Effects of Radiotherapy, Immune Checkpoint Inhibitors, and PIM Kinase Inhibition in Castration-Resistant Prostate Cancer

INTRODUCTION/OBJECTIVE: Immune checkpoint inhibitors (ICIs) have limited effi-cacy in prostate cancer. Radiation therapy (RT) combined with ICIs and PIM kinase inhibi-tion may enhance anti-tumor immune activity. METHODS: RT-induced cytosolic double-stranded DNA (dsDNA) was measured in human and mouse prostate cancer cell lines as the surrogate upstream marker consistent with cGAS–STING engagement. In a syngeneic mouse model for castration-resistant prostate cancer (Myc-CaP in FVB mice), triple therapies were studied: (1) anti-CTLA-4, anti-PD-1, and RT, and (2) PIM kinase inhibitor PIM447, anti-PD-1, and RT. Mass cytometry (CyTOF) was used to measure the tumor-immune profile. RESULTS: The peak induction of cytosolic dsDNA was at an RT dose of 13 Gy. In the mouse model, triple therapy with anti-CTLA-4, anti-PD-1, and RT doubled the median survival compared to monotherapy (32 days vs 11 to 22 days, p