Journal article
Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models
LH Porter, JJ Zhu, NL Lister, SG Harrison, S Keerthikumar, DL Goode, RQ Urban, DJ Byrne, A Azad, I Vela, MS Hofman, PJ Neeson, PK Darcy, JA Trapani, RA Taylor, GP Risbridger
Nature Communications | Published : 2023
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 (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammato..
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Grants
Awarded by Olivia Newton-John Cancer Research Institute
Funding Acknowledgements
We also acknowledge the members of the Prostate Cancer Research program, the patients, families, and consumers who support our research, and the members of the Melbourne Urological Research Alliance (MURAL). We wish to thank the Prostate Cancer Biorepository Network (PCBN) for access to the tissue microarray, whose work is supported by the Department of Defense Prostate Cancer Research Program, DOD Award No W81XWH-18-2-0013, W81XWH-18-2-0015, W81XWH-18-2-0016, W81XWH-18-2-0017, W81XWH-18-2-0018, and W81XWH-18-2-0019 PCRP PCBN. We acknowledge the association with the Bristol-Myers Squibb (BMS) study #CA209-7TK and thank BMS for providing access to the Le<SUP>Y</SUP> CAR T cell construct. We also thank Andrew Scott (Oliver Newton-John Cancer Research Institute) for access to the anti-Le<SUP>Y</SUP> antibody. This work was supported by Movember and MRFF (Upfront PSMA Prostate Cancer Research Alliance). Fellowship and grant support was obtained from the National Health and Medical Research Council (GPR, APP1102752: PKD, APP1136680; JAT, APP1102752; RAT, LHP, Ideas grant, APP2011391), Cancer Council Victoria (JAT, LHP, TP834128), Department of Health and Human Services acting through the Victorian Cancer Agency (RAT; MCRF15023), Prostate Cancer Foundation of Australia (LHP, PIRA YI-0322); and~Monash University (LHP, Bridging Fellowship; LHP, Platform Access Grant PAG2-9067770177). Infrastructure support was obtained from the EJ Whitten Foundation, Movember Foundation (Global Action Plan 1), the Peter and Lyndy White Foundation and TissuPath Pathology. This research was supported by the Monash University Histology Platform, Monash University Animal Research Laboratories, Monash Biomedicine Discovery Institute Organoid Program. This research was funded by a Prostate Cancer Research Alliance (PCRA) funded by Movember and the Medical Research Future Fund (MRFF). ProsTIC is additionally supported by the Prostate Cancer Foundation (PCF).