CAR T-Cell Use Possible in Metastatic Castration-Resistant Prostate Cancer

Tanya Dorff, MD

Unlike hematologic malignancies, there has not been much exploration of chimeric antigen receptor (CAR) T cells in solid tumors, according to Tanya Dorff, MD. There are several reasons why CAR T cells are so novel in solid tumors, but preclinical and phase 1 research signal benefit of CAR T-cell therapy in the prostate cancer space.

Preclinically, researchers from the Saul Priceman lab at City of Hope found that adding lymphodepleting chemotherapy to prostate stem cell antigen (PSCA) CAR T cells in metastatic prostate cancer models significantly changed the immunosuppressive tumor microenvironment. Further, the therapeutic strategy did not lead to toxicities in normal tissues.¹

Dorff et al sought to confirm what was observed in preclinical models by launching a phase 1 study (NCT03873805) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). The ongoing study aims to primarily determine the full toxicity profile of the novel CAR T cells and the dose-limiting toxicities. The secondary end points of the study include CAR T cells. Persistence, expansion of CAR T cells, disease response, overall survival, progression-free survival, PSCA expression, and serum cytokine profile.²

Preliminary findings presented during the American Society of Oncology Genitourinary Cancers Symposium (ASCO GU) showed that PSCA CAR T cells can induce an anti-tumor effect with dosed at 100 million CAR T cells or higher with lymphodepleting chemotherapy in patients with mCRPC.³

In an interview with Targeted Oncology™, Tanya Dorff, MD, a medical oncologist, section chief of Genitourinary Disease Program, and associate professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, discussed the exploration of CAR T-cell therapy in prostate cancer, including recent findings from a phase 1 clinical trial.

TARGETED ONCOLOGY: Can you discuss the introduction of CAR T cell into the prostate cancer space?

Dorff: This is a technology that's been super successful in hematologic malignancies. But there are certainly challenges in bringing it into solid tumors, and particularly, I would say for prostate cancer because of the differences in the kinds of diseases, where they reside, and the tumor heterogeneity in solid tumors that you don't see with leukemias and lymphomas. There are a number of specific targets that define prostate cancer cells that we can use to produce CAR T cells. And they've been shown in preclinical models to be able to find the prostate cancer and destroy it. And so, it's just a question of how to make that translate into clinical trials and what to expect in terms of toxicity. It just looks completely different than hematologic malignancies although, of course, we're learning from the experience in those diseases.

Can you explain the need for novel mechanisms for the treatment of mCRPC?

Whereas immune checkpoint inhibitors have really changed prognosis in a major way for diseases like melanoma and renal cell carcinoma, creating these durable remissions, you just don’t see that same impact of standard immunotherapy like checkpoint inhibitors in prostate cancer. So, we have a lot of great treatments for prostate cancer, many different hormonal agents that are extremely powerful, and are improving our patients lives. Then, we have chemotherapy and radioactive particles, and there is immunotherapy sipuleucel-T. But there’s nothing yet that creates durable remissions. And so, the hope is that T-cell technology is where we might start to achieve that.

What are the key goals of your phase 1 PSCA-targeted CAR T-cell therapy for patients with mCRPC?

Like most phase 1 studies, our first-in-human CAR T-cell trial is designed to first assess safety. We want to make sure this is something that won't hurt people. Our CAR T is designed to target PSCA prostate stem cell antigen. That is mostly expressed only on prostate cancer. But there is a little bit of expression in some normal tissues, and we wanted to make sure the CAR T cells would be tolerable. So, the goal is safety, and then of course, we'd like to see that there's some evidence that this can have a strong anti-cancer effect as well.

What is the design of this study and what study methods are being utilized?

We decided to start with the CAR T cells themselves because this is such a novel target and it's so novel to use CAR T-cell therapy in prostate cancer. So, our design was to start with just 100 million CAR T cells. We produce them very similarly to the FDA-approved leukemia and lymphoma CAR T cells. We do a leukapheresis, we use a viral transfection to change what the T-cell receptor is targeting, and then we produce hundreds of millions of cells. So, the process is the same. It's just different what we are targeting the CAR T cells to.

We decided to start out with just the cells. And then if that looked safe, then we could add in the lymphodepleting chemotherapy. So traditionally, with CAR T cells in leukemia and lymphoma, they give cyclophosphamide and fludarabine. We weren't sure whether that would be necessary when we were translating this to solid tumors because the solid tumor is not in the space where leukemia and lymphoma reside. And, it turns out that it's important to use lymphodepletion, it seems to increase the ability of the CAR T cells to work, but it probably does it by a very different mechanism in this disease. So, we were planning to add in the lymphodepletion, keeping the dose at 100 million cells, and then try to escalate to 300 million and 600 million CAR T cells.

What results were recently announced from this study?

We're excited to present our first ever results from the phase 1 trial during ASCO GU. We've treated 12 patients, and things didn't go exactly according to plan. We did see some activity of the CAR T cells alone, which was exciting, but not big durable responses.

When we added in the lymphodepletion, we did see some very dramatic responses. One of them was a 95% reduction in PSA as well as radiographic response and circulating tumor cell response. We looked at it this patient's disease and it was clearly significantly reduced by the CAR T cells.

And then we show another patient who was a responder with liver metastases, but we did hit a dose-limiting toxicity of cystitis. So, because PSCA is expressed on the bladder, the CAR T cells were causing irritation inflammation in the bladder. So instead of dose escalating, we had to expand at the same dose level. And in fact, we wanted to avoid having this side effect because it's symptomatic for patients. We reduce the dose of the chemotherapy, which we figured was probably contributing to the severity. And so far, it seems like that was correct. So, with the lower-dose chemotherapy and 100 million CAR T cells, we're not seeing the severe cystitis. We have seen still responsiveness against the cancer. So, we're just going to finish this out and then we want to move into more of a phase 1B to explore some different dosing strategies that we think will optimize efficacy versus toxicity.

What conclusions were drawn from this initial research?

The most important conclusion that can be drawn from our study is that there is the ability of CAR T-cell therapy to have an impact in prostate cancer. We wouldn't expect to solve this with just 12 patients. So, we know there's more work to be done. But there's a clear signal that this is a promising therapeutic modality. Also, that prostate stem cell antigen, which is a new target in prostate cancer, can induce anti-prostate cancer responses.

Finally, I think it's important that we've validated what was learned preclinically, that CAR T cells, when we're using them in solid tumors, we still do need to add in that lymphodepleting chemotherapy that impacts the tumor microenvironment in a very significant way and leads to some of these responses that we've seen.

_References:

_{1. Murad JP, Tiakawardane D, Park AK, et al. Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity. 2021;29(7):2335-2349. doi: 10.1016/j.ymthe.2021.02.024}

_{2. PSCA-CAR T cells in treating patients with PSCA+ metastatic castration resistant prostate cancer. Clinicaltrials.gov. Accessed March 4, 2022. https://bit.ly/3pF8dfQ}

_{3. Dorff TB, Blanchard S, Martirosyan H, et al. Phase 1 study of PSCA-targeted chimeric antigen receptor (CAR) T cell therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;20(suppl 6, abstr 91). doi: 10.1200/JCO.2022.40.6_suppl.091}