A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer
- Author(s)
- Ali, AI; Wang, M; von Scheidt, B; Dominguez, PM; Harrison, AJ; Tantalo, DGM; Kang, J; Oliver, AJ; Chan, JD; Du, X; Bai, Y; Lee, B; Johnstone, RW; Darcy, PK; Kershaw, MH; Slaney, CY;
- 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
- Publisher's Version
- https://doi.org/10.1158/1078-0432.CCR-21-1141
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-05-23 04:02:51
Last Modified: 2025-05-23 04:04:10