Novel
therapies combined with radiation continue to be of significant interest in the developmental treatment paradigm of gynecologic
cancers. Clinical implementation of
immunotherapy in oncology has rapidly changed the treatment landscape, options, paradigm, and outcomes through clinical trials.
Immunotherapy has emerged as a therapeutic pillar in the treatment of solid
tumors with demonstrable synergistic activity when combined with
radiation therapy and
chemoradiotherapy by an alteration or enhancement of the immune system. In solid
tumors,
radiation therapy induces migration of dendritic cells, T cell activation, and proliferation, and increases in tumor-infiltrating lymphocytes. These immunomodulatory effects in conjunction with
immune checkpoint blockade are currently under active investigation in the adjuvant, definitive, and metastatic settings. Results from early phase trials demonstrate promising efficacy and overall tolerable toxicity profiles of combined modality treatment. There is significant interest in optimizing the treatment for patients with locally advanced
cervical cancer beyond the standard of care-chemoradiation-which has been in place for the last 30 years. The majority of
cervical cancer emerges after
persistent infection with a high-risk subtype of the human papillomavirus, where viral
oncoproteins lead to cellular changes and immortalization. As a result, immune tolerance can develop, resulting in
cancer. Knowledge of the mechanism of human papillomavirus-related
oncogenesis suggests that immune
therapy or checkpoint blockade can reinvigorate an antitumor immune response. Current clinical trials are exploring the therapeutic potential of these approaches.
Uterine cancers have been grouped into 4 molecular subclasses by their driver mutations, mutational burden, and copy-number alterations. Of these subgroups, the polymerase epsilon-mutated and microsatellite-unstable may represent up to 40% of
endometrial cancers, and they have been shown to be immunogenic. Because of the inherent immunogenicity of these MSI-high
tumors, combined immune modulation strategies, including
chemotherapy, radiation, and
immunotherapy and
immune checkpoint inhibitor therapy, are being explored to improve treatment outcomes. In this review, we explore current immunomodulatory and multimodality therapeutic approaches in the treatment of cervical and
uterine cancer through ongoing clinical trials investigating the combination of
immunotherapy and
radiation therapy.