PSMA-Directed CAR-T First-in-Human Trial in Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Vivek Narayan

March 3, 2021

Joining Alicia Morgans to discuss the first-in-human phase 1 clinical trial to evaluate the feasibility, safety and preliminary efficacy of PSMA-directed/TGFβ-insensitive CAR-T cells (CAR-T-PSMA-TGFβRdn) in patients with metastatic castration-resistant prostate cancer (mCRPC) is Vivek Narayan, MD, MS. Dr. Narayan presented this novel evolving therapeutic approach to mCRPC at the 2021 ASCO GU symposium. Dr. Narayan highlights the safety, feasibility, and initial anti-tumor activity of the administration of these CAR T-cells in metastatic castration-resistant prostate cancer patients.

Biographies:

Vivek K. Narayan, MD, MS, Medical Oncologist, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Vivek Narayan, who is an Assistant Professor of Medicine and the GU Medical Oncologist at the Hospital of the University of Pennsylvania. Vivek presented some really lovely and groundbreaking work on CAR-T therapy, a first-in-human study in patients with metastatic castration-resistant prostate cancer. Thank you so much for being here to talk with me about this.

Vivek Narayan: Thanks, Alicia, for the opportunity.

Alicia Morgans: Wonderful. So GU ASCO 2021 has a lot going on, and I think this is one of the abstracts that I was most excited about just because it's a novel approach, an evolving therapeutic way for us to really attack metastatic CRPC. Can you tell us a little bit about this study?

Vivek Narayan: Yeah, sure. So what we are reporting in this abstract is a first-in-human phase one clinical trial of a CAR-modified T-cell approach to treat castration-resistant prostate cancer. The target of interest, the tumor-associated antigen is PSMA, which is a highly sought-after target currently in prostate cancer. But our construct also incorporates a dominant-negative TGF beta receptor. And the idea there is a source of functional armoring for the CAR T-cells to try to circumvent a common immune inhibitory mechanism that is prevalently seen in advanced prostate cancer.

Alicia Morgans: So it sounds like you actually treated three different cohorts in different dose levels, and you also use some lymphodepleting chemotherapy in some of that approach to try to really get a better response even from these CAR-Ts. So can you tell us a little bit about that?

Vivek Narayan: So we initially sought to evaluate three different dose level cohorts in a standard three plus three escalation. So our first two cohorts looked at increasing doses of the CAR T-cell construct, but without any lymphodepletion chemotherapy. In the highest dose level cohorts, so, that's our dose level three, we did give a higher dose of the CAR T-cells following a lymphodepletion chemotherapy regimen, which we know can augment the expansion and persistence of the CAR T-cells in the peripheral blood.

Alicia Morgans: Thank you. As I think about it and I wonder, how do you understand if you are actually getting the expansion of these CAR-Ts, how did you assess that in this study?

Vivek Narayan: Yeah, so that is one of the key questions from this first-in-human trial, was to really get a sense of the peripheral blood expansion and also the tumor trafficking ability of this CAR construct. And so we evaluated that primarily through a quantitative measure of the CAR-T-cell expansion using quantitative PCR of the CAR DNA. And so we looked at that at serial longitudinal time points at baseline, and then following the CAR-T infusion, but we also got baseline and on treatment tissue metastatic biopsies to get a sense of CAR-T homing to metastatic tissue.

Alicia Morgans: Wow, so it's impressive even that you were able to have enough patients to participate in this. That really speaks to the accomplishment of your group and of course, you are a GU medical oncology group but have a really accomplished BMT and transplant group as well. And it also speaks to the enthusiasm of the patients who are really excited about this because it is hard to get this pre and then-on-treatment biopsies. So I commend you and the team for making that happen. So can you tell me a little bit about what you found? Did you find the expansion of these CAR-Ts in all of your cohorts and what did the toxicity look like for patients?

Vivek Narayan: Yeah, so what we report in this abstract is the experience with the first 10 patients across these various dose level cohorts. And I think the key takeaways are that as we increase the dose-escalation, we saw a number of things. So we saw that there was an increase in expansion in the peripheral blood and also trafficking to metastatic tissues. We saw that when we included lymphodepletion chemotherapy, this also correlated with an increase in cytokine expression in the peripheral blood, but this also correlated with increased clinical inflammatory toxicities, so the cytokine release syndrome that is common to these cell-based therapies.

Vivek Narayan: And in fact, seven patients treated in the higher dose level cohorts, we saw high-grade CRS in five of those seven patients. So it was a relatively common event. And so what we observed was that this new construct appears when we give lymphodepletion chemotherapy and when we escalate the dose intensity of the CAR T-cells, we see increased persistence and expansion. We see increased cytokine expression, but we also see increased CRS-related toxicity.

Alicia Morgans: And I think that's important to acknowledge because patients do need to be well enough to get these kinds of therapies. I think, interestingly, in some conversations that I've had with folks talking about BiTE technology, where we also see this cytokine release syndrome, they were able to get around some of that or reduce some of that CRS by giving steroids or giving lower doses over an extended period of time. I'm wondering, were there ways that you and the team could help to sort of alleviate some of that CRS and help make it a little more tolerable? Or is this something that just needs to happen because that is the mechanism of the drug?

