PSCA CAR T-Cell Therapy for Metastatic CRPC: Phase 1 Trial Results - Tanya Dorff

June 21, 2024

Tanya Dorff discusses her team's Phase 1 trial on PSCA CAR T cell therapy for metastatic castration-resistant prostate cancer, published in Nature Medicine. Dr. Dorff highlights that prostate cancer's immunosuppressive environment poses significant challenges, making the development of potent therapies like CAR T cells crucial. The trial involved administering CAR T cells, initially without and then with lymphodepletion, to heavily pretreated patients. Key findings show that lymphodepletion significantly enhanced CAR T cell expansion and effectiveness, with notable tumor reductions and PSA declines in some patients. However, the therapy also faced challenges, such as dose-limiting cystitis, managed by adjusting cyclophosphamide dosage. Moving forward, the Phase 1B trial explores incremental dosing and combination strategies to improve therapeutic outcomes. Dr. Dorff emphasizes the importance of continued research into biomarkers and tumor heterogeneity to refine and optimize these promising immunotherapies for prostate cancer patients.


Tanya Dorff, MD, Medical Oncologist, Associate Professor, Department of Medical Oncology & Therapeutics Research, Section Chief of the Genitourinary Disease Program, City of Hope, Duarte, CA

Andrea K. Miyahira, PhD, Director of Global Research & Scientific Communications, The Prostate Cancer Foundation

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Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira here at The Prostate Cancer Foundation. Joining me is Dr. Tanya Dorff, a professor at City of Hope. Dr. Dorff will present her group's recent paper, "PSCA CAR T Cell Therapy for Metastatic Castration-Resistant Prostate Cancer: A Phase 1 Trial," that was published in Nature Medicine. Dr. Dorff, thank you for joining me and sharing your work with us today.

Tanya Dorff: Pleasure to be here. We're very excited to finally be sharing the full results from our Phase 1 trial of PSCA targeted CAR T cell therapy. We know that prostate cancer suffers from an extremely immunosuppressed tumor microenvironment. It's been called an immune desert. So not only do T cells not traffic well into tumors, but certain components limit their function once they are in the prostate cancer microenvironment. So it's going to take a really powerful immunotherapy like CAR T cells potentially to overcome that, and yet prostate cancer has some attributes that make it really amenable to this kind of therapy, such as the unique antigens, things like PSMA, or in this case PSCA, being very, very highly expressed, especially in metastatic castrate-resistant disease.

So our Phase 1 study started with a hundred million CAR T cells without lymphodepletion, and then we went to lymphodepletion plus the same dose and had planned to escalate to 300 million, but ended up having to stick with the hundred million dose. You can see that our patient population was heavily pretreated. Most had had two lines of taxane chemotherapy and certainly all had one or two AR pathway inhibitors, and a significant proportion had visceral involvement. One of the things we learned early on was that lymphodepletion made a big difference, which hadn't previously been known in solid tumors whether it made sense the way it does in leukemia lymphoma, but you can see on the bottom left that CAR T cell expansion was significantly increased in cohorts two and three, which had the lymphodepletion chemotherapy. Subsequently, Dr. Priceman's lab has shown that there are really favorable immune modifications in the tumor microenvironment that explain this.

So top line results, this can be effective. We still have work to do, but we saw proof of principle even in this small Phase 1 experience that this PSCA CAR T cell therapy could be effective. The waterfall plot depicts PSA declines during the 28-day DLT period, and you can see a patient with liver metastasis, heavy disease burden, significant improvement after the CAR T cell therapy. On the right, we show a bone scan of a patient who had a 95% PSA decline, his soft tissue disease in his pancreas improved and then his bone scan improved as well. One of the correlative studies that we will be further analyzing and sharing later has to do with the circulating tumor cells, but in this patient we do show that both in the peripheral blood and depicted here in the bone marrow, there was a dramatic decrease in cytokeratin positive circulating tumor cells after CAR T cell therapy.

