Multimodal C9-66 CAR-T cell immunotherapy improves outcome in preclinical models of pancreatic cancer
Menée à l'aide de modèles murins et de xénogreffes d'adénocarcinome canalaire du pancréas d'origine humaine, cette étude met en évidence l'efficacité antitumorale de lymphocytes CAR-T optimisés structurellement par le variant C9-66 et ciblant le sulfate de chondroïtine oncofoetal
Background : Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers due to its aggressive biology and resistance to existing therapies. Oncofetal chondroitin sulfate (ofCS) is a tumour-restricted glycosaminoglycan broadly expressed across solid cancers but largely absent from normal adult tissues. We developed C9-based chimeric antigen receptor (CAR)-T cells targeting ofCS to overcome poor antigen specificity and the immunosuppressive tumour microenvironment (TME).
Objective : To optimise ofCS-targeted C9 CAR-T cell therapy for PDAC through integrated CAR design optimisation, metabolic enhancement and TME reprogramming.
Design : C9 and charge-optimised C9-66 CAR-T cells were engineered using a humanised ofCS-binding single-chain antibody fragment. Antitumour efficacy, functional durability and metabolic fitness were assessed in murine and patient-derived PDAC models. Enhancement strategies included inosine-mediated metabolic reprogramming, Nr5a2 overexpression and sequential TME remodelling using GLP-1R modulation, CSF-1R blockade and programmed cell death protein-1 inhibition.
Results : C9 CAR-T cells exhibited potent cytotoxicity, delayed tumour progression and extended survival in PDAC models. Compared with the parental construct, charge-optimised C9-66 CAR-T cells showed reduced exhaustion and more sustained activity in vivo. Inosine enhanced cytokine production, promoted central-memory differentiation and mitigated exhaustion, whereas Nr5a2 overexpression increased mitochondrial respiration and cytotoxicity. Sequential GLP-1R on–off modulation with macrophage and checkpoint blockade enhanced intratumoural CAR-T cell activity and prolonged survival. Human C9-66 CAR-T cells retained specific ofCS recognition and lysed patient-derived PDAC cells in vitro and in vivo.
Conclusion : C9-66 CAR-T cells with metabolic optimisation and TME reprogramming represent a tumour-specific and clinically translatable immunotherapeutic strategy for PDAC and other ofCS-expressing solid tumours.
Gut , article en libre accès, 2026