Benton and Liu et al. utilized the Retained Display library to identify high-affinity KRAS G12V binders, and incorporated them into CAR T cells to create mKRAS NeoCARs. mKRAS NeoCARs demonstrated robust antitumor responses against cancer cells expressing mutant KRAS peptides, but failed to achieve full tumor control in vivo due to low sensitivity or potency. Armoring mKRAS NeoCAR T cells with NFAT-inducible IL-12 enhanced their efficacy, but introduced low-level TCR-mediated xeno- or alloreactivity. Combining iIL-12 NeoCARs with TCR KO prevented T cell xenoreactivity and resulted in robust tumor clearance and enhanced survival in the NSCLC xenograft model.
Contributed by Shishir Pant
ABSTRACT: Despite the success of chimeric antigen receptor (CAR)-T cell therapies in hematological malignancies, clinical success against solid tumors is limited due to low therapeutic efficacy or dose-limiting toxicity. Developing therapies that trigger potent, yet manageable, immune responses capable of eliminating highly heterogeneous and immunosuppressive tumor cell populations remains a key challenge. Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS G12V mutations presented by peptide-MHC complexes. Subsequently, we incorporate these neoantigen binders into CAR-T cells (mKRAS NeoCARs) and demonstrate their efficacy in xenograft models of metastatic lung, pancreatic, and renal cell cancer. Finally, we enhance the in vivo efficacy and safety profile of mKRAS NeoCARs via inducible secretion of IL-12 and T cell receptor deletion. Together, these screening and engineering processes provide a modular platform for expanding the therapeutic index of cellular immunotherapies that target cancer.
Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of
Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Bioengineering Graduate Group, Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (5) Myrio Tx, Melbourne, VIC, Australia. (6) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA. (7) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (9) Myrio Tx, Melbourne, VIC, Australia. (10) Myrio Tx, Melbourne, VIC, Australia. (11) Myrio Tx, Melbourne, VIC, Australia. (12) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: poda@pennmedicine.upenn.edu.
