Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated efficacy in the treatment of haematological malignancies. However, the activity and trafficking of these genetically engineered T lymphocytes is hindered in the context of highly heterogenous, immunosuppressive solid tumours, such as prostate cancer, limiting impactful patient outcomes. Previously, we assessed the capacity of the platinum-based chemotherapeutic carboplatin to elicit immunomodulatory changes within the tumour microenvironment (TME), fostering a suitable pro-inflammatory landscape for enhanced Lewis-Y (LeY)-specific CAR T cell activity within patient-derived xenograft (PDX) models of prostate cancer. Conventional retroviral-transduced CAR T cells in combination with a single dose of carboplatin were shown to induce significant tumour regression within a LeY+ PDX in vivo model, with validated on-target specificity in vitro. However, the response was not conserved within a different LeY-expressing PDX line, PDX-224R-Cx.
Here, we aimed to investigate whether next-generation CAR T cells, overexpressing the memory-associated transcription factor FOXO1, could more effectively combine with the pro-inflammatory TME changes induced by low-dose carboplatin, to induce a complete response within this model, typified by overall tumour regression. Using flow cytometric techniques and immunohistochemical staining, we demonstrated that lentivirus-transduced FOXO1-overexpressing CAR T cells effectively accumulated within PDX-224R-Cx subcutaneous grafts within all CAR T cell treated groups. Further, when combined with carboplatin, tumour volume was significantly reduced to <35% of the starting volume as early as 3-weeks post-CAR T cell infusion.
This study demonstrates that the optimisation of both TME-modulating agents and CAR T cells improve the efficacy of CAR T cells in vivo, offering a potential immunotherapeutic option for patients with carboplatin-sensitive LeY-positive prostate tumours.