Vogt and Silberman et al. engineered TME-actuated T cells (MEAT cells) using an αP-selectin synNotch to restrict CAR expression to malignant tissue. MEAT cells demonstrated P-selectin-specific actuation and CAR expression, activation, and target cell killing in vitro. Compared to conventional GD2 CAR T cells, which caused fatal neurotoxicity, P-selectin-gated GD2 CAR T cells in mice bearing neuroblastomas demonstrated antitumor efficacy, without detectable neurotoxicity or T cell infiltration in the brain. P-selectin-gated CD19 CAR T cells showed improved metabolic fitness, higher persistence, and enhanced antitumor efficacy in vivo.
Contributed by Shishir Pant
ABSTRACT: A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2(+) normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets.
Author Info: (1) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065
Author Info: (1) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Pharmacology Program, Weill Cornell Medicine, New York, NY 10065, USA. (3) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. BCMB Program, Weill Cornell Medicine, New York, NY 10065, USA. (4) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Pharmacology Program, Weill Cornell Medicine, New York, NY 10065, USA. (8) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Pharmacology Program, Weill Cornell Medicine, New York, NY 10065, USA.
