Immunotherapy and radiation combinatorial trials in gynecologic cancer: A potential synergy?

Immunotherapy (IO) is an important new pillar in the treatment of solid tumors, and the integration of IO agents with chemotherapy, targeted therapy, surgery and radiation has yet to be defined. As preclinical and clinical studies have described synergistic activity with the combination of radiation and immunotherapy, many clinical trials are underway to explore both the safety and efficacy of this approach both in the metastatic and definitive setting. Through immune priming, radiation may enhance local tumor control at the irradiated site, as well as induce a systemic response to control distant metastasis, known as the abscopal effect. On a mechanistic level, radiation therapy releases tumor neoantigens and activates an adaptive immune response that is mediated by cytotoxic T-cells, which then hone to sites of irradiated tumor as well as non-irradiated tumor metastases to induce immunogenic tumor cell death. Although the abscopal effect is rare in clinical practice, strategies that combine immune checkpoint blockade with radiation are being studied to overcome immune tolerance or suppression and increase systemic response rates to IO agents. Gynecologic cancers are attractive targets for immune checkpoint blockade, and IO agents may be used in combination with definitive chemoradiotherapy to enhance radiosensitivity and thus local control for unresected disease as well as control distant micrometastatic spread. For patients with metastatic disease, immune checkpoint blockade in combination with stereotactic radiotherapy is being evaluated as a strategy for immune activation and tumor cytoreduction. In this review, we highlight the current use of IO agents in gynecologic cancer, describe the immunogenic potential of radiation through clinical observation and preclinical study, and discuss strategies for combining IO and radiation in reported and ongoing clinical trials.