Vivek Narayan: Yeah, so it's a great question. So, first of all, from a monitoring standpoint, we admit all of these patients into the hospital for increased monitoring during the time of the cell infusion and thereafter. And we largely found that the CRS toxicity was manageable with a lot of the same techniques that's been employed in BiTE therapy or in other cell-therapy trials and experience to date. So for example, a lot of this toxicity could be reversed with tocilizumab or steroid administration. And with the exception of one patient who was treated in the highest dose level cohort, we were able to successfully achieve that. I should mention that the patient who was treated at the highest dose level cohort with lymphodepletion chemotherapy did develop severe grade four CRS, which ultimately led to dose-limiting toxicity. And so we actually de-escalated with the subsequent cohort and treated three additional patients at a lower T-cell dose and were again, able to have manageable toxicity with tocilizumab or other immunosuppressive measures.

Alicia Morgans: That is good to know, and very important. And I'm glad that the way the study was designed, it allowed you to really expand at a dose that was a little bit more tolerable. So in terms of this, how this is actually done, I understand that you admit patients to the hospital. Do you partner with other teams to try to really give these treatments safely? Or do you, as GU medical oncologists actually do all of the inpatient monitoring and dose delivery for patients?

Vivek Narayan: Yeah, so it's a little bit of both. We are really fortunate at my institution that we have really great colleagues who have a tremendous wealth of experience in cell therapy, primarily for hematologic malignancies. And so for these patients, when we admit them to the hospital for their CAR T-cell therapy, we do admit them under the service of a hematologic malignancy transplant and cell therapy oncology service. And so they are a tremendous resource in managing some of this acute toxicity as it may develop, but primarily, the enrollment, the screening, the initial management of the patients, and in the post-acute period is largely managed by us as GU medical oncologists.

Alicia Morgans: Well, that is encouraging because I think over time, as we are able to roll these therapies out, having as much control over that symptom management and monitoring in the hands of the medical oncologists, who are so familiar with these patients is going to be important. But I have a feeling this is going to be the type of treatment that patients are probably going to need to travel to get, at least for some time, and really, to receive these kinds of therapies in the hands of experts like you. So as you think about these CAR-T therapies, moving on to the next steps and where they ultimately may go, and when, what are your thoughts? How are we as a field to expect the development of CAR-Ts in the metastatic CRPC setting?

Vivek Narayan: Yeah. So there is no doubt that bringing this kind of technology to solid tumors and especially prostate cancer is going to be a challenge. But I think that what we are seeing in our study and similar studies that are beginning to report is that we can see on target biologic activity with these CAR T-cells. And in fact, in our experience, we not only saw the increased expansion in cytokine expression and the CRS toxicity, which we believe to be an on-target effect of this drug, but we also began to see some preliminary anti-tumor activity. And in fact, several of the patients in the study had some initial robust PSA decline as a measure of anti-tumor response. And the one patient I mentioned at the highest dose level who unfortunately developed severe CRS toxicity actually had a robust and rapid PSA decline to nearly undetectable levels.

Vivek Narayan: And so it is all preliminary, but certainly speaks to some of the potentials of this therapy. And so, I think as we move forward, some of the strategies that we'll need to think through are how do we improve the toxicity profile and management of these patients, and how can we use other strategies to try to augment or circumvent any immune inhibitory mechanisms that we know are going to be up-regulated and present in a prostate cancer microenvironment?

Vivek Narayan: And so with this particular study, it has been moving forward in a multi-center fashion now within a currently-enrolling trial at multiple experienced centers across the nation. And so I think that is just one example of how we can continue to try to address some of these questions moving forward.

Alicia Morgans: Wow. It's really exceptional work. Can you give us a summary and a take-home message to consider?

Vivek Narayan: Sure. So I think what we can say from this initial experience is that the administration of these CAR T-cells in advanced prostate cancer patients is safe, feasible, and shows some initial anti-tumor activity. But I think one important point is that this was truly a very collaborative endeavor, starting with the PI of this study, Naomi Haas, and a huge team of translational scientists who we work with. And we certainly would want to acknowledge our supporters for this study. So both the Prostate Cancer Foundation, as well as Tmunity Therapeutics.

Alicia Morgans: I think it is really exciting. And I appreciate you taking the time to speak with me today about this. And I really look forward to hearing how you and the other centers fare with the ongoing work that you are doing. We will make sure to have the clinicaltrials.gov NCT number with this video so that people who are interested can identify sites that may be near them, and hopefully consider enrolling in these ongoing trials as an option for them, if it is appropriate.

Alicia Morgans: Thank you so much for your time. Congratulations to you and your team. You really are partnering with an excellent team in the heme malignancy group to just push boundaries for our patients with metastatic CRPC and maybe even earlier phases of prostate cancer as time evolves. And I really appreciate you taking the time to explain all of this to us today. Thank you.

Vivek Narayan: Thanks so much, Alicia.
email news signup