A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
Details
Publication Year 2021-11-15,Volume 27,Issue #22,Page 6222-6234
Journal Title
Clinical Cancer Research
Publication Type
Research article
Abstract
PURPOSE: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. EXPERIMENTAL DESIGN: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). RESULTS: The combination treatment enabled significant suppression of Her2(+) pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. CONCLUSIONS: We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.
Keywords
Animals; Cell Line, Tumor; Histone Deacetylase Inhibitors/pharmacology; Humans; Immunotherapy, Adoptive/methods; Mice; *Pancreatic Neoplasms/therapy; Panobinostat; Receptors, Antigen, T-Cell/genetics; *Receptors, Chimeric Antigen; T-Lymphocytes; Xenograft Model Antitumor Assays
Department(s)
Laboratory Research; Medical Oncology
PubMed ID
34475103
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