Exploring the Potential of PSCA-Targeted CAR T-Cell Therapy to Treat mCRPC

Metastatic castration-resistant prostate cancer (mCRPC) remains highly lethal despite advances in treatments. New approaches continue to be explored to treat patients with mCRPC, including newer immunotherapy approaches.

Immunotherapy has proven effective in creating durable remissions for many cancer types. However, that has yet to be true for mCRPC. In patients with refractory hematologic malignancies, chimeric antigen receptor (CAR) T-cell therapy has provided cures. Additionally, the therapy shows promise in solid tumors. However, identifying and targeting the optimal agent will be of paramount importance for success.

A phase 1 study (NCT03873805) is underway exploring the use of prostate stem cell antigen (PSCA)–targeting chimeric antigen receptor (CAR) T-cell therapy in patients with mCRPC. The study is using a toxicity equivalence range to evaluate the selected doses of PSCA-BBζ cells in order to determine the maximum tolerated dose. The 4 cohorts (1, 1b, 2, and 3) will each receive a different dose of CAR T cells. Cohort 1 will receive 100 million CAR T cells, cohort 1b will receive 100 million CAR T cells after lymphodepletion, cohort 2 will receive 300 million CAR T cells after lymphodepletion, and cohort 3 will receive 600 million CAR T cells after lymphodepletion. The estimated enrollment is 33 participants. 1,2

The study has primary objectives of safety and tolerability and define the recommended phase 2 dose. Secondary outcomes include assessing the expansion and persistence of PSCA CAR T cells and survival outcomes. In order to enroll, patients must have documented mCRPC previously treated with enzalutamide (Xtandi), abiraterone acetate (Zytiga), or both. Prior chemotherapy and radium-223 (Xofigo) is allowed but not required. Participants with a history of optic neuritis or other inflammatory disease affecting their central nervous system are ineligible to participate.

Already several patients have been treated with PSCA-BBζ cells manufactured successfully and one patient has shown suggestions of clinical and prostate-specific antigen (PSA) responses to the treatment, but investigators are waiting for more data to emerge before a response is confirmed.

Tanya B. Dorff, MD, a medical oncologist at the City of Hope Cancer Center, discusses the reasoning behind using PSCA-targeted CAR T-cell therapy and the design of this early study in an interview with Targeted Oncology.

TARGETED ONCOLOGY: Could you provide an overview of your presentation on the clinical development of PSCA-targeted CAR T cells for patients with advanced prostate cancer?

DORFF: So importantly, our presentation is not a complete presentation of clinical trial results. Because the study is still ongoing, we're still actively recruiting and treating patients. So, it could be viewed more as a progress report or an exploration of the science that is going to help continue the development beyond this phase 1 dose escalation first step. But that being said, we are showing a little bit of one patient's experience on our first-in-human trial with a second-generation CAR T targeting the unique antigen of PSCA, which is prostate stem cell antigen.

TARGETED ONCOLOGY: What's the rationale for using these PSCA-targeted CAR T cells?

Well, PSCA is very strongly expressed in prostate cancer and even more so once it becomes metastatic. Also, when you're trying to target something with a really powerful driver like CAR T, it's important to know where it's not expressed. So largely there's low levels or absent expression of PSCA in normal tissues, where there is a little bit in gastric lining and bladder. Also, importantly, PSCA is expressed in 2 other cancers, which are pancreatic cancer and bladder cancer, which means that potentially with 1 CAR-T, 3 different cancers could be targeted.

TARGETED ONCOLOGY: Can you speak more to the design of this ongoing study?

DORFF: Yeah, so Saul Priceman, PhD, in the T-cell therapies lab here on campus at City of Hope, designed a CAR T to target PSCA with a 4-1BB costimulatory domain. We have treated patients at a dose of 100 million cells. These are CAR T cells that are produced right here on our campus at City of Hope. We started without lymphodepleting chemotherapy and then moved into a cohort with lymphodepleting therapy. And the goal is to escalate to 300 million cells and potentially 600 million cells, once we determine the safety of the current cohort.

TARGETED ONCOLOGY: Are there any data available so far for these CAR-T cells?

DORFF:So again, we aren't able to present full clinical results. We did have a patient who have had a very strong PSA response as well as a radiographic response. So, it's encouraging to see some evidence of activity even at this very, very early stage when only 7 patients have been treated. We are really looking at the science. So, we have this great collaboration with Peter Kuhn, PhD, over at University of Southern California, that uses his platform for both peripheral blood and bone marrow, because we're getting biopsy samples largely from bone before and after treatment on the study. So, we can see all types of circulating tumor cells and other rare cell events that are helping us understand the interaction of the immune system with the cancer. And we'll also be able to learn a bit more about PSCA expression, whether it changes over time, using this really powerful platform.

We also look at imaging, so we're looking at MRI in the bone, because CT and bone scans aren't really helpful often in determining whether bone metastases have improved. So, we show a little bit about what we're able to see using the MRIs during the trial. And then we look at the cytokines and the potential role for lymphodepletion chemotherapy, which does seem to increase the amount of cytokines that are being released. So, it suggests it is an important component, even in the setting of a solid tumor, like prostate cancer.

TARGETED ONCOLOGY: What are the key points that you'd like to make from your presentation?

DORFF: It's hard to make any definitive conclusions. This is a very early foray into a very promising technology. It's certainly something that has to be done with the utmost caution. It’s very powerful treatment patients are treated in the hospital, we do see [adverse] effects, including cytokine release syndrome. But that being said, at least we can say that we're already seeing a signal that unlike other immunotherapies in the past for prostate cancer, we can quickly induce visible response. So as we study our tissue samples, before and after treatment, we'll learn what potential mechanisms the cancer has to resist this type of therapy, because we anticipate we might need combination treatment in the future to overcome that kind of resistance of prostate cancer to immunotherapy that we've seen over the years. So, the bottom line is that this is exciting. Stay tuned for more.

_REFERENCE:

_{1. Mustang Bio announces MB-105 data selected for presentation at the virtual 27th Annual Prostate Cancer Foundation Scientific Retreat. News release. Mustang Bio, Inc. October 8, 2020. Accessed March 23, 2021. https://bit.ly/3ccNd9O}

_{2. Dorff T, Blanchard S, Carruth P, et al. A phase 1 study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 6):TPS250[LA1] . doi:10.1200/JCO.2020.38.6_suppl.TPS250}