Pedro Barata: Hello, and welcome to another video for UroToday. My name is Pedro Barata, I'm a GU medical oncologist out of Case Western in Cleveland, Ohio. I'm super happy to be joined today by Dr. Carissa Chu, urologic oncology from UCSF, a superstar in GU tumors, but in prostate cancer specifically. And so, thank you Carissa, being here with us today and taking the time.

Carissa Chu: Thank you for having me, Pedro.

Pedro Barata: Absolutely. So today we'll be highlighting a little bit your amazing work that was awarded, Young Investigator Award out of Prostate Cancer Foundation. So it's a big deal. It's very hard to get, so it speaks to the quality of your work. So congratulations. And your work is around STEAP1 and T-cell engager and the study around that. So I guess one way to, kind of set the stage, tell us a little bit about why STEAP1 is important in prostate cancer.

Carissa Chu: Yeah, so thank you for having me and I'm happy to talk all about my work on STEAP1. So STEAP1 stands for the six transmembrane epithelial antigen of the prostate. It's a surface protein, it's actually part of a family of proteins, there's one through four. And they homodimerize, heterodimerize. It's thought that there's some sort of ion metabolism, ion homeostasis, potentially role of metabolism for these different proteins. So that's still sort of being defined and characterized. But what's exciting is that it's now sort of the next big target in prostate cancer. We know it's highly overexpressed in primary prostate cancers as well as metastatic sites at levels that compete or are comparable or even higher than PSMA. And at an ESMO meeting a couple of years ago now, presentation by Dr. Kevin Kelly from Thomas Jefferson, presented some really impressive data showing incredible responses in some of these very treatment refractory patients who have progressed after MCRPC, progressed after chemo, progressed after radioligand therapy. And so, as is the paradigm of all of these new novel agents, can we try to test it in earlier disease states? So we kind of thought through it and this is an exciting new target, let's try to characterize it better, let's try to figure out how it's regulated, let's try to figure out what it's doing and how we can maybe manipulate levels of STEAP1 to enhance targeted therapy.

Pedro Barata: Got it. So just for context, for folks who might be listening to this, so I agree with you fully, beyond PSMA there's a number of targets that have been emerged, right? STEAP1 being one, B7-H3, PSMA, perhaps KLK2. Those really have been playing an important role, especially because there's a lot in oncology world. It gets a lot of our attention once we start getting therapies against it, which is the case as you're describing. And so, just for those who might be less familiar, can you walk me through a little bit the mechanism of action of these bispecific T-cell engagers? How does that work with the immune system within our body and STEAP1 cells?

Carissa Chu: Right. Now, I'm a urologist, I'm not an immunologist, so I'll explain kind of how I think about it. So it's sort of an engineered antibody and it's bringing together two players. Okay, there's the prostate cancer cell and that's the one expressing STEAP1. And then there's another arm, it's called bispecific, because there's another kind of arm that's got CD3 that will bring in and activate a T-cell in the neighborhood, is the assumption. And so, you're recruiting specific T-cell populations to the cancer cells. And so, it's sort of an advanced cellular therapy, advanced immunotherapy. But it's also remarkable, because it's really the first immunotherapy that has proved to have such a level of activity in prostate cancer.

Pedro Barata: That's a fantastic way. I kind of use similar explanation, I guess, and walk through that with my patients in clinic when we have them on study. Okay, so as you said, very promising data. Kevin has been doing an amazing job kind of leading those efforts in late MCRPC settings. I really loved your concept in the neoadjuvant setting, I believe, because you actually have an opportunity to get a lot of correlative work in your lab around that. So walk us a little bit about what made you go to the neoadjuvant space and what kind of you are doing in the lab to complement your understanding and knowledge about what are you going to do with patients?

