use these agents for prostate cancer. So I'd love to hear your experience with that and what inspires you in this realm of immunotherapy for prostate cancer.

Akash Patnaik: Yeah, no, I think that that's a very insightful set of comments that you just made. And I'd like to maybe just take a step back and say that, you know, there's been obviously a lot of excitement about immunotherapy in cancer across the board, but if you take all cancers, it's about 20% of patients that respond. And so there are clearly subsets of patients across all cancers that don't respond, and prostate cancer in particular, their response rates have been a bit lower, at more like 10% of all patients. But there are clearly patients that respond exceptionally well, and one of the things that we're trying to do is understand why those patients respond really well, and how can we learn from our exceptional responders to then develop strategies that work for the patients that don't respond?

Just to give you an example, we participated in a clinical trial combining two different immunotherapies targeting CTLA-4 and PD-1, and we found that in two patients, we had exceptional responses. One patient went into a complete remission and no evidence of disease years out, which was really phenomenal. You know, we still treat him with androgen deprivation therapy because we feel like we should be doing something in somebody that had a prognosis of four to six months. And then the other patient actually had a really good response and then developed acquired resistance. And so that's another area that we're very interested in is understanding, what are some of the mechanisms of resistance and how can we figure out smart combination therapies that can overcome resistance, both de novo, as well as acquired. And that's what a lot of my work as a translational physician-scientist is focused on both in the laboratory and early phase clinical trials.

Alicia Morgans: So I love that your eye, even as a physician-scientist where you're often in your laboratory trying to really move the needle for us, is still on the patient experience and on patient examples that you want to try to recapitulate for more patients to really get that benefit. So what are you doing in terms of strategies, whether it's getting patients who shouldn't respond to respond, or getting patients who have developed resistance to respond to new? What are you doing in the lab?

Akash Patnaik: Yeah, so one of the approaches that we're taking to increase the fraction of patients that respond to immunotherapeutic interventions is targeting signaling pathways within cancer cells that either control how a cancer cell grows and divides, or canonical signaling pathways, oncogenic signaling pathways, which are activated in a large subset of prostate cancers, as well as pathways that regulate DNA repair in prostate cancer. And that's... You know, the work that has been done by us and others in the field has clearly shown the importance of DNA repair mutations in prostate cancer and how they affect not only the biology of how these cancer cells might be more vulnerable to targeted therapeutic approaches, but perhaps also how these mutations might control the microenvironment around the cancer, including the immune cells that might be trafficking into the cancer.

So we want to take advantage of our ability from a technology standpoint to molecularly profile patients, do genomic sequencing in a lot of our clinical trials that we're participating in. And we've had several discussions about that in the context of our spore projects. We are collecting metastatic biopsies of these patients before treatment on treatment to get a better understanding of the biology following treatment in terms of, what are the immune cells that are coming into the cancer? Are they good immune cells or bad immune cells? Can we reprogram the bad ones to good ones by targeting these oncogenic signaling pathways or DNA repair pathways? And that's kind of where we're at, to a lot of our translational clinical trials from bench to bedside and taking the experience from the bedside and then reverse translating it back to the bench.

Alicia Morgans: So what are the next steps that you're taking in terms of clinical trials and development? And what are the therapeutics that you're trying to combine to move things?

Akash Patnaik: Yeah, so there are two major areas that we've been focusing on, both in the laboratory and in clinical trials. And that is really targeting the PI3-kinase pathway, which is one of the most frequently mutated pathways in human cancer. In prostate cancer, about 50% to 75% of patients have mutations, particularly in a gene called P10, which inhibits PI3-kinase activity, and P10 loss of function is found in at least 50% to 75% of patients.

We also see activating mutations in PI3-kinase, so clearly that pathway is important to target, not so much in the context of just killing tumor cells, but in the context of immune reprogramming. And we have some data now to support the idea that targeting these PI3-kinase signaling pathways can reprogram the tumor in many ways. Convert, repolarize... macrophages, which were thought to be tumor-promoting... to becoming more anti-tumor killer cells.

And in addition, we're also using strategies to target DNA repair pathways, like PARP inhibitors, in combination with immunotherapy. And so the idea is to really light the fire in these tumors using approaches that can turn on the innate immune arm of the immune system, as opposed to the adaptive arm, which has been the focus of a lot of prior work, which has mostly been focused on T-cells. We're more interested in these sort of... this fortress of immunosuppression, if you will, around the cancer and how we can light the fire by turning on or reawakening these myeloid cells to now attack the tumor, and secondarily then enhanced T-cell infiltration.

So the third approach that I should just briefly talk about in the context of innate immune sensing is targeting an evolutionarily conserved signaling pathway called the STING pathway, which has recently been a focus of attention from a pharmaceutical drug development standpoint. And this was a pathway that was evolutionarily evolved to control viral and bacterial infections. But these pathways can actually be repurposed, if you will, to awaken the dormant myeloid innate immune arm in the tumor microenvironment so as to now make the immune checkpoint inhibitors, which are not so successful in prostate cancer, work better. So that's something that we're heavily focused on, and hopefully we'll see some results soon.

Alicia Morgans: Absolutely. So just to make sure everyone remembers because this is really kind of reaching to the recesses of many peoples' memories, I think. But we have to all remember that the innate immune system is different. It's that initial response with macrophages and things like that. But the adaptive immune system is one that we're targeting when we're using things like PD-L1 and PD-1 inhibitors. And so these are two separate arms that if we could get them to work together, perhaps we could sort of reenergize things. And that's really exciting. And one quick question about the PI3-kinase work: isn't that one of the most undruggable pathways or targets?

Akash Patnaik: Yeah, so there's been a lot of... I would say over the last five years or so, there's been a lot of interest in targeting PI3-kinase, and there was an explosion of small molecule inhibitors over a dozen PI3-kinase inhibitors that entered clinical trials. However, the majority of those agents have been largely disappointing as single agents. And I think the reason for that... and I could think of several reasons, but assuming that you have a good drug, I think a lot of it has to do with what state of the disease you're targeting. And by itself, it's likely not going to be as successful, but in combination, which is what we're looking at with the immune-based approaches, it sort of begs the question of, can you now see much more of a clinical response, which we weren't seeing with the agents. So while it's a druggable pathway, the success with these agents has been somewhat limited, with a few exceptions.

Alicia Morgans: And I'm hoping that your work will be the exception so that we all have this as a new tool to work with for these patients. I sincerely appreciate your time. Would love to hear any closing remarks you have or just take-home messages for the audience?

Akash Patnaik: Yeah, no. So I think coming back to your point about the innate and adaptive arms of the immune system, what we've also grown to recognize is that there is reciprocal crosstalk, if you will, between these arms. And I think when we all took immunology in medical school, we learned that this is two distinct entities, but in reality, there's really a lot of crosstalk and overlap, and the innate arm can influence the adaptive arm, and vice versa. And so I think we really have to think of these approaches in concert. And even targeting PD-1, PD-L1 can affect innate immunity because some of these molecules that are pharmaceutical targets for PD-1, PD-L1 are actually expressed on the innate immune cells as well. So in addition to the t-cells and the tumor cells, macrophages can express PD-L1 or PD-1. So I think the biology is complex, and we're only now starting to understand some of this better, so we can now develop optimal immuno-oncology strategies to combat this devastating disease.

Alicia Morgans: Well, thank you for your efforts along those lines, and thank you so much for your time. Just a wonderful set of knowledge that you had to share with us today. So, thank you.

Akash Patnaik: Thank you, Alicia, for having me.