Alicia Morgans: Hi, I'm thrilled to be at ASCO 2022 with Dr. Vivek Narayan, who is here from the University of Pennsylvania. Thank you so much for speaking with me.

Vivek Narayan: Thanks so much, Alicia. Glad to be here.

Alicia Morgans: Well, I'm glad too. And one of the reasons is that you and your team at University of Pennsylvania have really made great strides and inroads into our understanding of CAR T and cellular-based therapies. And part of that work of course was supported by Prostate Cancer Foundation, funding that really supported that initial work in CAR T. But you've taken it so much farther and really have continued to contribute to the field. Can you give us a little bit of the lay of the land?

Vivek Narayan: Sure, yeah. I think we've all known for a long time that there's been a nice established track record of cell therapies for hematologic malignancies. And so Penn, among other institutions, we're really interested in trying to bring this to the world of solid tumors and prostate cancer in particular. And so about five or six years ago, we were very fortunate to have funding from the Prostate Cancer Foundation, as you mentioned, to really inspire a challenge award to try to develop a therapy in prostate cancer for men with treatment-refractory disease. And so that was our initial foray into this and certainly started with all the preclinical work, but then moved on to a first-in-human phase one clinical trial, which we recently completed and published at least the initial experience of the first 13 treated patients.

Alicia Morgans: Well, that's really exciting. And now before we get to the results of that trial, can you tell me a little bit about the logistics? I was fortunate actually to train as a student and a resident at the University of Pennsylvania, so I'm very familiar with the great collaborations that you can have with the liquid oncology team that is so strong and powerful at Penn and has been working on the cellular-based therapies too for their malignancies. Did you partner with those kinds of individuals, because at many institutions that partnership is what helps support the development and the safety of patients and the care when using CAR T?

Vivek Narayan: Absolutely. We're very fortunate to have great colleagues in the hemalignancy world who really helped, all the way from the early planning of the protocol, the writing of protocol, into all the way through toxicity management in the inpatient setting and even analysis of the results and putting all the story together. So we're really fortunate in that regard.

Alicia Morgans: And I think that collaboration, whether you're at Penn or whether you're at another institution, if that's available, is something that can be so valuable in teaching us, those who really focus on solid tumor oncology, how we can best use some of these therapies. So I'm glad that you had that resource. Now, when you published that data, I'd love to hear, what was the initial experience with your first cohort of patients?

Vivek Narayan: This was, again, a first-in-human study, so very early testing of this novel approach, and it was a dose-escalation study. And so we wrote it and planned it in such a way where safety was our primary objective to evaluate the feasibility of manufacturing and delivering these CAR T-cells, and then whether we can get them into patients in a safe manner. So we started at a low-dose level and began to see some early indication of some on-treatment toxicity, as well as some on-treatment anti-cancer benefit. And as we escalated, both of those things really seemed to increase. We saw more in the way of PSA reduction, indicating some early anti-tumor response.

But then on the flip side, we also began to see a lot more in the realm of cytokine release syndrome, which of course is the standard inflammatory toxicity that can be observed with cell therapies in any tumor. And we certainly saw that in our case as well. And so I think those are really the key learnings, is that it was feasible, but we both need to improve both the efficacy, to get more durable remissions for prostate cancer patients, but also find ways to mitigate some of the treatment-related toxicity that we observed as well.

Alicia Morgans: So, let's dig in a little bit more to the Cytokine Release Syndrome, also nicknamed CRS. I think this is something that, again, in solid tumors we have little experience with, but I think as we think back to experiences with IL-2 and some of these other approaches, we might realize that we have more knowledge than we think. But tell us a little bit about what kinds of symptoms we see with CRS. Where are these patients normally kept, so that we can care for them and how do you best care for these patients?

Vivek Narayan: Yeah, so I think this is something that is completely foreign to most of us in the solid tumor world. And really we're learning as we go and learning a lot from our hemalignancy colleagues, but I think in most cell therapy protocols thus far in the solid tumor world and certainly ours as well, we admit these patients into the hospital following lymphodepletion chemotherapy and admit them for safety monitoring while they're getting their CAR T-cell infusion, and usually for a prolonged period even up to one or two weeks after their CAR T-cell infusion. And I think part of the reason for that is that the ability to predict the onset and the severity of CRS is really challenging.

And as an example, in our series we had some patients who developed it within six hours of their CAR T-cell infusion, whereas other patients may have developed it a week or 10 days later. And so we always have to be vigilant for it. Also, what we learned, again from our hemalignancy colleagues, is a bit different from sometimes how we manage other solid tumor toxicities, is you have to be aggressive early with the management of it. So whether it's corticosteroids at high dosing, vasopressor support or other resuscitative measures, or other so-called antidotes to CRS, medicines like tocilizumab, and sometimes all three, we need to use those early and often to try to mitigate the toxicity.

Alicia Morgans: And did you have any grade 5 events in your first patients?

Vivek Narayan: We did, unfortunately. And I think this was a particularly, of course, sad scenario, but also very illustrative of what the potential benefits of CAR T-cell therapy are, but also a lot of the dangers are as well. This was a particular patient, standard, treatment-refractory, castration-resistant prostate cancer patient, and he was treated at our highest dose level in the dose-escalation plan and really developed a profound anti-tumor response where he had a PSA that was skyrocketing prior to the CAR T-cell infusion, but then really within a week or so of the infusion, his PSA reached near-undetectable levels and stayed there persistently. But what came along with that was really severe cytokine expression and a clinical cytokine release syndrome, which unfortunately progressed to a grade 5 event. Our learnings from that are, clearly, there was evidence of early anti-tumor benefit, but of course, we need to find better ways to make it safer for our patients. And so that's where we went back to the drawing board and are rethinking some strategies to try to mitigate some of the toxicity.

Alicia Morgans: So where do you go with CAR T therapy now? What are next steps for Penn and of course for the rest of the field?

Vivek Narayan: Yeah. I think first, starting with our institutional plan, it's really twofold. So one, we're taking our same construct and we are in an effort to mitigate some of the toxicity attenuating the dose level, because we do think that there is a dose-response toxicity relationship. But along with that, we're trying to investigate some adjunctive therapies that we can use as a rescue modality if we get into trouble with severe inflammatory toxicity. And so we're thinking through some early rescue anti-inflammatory measures that we can use, that might specifically target the pathways that we observe in these patients with severe toxicity.

Alicia Morgans: I think that's fantastic. Can you share just a little bit about how the CARs are designed and how they might evolve?

Vivek Narayan: Yeah. So in here, getting back to your previous question about where the field is going, I think that there's a lot of opportunity, and I think one of the potential advantages of CAR therapies is that the really adaptable constructs, there's a whole host of tumor-associated henogens that can be targeted, but also a lot of modifications that can be made to the actual CAR construct to try to boost efficacy and persistence in a patient, but also to try to mitigate some of the toxicity. And so CARs are, of course, our chimeric receptor on the cell surface, and one of the strategies that we're looking at is both trying to include adjunctive components of the CAR that might improve some of the on-target efficacy, but also swapping out some of the internal domains of the CAR to try to mitigate some of the cytokine toxicity that we've observed. So really a whole host of things you can swap in and out to see what might strike the best balance for prostate cancer.

Alicia Morgans: I just think this is a fascinating field and I sincerely appreciate the work that you and the team and the patients are doing and certainly look forward to hearing future conversations where we talk about how we can get really fantastic disease control in a way that is safe and effective for our patients. So thank you for your time.

Vivek Narayan: Thanks so much.