Carissa Chu: Yeah, so the YIA, the project that's funded by PCF is really a two-pronged approach. So there's the benchtop, the wet lab component, which is looking at prostate cancer cells and looking at what's regulating STEAP1 in expression in that model. And mentored by the late Felix Feng, Luke Gilbert, and many others, we have a way to do whole genome CRISPR screening to understand on an individual gene-to-gene level what is regulating STEAP1 expression. And so, the CRISPR screen is a design that you can find the top 10 and the bottom 10% of genes that are conferring extremes of STEAP1 expression. And so, you can say gene X is down-regulating STEAP1. And so, if that's a druggable target and you can then find a second therapeutic that can target that protein or that gene, then you can inhibit the inhibitor and bring up STEAP1 expression. So that's sort of the basis of the CRISPR screen.

And so, by doing the screen, we've identified other novel targets that may synergize with STEAP1 targeted therapy. And that could be a bispecific, that could be a CAR-T, it could be whatever, could be an ADC, could be whatever the next generation therapy targeting the surface will be. So that's exciting. And now we've validated across different cell lines and we're able to move into models and test some of our combinations. So hopefully that's coming in the future.

The neoadjuvant trial I think is interesting from both the clinical perspective and seeing if we can improve biochemical control, if we can improve pathologic response in patients with high-risk disease prior to prostatectomy. So there has always been a desire to do that in the field. From a scientific perspective, it gives us the opportunity to look at the biopsy tissue and then the post-treatment radical prostatectomy tissue, put them side by side, characterize them up and down, left and right, and say, "Are the observations that we're seeing in the lab, are they also seen in patients who respond, who don't respond? What is the tumor microenvironment around these tumors when you're giving a bispecific antibody? What's the mechanism? Can we observe that at that time point?" And as a surgeon, as a urologist who does a lot of prostatectomies, I just like the idea that we can go back and forth to the lab like that. So there's a lot of great questions to be answered in that.

Pedro Barata: For sure. I mean, congratulations. This is a really super interesting and timely project, because it really brings you back to clinic. This therapy, it's not approved yet. The phase three trial in the late stages, going on, it's actually accruing quite well. And so, the next step is, can we move it early on in studies like yours in actually a setting where we don't have actually any validated approval in the neoadjuvant mix, right? We've been struggling for so long. So it's very interesting, because maybe the answer is around immunotherapy, or in the case of bispecific T-cell engager. So I mean, this is amazing work, so congratulations. I don't know if you have any other thoughts, something you'd like to say about how the grant is going or how the project is going?

Carissa Chu: Yeah, things are moving along really well. I have to give a lot of credit to a postdoctoral scholar, Sasha Zhu in the lab who has been doing a lot of the day-to-day wet lab work. We're excited to move into animal model soon, testing novel combinations, seeing if we can enhance STEAP1 expression in prostate cancer cells, test some available patient derived xenografts that we have as well to see if we can get even closer to the patient by doing that. And I think what we learn will can be extrapolated beyond the neoadjuvant space. I think it can inform potential mechanisms of primary or secondary resistance in a metastatic setting. There's so much heterogeneity. The STEAP1 expression in the primary tumor may not reflect what's happening at the metastatic sites. And the live autopsy program from Fred Hutch actually showed that there's quite a bit of heterogeneity. So, we're moving along here. I'm excited. I think finding a good neoadjuvant regimen has been one of the great holy grails in urology too, so maybe this will be the one. But I think it's a paradigm for how we can improve our therapeutic approaches and also do some really exciting science at the same time.

Pedro Barata: Right. No, kudos to that. And just by what you described, it really has the potential to build upon what we already know, but there's more to learn, a lot more to learn. And by the way, there are several bispecific T-cell engagers being explored as we speak in different levels in the drug development process. So I think some of this can actually be extrapolated in our knowledge of it. So as a field, your contributions will be definitely welcome. So congratulations. I'm so happy Prostate Cancer Foundation is helping supporting this fantastic work out of your lab and UCSF. So congratulations to you and to the team.

Carissa Chu: Thank you.

Pedro Barata: Thank you for being here with us.

Carissa Chu: Thank you for the funding.