We did hit a dose-limiting toxicity in cohort two where we added the lymphodepletion, and that was cystitis. This was pretty symptomatic, and rather than increasing to 300 million CAR T cells, therefore, and rather than decreasing the dose, we opted to modify the dose of cyclophosphamide since that has an overlapping toxicity of hemorrhagic cystitis. We think this is an on-target off-tumor effect because PSCA is expressed in the bladder, but we were hoping we could maintain the dose of CAR T cells by reducing the cyclophosphamide. In fact, in that third cohort we did not have any DLT cystitis. Cytokine release syndrome, CRS, was present but in a minority of patients and only grade one and two. So we didn't have any high-grade CRS, we didn't have any HLH or macrophage activation syndrome.

We started looking at the biopsy. So patients had a biopsy as they joined the study prior to lymphodepletion, and then also at day 28, and our exceptional responder, his histology is shown to the right with immunofluorescence. You can see that post-CAR T cell infusion, there is much less tumor and there's an increase in infiltration of CD3 and CD8 cells, the pink and the green. You can see his cytokine profile on the bottom left with a peak in cytokines around day seven corresponding to when we saw expansion and also when we saw cytokine release syndrome as well. Then on the upper left, we show his timeframe of expansion of different populations of T cells. We did see induction of T memory cells and effector cells, and then with the PD1, LAG3 and Tim-3 also expression being depicted in part B there. So essentially, we could see that the CAR T cells post-infusion proliferated and showed markers of activation.

This gets into that a little bit more as well as showing the single-cell RNA-seq with the T-cell receptor clonotype analysis. The patient on the left in the top and the bottom is that exceptional responder. You see expansion of T effectors and T memory, especially around day 14 to 28, and below you can see a broad expansion of the T-cell repertoire, suggesting that there can be antigen spread induced as we're killing cancer through this mechanism. On the right, in comparison, are similar analyses from two other patients in the study. The patient on the bottom in C is the one with the liver metastasis. So there was anti-tumor effect, and we see the T-cell receptor diversity significantly increasing compared to the patient on the top right in panel A.

Overall these PSCA targeted CAR T cells showed potential to be effective, but there is more work to be done. We need to have a higher percentage of patients benefiting, longer duration of remissions, and always less toxicity if we can. So we've opened a Phase 1B now to build upon what we've learned in the Phase 1 and what we've learned through other CAR T-cell trials in prostate cancer to try to optimize that therapeutic window.

Andrea Miyahira: Thanks for sharing that Dr. Dorff. Could you talk more about your next steps in the clinic? What additional dosing strategies or other strategies such as combinations are you looking to test?

Tanya Dorff: Yeah, it's a great question. We knew we would need a higher dose to really see more patients having significant efficacy, and we see that in the proliferation parameters, but to go straight to 300 million, we also knew based on what we saw in the lab that it would create cystitis again. So in the Phase 1B, we're dosing 50 million every two weeks for up to six doses to try to get that 300 million in without creating that over-expansion, over-proliferation that we think is associated with a lot of the toxicity, including what was seen in some of the other CAR T trials where you did have HLH and MAS. It's that really big sudden expansion. So giving it bit by bit also gives us the ability to hopefully increase the durability of proliferation, the persistence of the CAR T cells, which we hope will end up creating longer-lasting responses.

We're hopeful about this new dosing strategy. We do want to start to combine it. If it is more successful as we anticipate, we'd like to combine it with metastasis-directed radiation and with radio ligand therapy. We're currently looking at this in the lab to see if it is immune-activating, but we know the metastasis-directed radiation appears to be modulating the tumor microenvironment in ways that should be favorable, and the preclinical data seems to be synergistic. Eventually, we may look at combinations with other immune modifiers such as immune checkpoint inhibitors, but for now, we're starting with these combinations.

Andrea Miyahira: Thanks. When is the Phase 1B open? Is it already going?

Tanya Dorff: We're actively recruiting patients on the Phase 1B now.

Andrea Miyahira: Awesome. I look forward to those results. So were you able to look at biomarkers, and did you see any biomarkers or clinical characteristics that suggest a response?

