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Enhancing CAR T Cell Therapy in Patients with Pancreatic Cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276061 | GEO | 2025/07/07

REPOSITORIES: GEO

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Project description:Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Murine mutants with pancreatic specific loss of Pten (Pten +/-) and K-ras activation (K-rasG12D) and either COX-2 over-expression (Cox-2 COE) or knockout (Cox-2 KO) under regulation of the Pdx-1 promoter developed pancreatic ductal adenocarcinoma. RNA was extracted from pancreatic tumors from individual mutants with pathology thought to closely mimic the human disease. Pancreatic tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.

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Enhancing CAR T Cell Therapy in Patients with Pancreatic Cancer

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