Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors

Abstract

Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

“… 80 , 81 , 82 Phase I clinical trials demonstrated that CRISPR-Cas9 guided disruption of PDCD1 does not lead to uncontrolled CAR T cell proliferation or persistence. 83 While the impact of PDCD1 knockout on CAR T immunotherapeutic clinical efficacy is still under investigation, these discoveries suggest that extrinsic and intrinsic blockade of the PD-1/PD-L1 axis protect CAR T cells from PD-1 induced exhaustion ( Figure 2 a).

Figure 2 Intrinsic T cell approaches to overcoming exhaustion in CAR T cell therapy.

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Effect of CRISPR/Cas9-Edited PD-1/PD-L1 on Tumor Immunity and Immunotherapy

“…The use of CRISPR/Cas9 gene editing technology opens a new world for the upgrading of fourth-generation CAR T cells ( Figure 4 ). Recently, several clinical trials by Stadtmauer ( 128 ), Lu ( 129 ), Wang ( 130 ), and Simon ( 131 ) confirmed the clinical feasibility and safety of CRISPR/Cas9- modified T cells.…”

Reprogramming the tumor microenvironment by genome editing for precision cancer therapy

“…The most widely studied inhibitory receptor is PD-1. Knocking out PD-1 in CD8 + T cells with the CRISPR/Cas9 system was demonstrated to have antitumor effects in several preclinical and clinical studies, including studies on cancers including melanoma, glioblastoma, ovarian cancer, prostate cancer, B-cell lymphoma, gastric cancer, and breast cancer [ 181 – 189 ]. In addition, gene editing can be used to reverse inhibitory signaling.…”

“…Fusing PD-1 expressed by CD8 + T cells to CD28 via CRISPR/Cas9 gene editing reverses the original inhibitory signaling to achieve stimulatory cell signaling. This reprogramming strategy ultimately restores the effector function of exhausted CD8 + T cells [ 187 – 189 ].…”