Phase 1 study of P-PSMA-101 CAR-T cells in patients with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

98 Background: P-PSMA-101 is an autologous CAR-T therapy targeting PSMA, with a high percentage of stem cell memory T cells (TSCM) associated with efficacy, safety, and bone homing (particularly relevant to prostate cancer). It is manufactured using a novel non-viral transposon system (piggyBac) that creates high TSCM products. Genes are inserted encoding a PSMA-targeted Centyrin CAR, iCasp9-based safety switch, and DHFR to purify CAR-T cells. P-PSMA-101 completely eliminated tumors in intractable murine models of prostate cancer, providing rationale for this phase 1 trial (NCT04249947). Methods: Patients with mCRPC treated with or not eligible for a CYP17 inhibitor or second-generation antiandrogen, and a taxane were enrolled. P-PSMA-101 was manufactured from apheresed T cells and administered IV following a standard 3-day cy/flu lymphodepletion regimen. Dose escalation from 0.25-15 x 106 cells/kg is planned. Results: As of September 30, 2021, P-PSMA-101 had been administered to 10 heavily pretreated patients (median 7 prior regimens; range 3-15). Single infusions of 0.25 (n=5) to 0.75 (n=5) x 106 cells/kg have been assessed, with dose escalation continuing. P-PSMA-101 cells were shown to expand in blood via qPCR assay, peaking 2-3 weeks after infusion, consistent with the high percentage of TSCM. Significant antitumor responses were seen in this preliminary data set. Declines in PSA were seen in 7 patients (>50% in 3 and >99% in 1). Of 4 patients who had pre- and post-treatment FDG and PSMA-PET imaging, 3 demonstrated marked to complete resolution of abnormal uptake at known metastatic disease sites, with concordance in bone and CT scans, and/or circulating tumor cells (CTC). In 1 case, post-treatment tumor biopsy demonstrated infiltration by P-PSMA-101 CAR-T cells and elimination of tumor cells (pathologic complete response). Safety was consistent with expectations for a CAR-T product. CRS was seen in 60% (10% Gr ≥3) of patients. DLT was seen in 1 patient with macrophage activation syndrome/uveitis, and was the only Gr ≥3 CRS event. Immune effector cell-associated neurotoxicity syndrome (ICANS) has not occurred. CRS marker elevations were modest (max IL-6: 642.6 pg/mL). The most common AEs were cytopenias, infections, and constitutional symptoms (Gr ≥3 60%, 10%, and 0%), as expected with lymphodepletion. Treatable related ocular AEs were noted in 3 patients. Conclusions: These results parallel preclinical findings that P-PSMA-101 can produce marked efficacy in mCRPC, and very low doses are highly efficacious, consistent with unique product attributes such as the TSCM phenotype and bone tropism. This is the first report demonstrating profound antitumor effects of a novel PSMA-directed CAR-T-cell platform with concordant biochemical, radiographic, and pathologic parameters, demonstrating that therapeutic benefit of unarmored CAR-T cells in a major solid tumor is possible. Clinical trial information: NCT04249947.

The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer

“…There have been five generations of CARs, and their molecular structures and physical properties significantly alter CAR-T cells’ effects in therapeutics [ 46 ]. Currently, PSMA-CAR-T cells (NCT04429451 and NCT04249947), PSCA-CAR-T cells (NCT03873805), and CAR-T-PSMA-TGFβRDN69 cells (NCT03089203 and NCT04227275) are highly effective in mCRPC tested in phase I or phase II clinical trials [ 37 , 47 , 48 , 49 , 50 ]. Natural killer (NK) cells can also be engineered to express the CAR, and recruitment is currently ongoing for an early phase I clinical trial evaluating anti-PSMA CAR-NK cells (NCT03692663) [ 51 ].…”

Developing New Treatment Options for Castration-Resistant Prostate Cancer and Recurrent Disease

“…During manufacturing, the genes are inserted in a DHFR selection gene, anti-PSMA centyrin CAR gene and iCASP-9-based safety switch to purify CAR-T cells. They are characterized by a lot of memory stem T cells [ 112 ]. In 2022 GU ASCO data, P-PSMA-101 CAR-T cells demonstrated a significant antitumor effect in patients with mCRPC (clinical trial NCT04249947).…”

“…In 2022 GU ASCO data, P-PSMA-101 CAR-T cells demonstrated a significant antitumor effect in patients with mCRPC (clinical trial NCT04249947). Seven of ten heavily pre-treated patients with mCRPC achieved a PSA decrease in the preliminary report [ 112 ]. PSMA-targeting TGF-β-insensitive armored CAR-T cells are designed to overcome the suppressive immune microenvironment of PCa [ 113 , 114 , 115 ].…”

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

“…In contrast, CAR T cell therapies targeting solid tumors have lagged due to additional challenges related to the lack of bona fide tumor-specific antigens, inhospitable tumor microenvironments, and poor trafficking, persistence, and expansion of CAR T cells. Despite the challenges observed in driving effective immune responses toward solid tumors, recent early phase clinic trials investigating CAR T cell therapies targeting PSMA in mCRPC have reported safety and evidence of significant biochemical and radiographic responses 8,9 .…”

“…Despite the challenges observed in driving effective immune responses toward solid tumors, recent early phase clinic trials investigating CAR T cell therapies targeting PSMA in mCRPC have reported safety and evidence of significant biochemical and radiographic responses 8, 9 . These preliminary results serve to embolden efforts to develop and optimize new CAR T cell therapies for prostate cancer.…”