Exhaustion, rather than lack of infiltration and persistence, of CAR-T cells hampers the efficacy of CAR-T therapy in an orthotopic PDAC xenograft model

• Published in: Biomedicine & pharmacotherapy Vol. 170; p. 116052
• Main Authors: Takeuchi, Yuta, Wang, Yizheng, Sasaki, Katsunori, Sato, Osamu, Tsuchikawa, Takahiro, Wang, Linan, Amaishi, Yasunori, Okamoto, Sachiko, Mineno, Junichi, Hirokawa, Yoshifumi, Hatanaka, Kanako C., Hatanaka, Yutaka, Kato, Takuma, Shiku, Hiroshi, Hirano, Satoshi
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-01-2024; Elsevier
• Subjects: Chimeric antigen receptor; Metabolic pathway; Mitochondrial dynamics; Pancreatic cancer orthotopic xenograft model; Tumor infiltrating lymphocyte; Tumor infiltrating lymphocyte; Metabolic pathway; Chimeric antigen receptor; Mitochondrial dynamics; Pancreatic cancer orthotopic xenograft model
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.116052

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated impressive success in the treatment of patients with hematologic tumors yet achieved very limited efficacy for solid tumors due to hurdles unique to solid tumors. It is also noted that the tumor microenvironment composition varies between tumor type, which again imposes unique set of hurdles in each solid tumor. Therefore, elucidation of individual hurdles is key to achieving successful CAR-T therapy for solid tumors. In the present study, we employed an orthotopic human PDAC xenograft model, in which quantitative, spatial and functional dynamics of CAR-T cells in tumor tissues were analyzed to obtain insights into ways of overcoming PDAC related hurdles. Contrary to previous studies that demonstrated a limited persistency and infiltration of CAR-T cells in many solid tumors, they persist and accumulated in PDAC tumor tissues. Ex vivo analysis revealed that CAR-T cells that had been recovered at different time points from mice bearing an orthotopic PDAC tumor exhibited a gradual loss of tumor reactivity. This loss of tumor reactivity of CAR-T cells was associated with the increased expression of AMP-activated protein kinase and Mitofusin 1/ Dynamin-related protein 1 ratio.
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●CEA-specific CAR-T cells demonstrate efficacy in an orthotopic PDAC xenograft model.●CAR-T cells persisted tumors but later faced exhaustion/dysfunction.●Exhausted CAR-T cells in PDAC upregulated expressions of AMPK and Mfn1/Drp1 ratio.●Resistance to exhaustion is required for effective CAR-T cell therapy for PDAC.