Tanya Dorff: It's a little bit hard with such a small number of patients and a small number of responses to start to look at biomarkers, but of course, we think PSCA expression is probably important. We did look at immunohistochemical staining of PSCA, pre-screening on archival tissue as well as in the on-study and post-treatment biopsies, but more work to be done. We're hoping to look at it on the circulating tumor cells to also give us a sense of how predominant it is in comparison to some other antigens, potentially other biomarkers. Genomics will be very interesting. Our exceptional responder actually had PTEN deletion, which tends to predict for lack of response to immunotherapy. The patient with the liver metastases had a CDK12 alteration but had failed to respond to checkpoint inhibitor therapy on a clinical trial. He had been on cabozantinib and atezolizumab. So I think genomics will be really hard to tease out again with these small numbers, but it is something we will be looking at.

Andrea Miyahira: I think you guys are looking at PSCA expression. Do you see any relationship between PSCA heterogeneity and response, and in patients that progressed, was PSCA expression lost?

Tanya Dorff: So we did have a patient who, on-study biopsy revealed some neuroendocrine transformation, and yet there was still some PSCA expression, so probably had a bimodal population and really wanted to proceed to get his CAR T cells, which had already been manufactured at that point. In that patient, the post-treatment biopsy really showed complete transformation to neuroendocrine and no PSCA expression. So tumor heterogeneity is something that worries us, and dual targeting is a strategy that may become important, especially if we are using these therapies in later lines where we know that our prostate cancer can evolve and de-differentiate and transform. But generally speaking, in the samples where there was tissue still with cancer that we could stain, we saw retention of PSCA expression. So it doesn't appear that antigen loss is a major driver of lack of response, but heterogeneity will be interesting and we need sort of better tools maybe to quantify maybe looking at spatial transcriptomics almost to understand because there were patients with mixed responses in different tissues. So lots to learn there.

Andrea Miyahira: Awesome. Are you doing other correlative studies, and could you describe what you're investigating in those?

Tanya Dorff: The big set of correlative studies that are not yet ready for publication that we're still working through are the collaborations with Peter Kuhn's lab with the circulating tumor cells, and there's so much that we can do there. A basic one will be PSCA expression, but also looking at the populations of these very pleomorphic different kinds of circulating tumor cells. I think there's really a lot more we'll learn from that. But aside from that, we've done most of the correlative studies in this paper, especially things like the single-cell RNA-seq and cytokines and T-cell populations.

Andrea Miyahira: Thank you. Are you able to compare safety and efficacy of this CAR-T cell product with other CAR-Ts or immunotherapies that are being tested in trials for prostate cancer?

Tanya Dorff: It's been my privilege to work on a couple of different protocols with industry agents, CAR-T constructs. We can't make formal comparisons. These are all early phase, first in human Phase 1 trials, and they're also different. You have the Bellicum PSCA CAR T, which I didn't personally work on, but the idea of driving the proliferation makes a lot of sense when you see our kinetics of lack of persistence. So having that ability to use rimiducid to drive proliferation is very interesting. On the other hand, the PSMA CAR T from Poseida that we worked with, we had the option to use rimiducid as a "kill switch" or safety switch and needed to use it. So it's that balance between driving enough proliferation to get the anti-cancer effect, but not driving too much, and the kinetics of that and the methods by which we do it are what we're all learning about from these early phase studies.

So I would say we've all had good responses in some patients, we've all had toxicity, and we need to really look broadly across these experiences to try to learn the best way to navigate and most efficiently move these into trials with greater success. I don't want to directly compare, but I certainly have had the opportunity to learn as I've seen patients on these different cellular immunotherapies and it's given us a lot to test in the lab as well as implementing in our design for upcoming studies.

Andrea Miyahira: Well, thank you again for sharing this and congratulations again to your team.

Tanya Dorff: Thank you so much to the Prostate Cancer Foundation for supporting the work and continuing to believe in it and supporting the science so that we can learn as much as possible and make this hope a reality for our patients.