Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade

Abstract

Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second-generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb). PDL-1 expression was detected in Myc-CaP murine prostate tumors growing in immune competent FVB/N and immune-deficient SCID mice. Endogenous CD3+ T cells were restricted from the centers of Myc-CaP tumor nodules growing in FVB/N mice. Following anti-programmed cell death protein 1 (PD-1) treatment, the restriction of CD3+ T cells was reversed, and a tumor-treatment response was observed. Adoptive hPSMA-CAR T cell immunotherapy was enhanced when combined with PD-1 blockade, but the treatment response was of comparatively short duration, suggesting other immune modulation mechanisms exist and restrict CAR T cell targeting, function, and persistence in hPSMA expressing Myc-CaP tumors. Interestingly, an “inverse pattern” of CAR T cell BLI intensity was observed in control and test tumors, which suggests CAR T cells undergo changes leading to a loss of signal and/or number following hPSMA-specific activation. The lower BLI signal intensity in the hPSMA test tumors (compared with controls) is due in part to a decrease in T cell mitochondrial function following T cell activation, which may limit the intensity of the ATP-dependent Luciferin-luciferase bioluminescence signal.

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Immune inhibitory molecules on the surface of cancer cells also affect the efficiency of CAR-T cell therapy. The transduction of immune checkpoint signals may decrease the therapeutic efficiency of CAR-T cells [230,231], while combinations of ICIs and CAR-T cells can increase the antitumor effects of CAR-T cells [232,233]. Tanoue et al used an OAd expressing anti-PD-L1 mini-antibody (CAd-VECPDL1) to block the transduction of the PD-1/PD-L1 inhibitory signaling pathway and improve the antitumor effect of CAR-T cells; the median survival of mice treated with CAd-VECPDL1 and HER2.CAR-T cells was 110 days, which is twofold longer than that of mice treated with single agent of OAd or CAR-T cells [208].…”

A brief history of CAR-T cells: from laboratory to the bedside

“…An option to increase the potential of CAR-T cells is its enhancement by combining CAR-T cells with a monoclonal antibody targeting the human programmed death receptor 1 (anti-PD1) performed so far in the prostate cancer model [25].…”

Chimeric Antigen Receptor T-cell Therapy for Cancer: A Basic Research-Oriented Perspective

“…ICB achieved great therapeutic success in various cancers [135][136][137][138]. Since its main mechanism of functioning involves the reinvigoration of exhausted antigen-specific T cells [139], a combination therapy using CAR T cells and ICB may further increase the therapeutic efficacy in the clinic, as seen in preclinical studies [140][141][142].…”