Oral Presentation MIN Spring Retreat 2023

Tumour microenvironment modification by low-dose carboplatin bolsters CAR T cell efficacy in human prostate cancer models (#28)

Sophie G Harrison 1 , Laura H Porter 2 , Joe J Zhu 3 4 , Natalie L Lister 2 , Shivakumar Keerthikumar 3 4 , Paul J Neeson 3 4 , Phillip K Darcy 3 4 , Joseph A Trapani 3 4 , Gail P Risbridger 2 3 4 , Renea A Taylor 1 3 4
  1. Department of Physiology, Monash University, Melbourne, VIC, Australia
  2. Department of Anatomy and Developmental Biology, Monash University , Melbourne, VIC, Australia
  3. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia

Chimeric antigen receptor (CAR) T cell therapy, which uses genetically modified T cells to target particular tumour associated antigens, has demonstrated efficacy in the treatment of haematological malignancies. However, CAR T cell activity is hindered in highly heterogeneous solid tumours due to the presence of an immunosuppressive tumour microenvironment (TME) which limits effective anti-tumour immune responses. This barrier must be overcome to improve treatment outcomes for patients with solid tumours, including prostate cancer.

Here, we investigated the capacity of the platinum-based chemotherapeutic carboplatin to induce a pro-inflammatory response within the TME and improve the function of CAR T cells directed towards the Lewis Y (LeY) antigen in patient-derived xenograft (PDX) models of prostate cancer. In vitro, on target specificity of LeY was demonstrated in organoids established from PDXs, with LeY-CAR T cells directly killing organoids via perforin/granzyme-dependent granule exocytosis. In vivo, LeY-CAR T cells alone did not affect tumour growth; however, LeY-CAR T cell therapy following a single dose of carboplatin decreased tumour burden to <1% of its starting volume in a carboplatin-sensitive PDX model. Fluorescence-activated cell sorting (FACS) and RNA-sequencing demonstrated a cascade of anti-tumourigenic changes within the major TME cell populations following a single dose of carboplatin. These changes included the promotion of an inflammatory cancer-associated fibroblast phenotype, M1 macrophage polarisation and upregulated expression of endothelial cell genes encoding adhesion and selectin molecules. Combined, these changes favoured increased CAR T cell infiltration and persistence at the tumour site. However, in a separate PDX model less sensitive to carboplatin, CAR T efficacy was limited.

This study demonstrates the capacity of clinically applicable agents, such as carboplatin, to induce the transition from a “cold” immunosuppressive TME to a “hot” pro-inflammatory landscape and may improve the efficacy of CAR T cell therapy for patients with carboplatin sensitive LeY+ prostate tumours.