Aznar and Good et al. reported on a Phase I study assessing a mesothelin-targeting CAR T cell product (huCART-meso) in patients with advanced PDAC. Treatment was feasible and safe, but lacked efficacy. Biopsy and ascites analysis showed limited persistence of the CAR-T and remaining CAR-T upregulated transcription factors SOX4 and ID3, related to dysfunction. Murine studies showed limited effects of ID3KO in CART, while SOX4KO improved antitumor efficacy, but tumors relapsed. Double KO of ID3 and SOX4 in the CAR-T prevented relapses and improved relapse-free survival.
ABSTRACT: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK(+) phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, though with donor-dependent variability. However, single-knockout cells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Unive
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (2) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (3) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (4) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (5) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (6) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (8) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (9) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (10) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (12) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (13) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (14) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (15) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (16) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. (17) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (18) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (19) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (20) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (21) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (23) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (24) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (25) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (26) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (28) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (29) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: ryoung@upenn.edu. (30) Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: bergers@pennmedicine.upenn.edu. (31) Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: cjune@upenn.edu. (32) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: mark.ohara@pennmedicine.upenn.edu.
