Prostate stem cell antigen CAR T-cell therapy holds potential in mCRPC

Findings from a phase 1 study (NCT03873805) showed that a prostate stem cell antigen (PSCA)-directed chimeric antigen receptor (CAR) T-cell therapy demonstrated a manageable safety profile and preliminary therapeutic activity in patients with PSCA-positive metastatic castration-resistant prostate cancer (mCRPC).^1,2

CAR T cells did not persist at high levels beyond 28 days following infusion.

The data were published in Nature Medicine.¹

“Prostate cancer has been called an immune desert — the tumor microenvironment is difficult to treat with immunotherapies because you don’t get a lot of T cells inside the tumor. It takes something really powerful to overcome that. Our study showed that City of Hope’s CAR T-cell therapy for prostate cancer could be a step closer to doing that,” said lead author Tanya B. Dorff, MD, in a news release on the findings.² Dorff is thesection chief of the Genitourinary Disease Program and a professor in the Department of Medical Oncology & Therapeutics Research at City of Hope.

In total, the study treated 14 patients across 3 dose levels. The primary end points for the study were safety and dose-limiting toxicities (DLTs). The trial’s secondary end points were expansion and persistence of CAR T cells to 28 days following infusion, disease response, and survival.³

Overall, no DLTs were observed at dose level 1 in the study, which started at 100 million (M) CAR T cells without lymphodepletion, followed by the incorporation of lymphodepletion. In dose level 2 (with lymphodepletion), a DLT of grade 3 cystitis was observed. This finding led the investigators to add an additional cohort using a reduced lymphodepletion regimen plus 100 M CAR T cells for dose level 3. No DLTs were observed at this dose level.

Among all patients (n = 14), 5 experienced cytokine release syndrome of grade 1 or 2.

Preliminary efficacy findings showed that 50% of patients achieved any decline in prostate-specific antigen (PSA) levels from before treatment to day 28 following infusion. Of those, 4 patients experienced a PSA decline over 30%, in addition to radiographic improvements. However, only 1 of these patients maintained their PSA decline of over 30% beyond 28-day follow-up.

One patient in dose level 2 of the study who had received several prior therapies experienced a PSA decline of over 90%, as well as a decline of cancer in his bones and soft tissue. The positive response was observed for approximately 8 months.

“The patient’s results were very encouraging, and we are deeply grateful for his participation in our study as well as other patients and their families,” Dorff added in the news release.² “We want to continue with this therapy and increase the amount of CAR T cells, and continue to carefully monitor for any health problems, as we think this can improve the therapy’s effectiveness.”

Further, a subset of patients included in the study showed dynamic changes that were indicative of activation of peripheral blood endogenous and CAR T cell subset, TCR repertoire diversity, and changes in the tumor immune microenvironment.

However, CAR T cells did not persist at high levels beyond 28 days following infusion.

According to the news release, “This presented a common challenge in the solid tumor CAR T cell field that researchers plan to address in a follow-up City of Hope trial using the therapy that is now open for enrollment.”²

Overall, the follow-up phase 1b study (NCT05805371) plans to enroll up to 24 patients with mCRPC. The study’s primary objective is to assess the feasibility, safety, and initial activity of lymphodepleting chemotherapy followed by up to 3 cycles of 50 M PSCA-CAR T cell either alone or in combination with metastasis-directed radiation therapy.⁴

Senior author of the current study, Saul J. Priceman, PhD, concluded in the news release, “Our trial’s preliminary major finding is that PSCA-directed CAR T cells may be effective against mCRPC. This opens up the opportunity to continue to develop this type of cellular immunotherapy for these patients, who currently have no other effective treatment options.”²

References

1. Dorff TB, Blanchard MS, Adkins LN, et al. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nature Med. 2024. doi:10.1038/s41591-024-02979-8

2. City of Hope CAR T cell therapy for advanced prostate cancer demonstrates positive results in phase 1 clinical trial. News release. City of Hope. June 12, 2024. Accessed June 13, 2024. https://www.cityofhope.org/city-hope-car-t-cell-therapy-advanced-prostate-cancer-demonstrates-positive-results-phase-1

3. PSCA-CAR T cells in treating patients with PSCA+ metastatic castration resistant prostate cancer. ClinicalTrials.gov. Last updated April 29, 2024. Accessed June 13, 2024. https://clinicaltrials.gov/study/NCT03873805

4. PSCA-targeting CAR-T cells plus or minus radiation for the treatment of patients with PSCA+ metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Last updated May 2, 2024. Accessed June 13, 2024. https://clinicaltrials.gov/study/NCT05805371