Year-end Sale % OFF 
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.
Highlights
Mesothelin (MSLN) is an attractive target for cancer immunotherapy because it is highly expressed in a broad spectrum of solid tumors but present at low levels on normal tissues such as peritoneal, pleural, and pericardial mesothelial surfaces [1]
At a 1:1 effector to target (E: T) ratio, P4 chimeric antigen receptor T (CAR-T) cells lysed ~50% of CRL5826 cells after 2 days of incubation, while CRL5826-programmed cell death ligand 1 (PD-L1) cells showed notable resistance to the cytolytic activity of CAR-T cells (Fig. 1A)
We found no overt evidence of autoimmune reaction, on-target/off-tumor toxicities such as pleuropericarditis or peritonitis, or unexpected toxicities after administration of MPTK-CAR-T cells at a dose of up to 1.1 × 107/kg, and no aberrant T cell clones arose up to 7 months after infusion
Summary
Mesothelin (MSLN) is an attractive target for cancer immunotherapy because it is highly expressed in a broad spectrum of solid tumors but present at low levels on normal tissues such as peritoneal, pleural, and pericardial mesothelial surfaces [1]. Clinical trials of MSLN-targeted chimeric antigen receptor T (CAR-T) cells for the treatment of solid tumors have shown that this treatment is safe but has very limited efficacy [2, 3]. Programmed cell death protein-1 (PD-1), a key immune checkpoint receptor, is upregulated in T cells following antigen encounter. It mediates immunosuppression when engaged by its ligand, programmed cell death ligand 1 (PD-L1), which is predominantly expressed in the tumor microenvironment [4]. The combination of CAR-T cell therapy with anti-PD-1 antibody treatment has shown encouraging antitumor activity in patients [7, 8], suggesting that the PD-1 axis plays an important role in inhibiting CAR-T cell efficacy in the hostile solid tumor microenvironment. An alternative strategy to block the PD-1 axis in CAR-T cells is to disrupt cell-intrinsic PD-1 expression via clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) system (CRISPR-Cas9), which has resulted in enhanced antitumor activity in preclinical studies [9, 10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
