Enhancing CAR T Cell Therapy in Patients with Pancreatic Cancer
Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival time of less than a year, highlighting the urgent need for treatment advancements. We conducted a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with unresectable or metastatic PDAC. Though therapy was well tolerated, limited clinical efficacy was observed. Analyses of patient samples provide insights into mechanisms of treatment resistance. Using single-cell genomic approaches, we found that CAR T cells post-infusion express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for Treg and GZMK+ phenotypes. Single knockout of ID3 or SOX4 appeared to enhance efficacy in xenograft models, but eventually failed, whereas double-knockout ID3 and SOX4 CAR T cells exhibit prolonged relapse-free survival, demonstrating sustained therapeutic effect and a potential avenue for engineering a more potent CAR T cell in pancreatic cancer. Overall design: Examines gene expression by single-cell RNA-seq in T cells isolated from two patients undergoing a CAR T cell clinical trial, with isolation at 7 or 26 days post-CAR T infusion (isolation time not replicated); or tumor-infiltrating lymphocytes (TILs) extracted from three mice with recurrent tumors that had been treated with human CAR T cells, with two replicates subject to SOX4 knockout and one WT control.