Alicia Morgans: Hi, I'm so excited to be here with associate professor, Amy Moran, from Oregon Health Sciences University. Thank you so much for being here with me today.

Amy Moran: Thank you, Alicia, for the invitation.

Alicia Morgans: I wanted to talk with you today about your PCF, Prostate Cancer Foundation Young Investigator Award. I know you've been working hard in it for the last few years, and you actually had a wonderful presentation of some of that data at the PCF Scientific Summit just shortly ago. Could you tell us a little bit about the award that you were granted and what you applied for, and then what did you present today?

Amy Moran: I'm an immunologist and I'm curious about how sex hormones shape immune responses. Prostate cancer presents a really interesting paradigm in which there's great targets for the immune system to recognize, but the immune system falls short in recognizing them. That provides a really great opportunity to study how the hormone microenvironment androgens regulate T-cell responses, which are killer cells and can kill cancer cells.

My Prostate Cancer Foundation Young Investigator Award was to look at how testosterone or androgen actually holds back the killing capacity of T-cells. When you basically remove the testosterone receptor from the T-cell, it endows the T-cell with really enhanced killing capacity and increases its ability to respond to immunotherapy. The award was really around understanding this basic mechanism, which part of that was published in a Nature paper in June. I presented some of that data at today's symposium and then actually took the observation that was initially made in prostate cancer patients and then apply it to patients with melanoma, patients receiving CAR T-cell therapy, and show that this immune cell intrinsic biology around the androgen receptor is conserved across lots of cancer types, which sets up the potential for new clinical studies.

Alicia Morgans: Well, this is fascinating and I wonder if you could take a step back from cancer. Does this same relationship exist in people without cancer who of course just have T cells? Do we have the same dependence on androgen?

Amy Moran: Yeah. This is how my interest in this whole field began, is the immune system is an incredibly sensitive system to sex hormones. I think in women that's best exemplified by pregnancy requires the bone marrow to make a whole bunch of new immune cells and red blood cells to accommodate pregnancy. But it also plays out in disease. Autoimmune diseases are up to 11 times more common in women than men, and that's the immune system's detection of self and attacking of self. That tells us that something about the female immune system is activating and inflammatory. If we flip that, cancer of almost every non-reproductive tissue is more common in men than it is in women. Viral infections, the virus actually has an advantage to multiply in men over women, and that's in part why we saw more deaths due to COVID-19 in men versus women worldwide.

There's a huge epidemiological body of evidence that hormones can regulate immune responses, which is ultimately why I used prostate cancer as a model, because you go from hormones there to hormones gone, and standard of care. So we can untangle the biology and the immune system in the context of a cancer.

Alicia Morgans: What happens when we use androgen deprivation therapy and essentially remove testosterone as much as possible from the system, not necessarily with a target like an antagonist on the receptor, but just by lowering the ligand in the system? What happens?

Amy Moran: I think it's a little bit like lifting a curtain. If testosterone is this global anti-inflammatory and it's suppressing the immune system, when we first give androgen deprivation therapy, I think we get kind of a lifting of the curtain and there's immune activation. Usually we don't pair that initial lifting of the curtain with an immune system activator, like an immune checkpoint inhibitor. We wait until a patient is no longer responding to the anti-androgen, and then we add on layers of drugs. I think our data suggests that maybe we want to take advantage of lifting the curtain, reactivating the immune system by withdrawing testosterone, and then can you add in an immune activator. Will that be better, have better antitumor potential?

Alicia Morgans: That's so interesting, especially in light of you and your team's findings in a clinical setting. You work closely with Dr. Julie Graff, and some of her work suggests that in patients who are having progression of their prostate cancer in the setting of enzalutamide, if you then add pembrolizumab on, they may have actually quite a significant response to that addition, and they're not necessarily the patients that we would expect would respond to pembrolizumab because they have high tumor mutational burden or have Lynch syndrome type genes or MSI high status. This strategy is something that, in some level, in some low level perhaps, is playing out and is being investigated in a clinical trial. Is this something that you and your team think you might move into that hormone sensitive, really earlier disease state as you're suggesting?

Amy Moran: I'm not a clinical trialist, but I think that there's a lot of preclinical data and there's emerging preclinical data that maybe moving this to a hormone sensitive setting might have advantages. I think testosterone is a really important hormone for overall health, and so I think, just as a scientist, I want to be really cautious about how we rapidly move these observations into clinical practice out of the potential toxicity associated with just getting rid of all testosterone. Our initial observations were made in Julie's trial where patients responded, and that was that initial evidence for a T-cell intrinsic role for AR sensitizing to an immune therapy. Given that data, I think we should explore it before hormone blockade has been used for years.

Alicia Morgans: Very, very interesting. Where are you and your team going next? As you mentioned, of course you are a bench top researcher, so where do you go from here?

Amy Moran: We have a couple of things going on. Part of our work has identified that there's different... Testosterone can regulate inhibitory receptors on T-cells that are unique from settings in which you're not manipulating testosterone levels for cancer care. We've identified some of these new inhibitory proteins. Julie and I have been putting together a trial to move this back into the clinic based on our observations and target a couple of different inhibitory proteins. That's on the horizon.

From her initial studies, we've done correlative work to look at changes in the microbiome and have identified really unique microbiomes of patients who respond to immunotherapy, which is just a fascinating area because the microbiome is actually a source of de novo androgens. Perhaps we have castrate setting, but we have bugs that are metabolizing and producing androgens that are contributing to immune suppression and prostate cancer growth. We have a fecal transplant trial going in which we're doing analysis of our patients on trial. Then I really have a general curiosity around the crosstalk between different hormone receptors, androgen receptor, glucocorticoid receptor, estrogen receptor within T-cells and how that changes T-cell function within the context of prostate, but also other solid tumors.

Alicia Morgans: This is fascinating, and what an incredible body of work. I really want to say congratulations on this Young Investigator work, but also congratulate you as a co-investigator with Dr. Graff on a PCF Challenge Award. You and your team are really taking this to the next level, and I know that we are all actively looking to see where your next steps take you. Thank you so much for your time.

Amy Moran: Thank you, Alicia.