1. Potentiating Salvage Radiotherapy in Radiorecurrent Prostate Cancer Through Anti-CTLA4 Therapy: Implications from a Syngeneic Model.
- Author
-
Wang, Hanzhi, Gong, Linsey, Huang, Xiaoyong, White, Stephanie D., Chung, Hans T., Vesprini, Danny, Petchiny, Tera N., Fokas, Emmanouil, He, Hansen, Kerbel, Robert S., and Liu, Stanley K.
- Subjects
THERAPEUTIC use of monoclonal antibodies ,BIOLOGICAL models ,CANCER relapse ,RESEARCH funding ,T cells ,ANTINEOPLASTIC agents ,RADIATION ,PROSTATE tumors ,TREATMENT effectiveness ,CELLULAR signal transduction ,IMMUNE checkpoint inhibitors ,MICE ,CELL lines ,IMMUNOHISTOCHEMISTRY ,GENE expression ,ANIMAL experimentation ,CELL receptors - Abstract
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. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF