Adoptive CAR T-Cell Therapy Appears Feasible and Safe in mCRPC

Vivek Narayan, MD, MSCE

CART-PSMA-TGFβRd as adoptive chimeric antigen receptor (CAR) T-cell therapy administered as treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) appear safe and feasible a the dose level of 1-3 x 10⁷/m², in combination with lymphodepleting (LD) chemotherapy, according to the results of a phase 1 clinical trial presented during the27th Annual Prostate Cancer Foundation (PCF) Retreat Virtual Poster Session.

The study was a first-in-human investigation of safety and efficacy of using insensitive CAR T cells in men is treatment-refractory mCRPC (NCT03089203) following a 3 + 3 design. Three dose cohorts were explored including cohort 1, which received a single dose of 1-3 x 10⁷ /m², cohort 2, which received a 1-3 x 10⁸ /m² CAR T cells, and cohort 3, which received 1-3 x 108 /m2 following LD chemotherapy. Notably, the study design allowed patients from cohort 3 to receive the cohort 1 dose level following dose-limiting toxicity.

A total of 10 patients were infused with the CAR T-cell product. The median age of patients enrolled in the study was 70.5 years (range, 50-77). The median serum prostate specific antigen in for patients in the study was 26.0 ng/mL (interquartile range, 13.4-132.3). The most common metastatic site was the lymphoma node, which was seen in 60% of patients, followed by bone in 50%, and bladder in 20%.

Of the patients enrolled, 60% of whom had prior proctectomy, 80% had prior pelvic radiotherapy, 100% had prior treatment with an androgen receptor signaling inhibitor, and 40% received prior docetaxel.

The primary end point was the adverse events (AEs) experienced by infused patients. The results showed 4 of the patients had grade 3 or higher cytokine release syndrome (CRS). Most of the grade 3-5 AEs were observed in cohort 3, which included anemia, disseminated intravascular coagulation, acute kidney injury, sepsis, and CRS. Grade 3 encephalopathy and CRS were observed in cohort 2 and no key AEs were observed in cohort 1. One of the patients who had grade 5 sepsis in cohort 3 required a dose reduction.

Investigators, led by Vivek Narayan, MD, MSCE, assistant professor of Medicine at the Hospital of the University of Pennsylvania, analyzed peripheral blood to determine tumor responses to the CAR T-cell agent.

“There appeared to by a lymphodepleting chemotherapy enhancement in peripheral blood CAR T-cell expansion. Similarly, in the peripheral blood expression of inflammatory cytokines was enhanced in higher dose-level cohorts with lymphodepletion,” Narayan stated.

Preliminary anti-tumor responses were measured by PSA. A median PSA decline of 33.2% (range, 11.6%-98.3%) was observed with CAR T-cell treatment. Notably, there was 1 patient who achieved a PSA of < 0.1 ng/mL.

Utilization of adoptive CAR T cells is still a novel strategy in the prostate cancer field, but it was hypothesized that based on immunosuppressive microenvironment of prostate tumor, these patients could derive benefit from CAR T cells that TGFβRdnm which enhances antitumor immunity. The hypothesis was first tested in in vivo models. These phase 1 findings are the beginning of the growing research around this strategy. Naraya et al are now conducting correlative analyses of the tumor microenvironment from paired biopsies.

_Reference:

_{Narayan V, Barber-Rotenberg J, Fraietta J, et al. a phase 1 clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer. Presented at 27th Annual PCF Scientific Retreat Virtual Poster Session; Oct 20-23, 2020.}