PSCA-Targeted CAR T-Cell Therapy Demonstrates Safety, Anticancer Activity in mCRPC

Tanya B. Dorff, MD

The use of prostate stem cell antigen (PSCA)–targeted CAR T-cell therapy was well tolerated and produced evidence of anticancer effects in patients with metastatic castration-resistant prostate cancer (mCRPC), according to final data from a phase 1 study (NCT03873805) presented at the 2023 ASCO Annual Meeting.

Among 14 evaluable patients, grade 3 cystitis was a dose-limiting toxicity (DLT) experienced by 2 of 6 patients treated with PSCA CAR T cells plus standard lymphodepletion (dose level 2). This prompted the modification of the lymphodepleting chemotherapy regimen, with cyclophosphamide dosed at 300 mg/m2 instead of 500 mg/mg2 on days –5 to –3 for patients treated at dose level 3. No DLTs were reported in 5 patients treated at dose level 3; however, grade 2 cystitis occurred in 1 patient.

No grade 3 or higher cytokine release syndrome was reported. No instances of immune effector cell–associated neurotoxicity syndrome were observed, and no treatment-related deaths occurred.

Regarding efficacy, rates of stable disease were 0% for patients treated with PSCA CAR T cells alone (dose level 1; n = 3), 66% for patients treated at dose level 2 (n = 6), and 60% for those treated at dose level 3 (n = 5). One patient treated at dose level 3 received a second infusion of 1.0 x 108 CAR T cells with a clinical response and lower-grade toxicity after the second infusion.

“Expansion of CAR T cells was enhanced by lymphodepletion and not significantly impaired with modified lymphodepletion; persistence through day 28 was similar,” lead study author Tanya B. Dorff, MD, a professor in the Department of Medical Oncology and Therapeutics Research, and section chief of the Genitourinary Disease Program at City of Hope in Duarte, California. “Cytokine expression was also enhanced with lymphodepletion.”

PSCA is highly expressed on the surface membrane of mCRPC cells and has limited expression on healthy tissue. Preclinical studies demonstrated that 4-1BB co-stimulated CAR T cells targeting PSCA gravitated toward bone metastases and eradicated tumors, leading to the first-in-human trial evaluating PSCA-CAR T-cell therapy.

The study enrolled adult patients with mCRPC experienced disease progression following a minimum of 1 prior androgen receptor–targeted therapy. Notably, prior taxane chemotherapy was allowed but not required, and there was no limit to the number of prior lines of therapy.

Patients in cohort 1 received 1.0 x 108 PSCA-CAR T cells without lymphodepletion; those in cohort 2 were dosed with 1.0 x 108 PSCA-CAR T cells after lymphodepletion consisting of 500 mg/mg2 of cyclophosphamide plus 30 mg/m2 of fludarabine on days –5 to –3; and patients in cohort 3 were administered 1.0 x 108 CAR T cells after modified lymphodepletion with 300 mg/mg2 of cyclophosphamide plus 30 mg/m2 of fludarabine on days –5 to –3.

Moreover, PSCA tissue staining by immunohistochemistry (IHC) was performed prior to lymphodepletion, then again on day 28 post–CAR T-cell therapy.

DLTs and safety served as the trial’s primary end points. Secondary end points included the persistence of CAR T cells through day 28 and disease response.

In cohort 1, the median age was 62 years (range, 59-69), and all 3 patients were treated with both prior enzalutamide (Xtandi) and abiraterone acetate (Zytiga). Two patients were treated with both docetaxel and cabazitaxel. The median prostate-specific antigen (PSA) level was 16.5 (range, 10.7-20.4). Two patients had only lymph node metastases, no patients had bone metastases, and 1 patient had visceral metastases.

In cohort 2, the median age was 70 years (range, 42-73). Five patients received previous treatment with enzalutamide, 6 received previous abiraterone, and 5 received both. Moreover, 5, 3, and 3 patients received previous treatment with docetaxel, cabazitaxel, or both, respectively. The median PSA level was 88.0 (range, 11.7-590.2). One patient had only lymph node metastases, 4 had bone metastases with or without lymph node involvement, and 1 had visceral metastases.

In cohort 3, the median age was 69 (range, 62-72). Two patients had prior treatment with enzalutamide, 2 had prior abiraterone, and 1 patient received prior treatment with both. Additionally, 5, 3, and 3 patients received previous treatment with docetaxel, cabazitaxel, or both, respectively. The median PSA was 235.3 (range,1.79-3260). No patients had only lymph node metastases, 4 patients had bone metastases with or without lymph node involvement, and 1 had visceral metastases.

Regarding PSCA expression, 36% of patients at screening had an IHC of 3+ and 60% to 100% of cells; 43% of patients had an IHC of 2+ and 80% to 100% of cells; 14% of patients had an IHC of 2+ and 50% to 60% of cells; and 7% of patients had an IHC of 1+ and 20% to 30% of cells.

At baseline, 43% of patients had an IHC of 3+ and 60% to 100% of cells; 7% had an IHC of 2+ and 80% to 100% of cells, 7% of patients had an IHC of 1+ and 20% to 30% of cells, and 43% of patients had no sample. Post–CAR T-cell therapy, all 7 evaluable patients with samples had a PSCA IHC of 3+ and 60% to 100% of cells, and the other 7 patients had no sample.

At day 28, the persistence of CAR T cells was 66%, 66%, and 60% for dose levels 1, 2, and 3, respectively.

Additional safety data showed that at dose level 1, 2 patients experienced grade 3 anemia and 1 patient had grade 3 decreased lymphocytes. At dose level 2, 2 patients experienced grade 3 anemia, 2 had grade 3 fatigue, 1 had grade 3 pain, 1 had grade 3 hematuria, and 1 experienced grade 3 rash. At dose level 3, 1 patient experienced grade 3 decreased lymphocytes.

“Given evidence of anticancer effect, and based on clinical plus preclinical toxicity data, a phase 1b trial [NCT05805371] has opened, testing multiple doses of PSCA-CAR T cells to achieve higher total dose,” Dorff and colleagues concluded.

Reference

Dorff TB, Blanchard S, Martirosyan H, et al. Final results from phase I study of PSCA-targeted Chimeric Antigen Receptor (CAR) T cells in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 17):5019. doi:10.1200/JCO.2023.41.16_suppl.5019.