Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models
L. H. Porter, Joe Jiang Zhu, Natalie L. Lister, Sarah Harrison, Shivakumar Keerthikumar, D. L. Goode, Rosalía Quezada Urban, D.J. Byrne, Arun Azad, Ian Vela, Michael S. Hofman, Paul J. Neeson, Phillip K. Darcy, Joseph A. Trapani, Renea A. Taylor, Gail P. Risbridger
Abstract
Abstract Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (Le Y )-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, Le Y CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although Le Y CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.