Potentiating Salvage Radiotherapy in Radiorecurrent Prostate Cancer Through Anti-CTLA4 Therapy: Implications from a Syngeneic Model

Simple Summary Advanced prostate cancer (PCa) is a prominent contributor to cancer-related fatalities and is associated with significant morbidity and mortality. Currently, addressing the local recurrence of the disease after radiation therapy (RT) poses a significant clinical challenge. We established the first syngeneic model of radiorecurrent PCa to evaluate the effectiveness of immune checkpoint inhibitors (ICIs) in combination with high-dose ionizing radiation (IR). We observed an enhanced anti-tumor response, which led to a delay in tumor growth and, in some cases, a complete elimination of tumors when combining IR with anti-CTLA4. This improvement was linked to an enhanced activation of total T cells, CD4+ helper T cells, and CD8+ cytotoxic T cells in both the draining lymph node and tumor. These results hold substantial potential for translation into clinical practice, serving as a proof of concept for the application of brachytherapy and immune checkpoint inhibitors (ICIs) in cases of recurrent disease.Abstract High-risk prostate cancer (PCa) is a leading cause in cancer death and can elicit significant morbidity and mortality. Currently, the salvage of local disease recurrence after radiation therapy (RT) is a major clinical problem. Immune checkpoint inhibitors (ICIs), which enhance immune activation, have demonstrated clinical therapeutic promise in combination with ionizing radiation (IR) in certain advanced cancers. We generated the TRAMP-C2 HF radiorecurrent syngeneic mouse model to evaluate the therapeutic efficacy of ICIs in combination with RT. The administration of anti-PDL1 and/or anti-CTLA4 did not achieve a significant tumor growth delay compared to the control. The combination of IR and anti-PDL1 did not yield additional a growth delay compared to IR and the isotype control. Strikingly, a significant tumor growth delay and complete cure in one-third of the mice were seen with the combination of IR and anti-CTLA4. Immune cells in tumor-draining lymph nodes and tumor-infiltrating lymphocytes from mice treated with IR and anti-CTLA4 demonstrated an upregulation of genes in T-cell functions and enrichment in both CD4+ and CD8+ T-cell populations compared to mice given IR and the isotype control. Taken together, these results indicate enhancement of T-cell response in radiorecurrent PCa by IR and anti-CTLA4.