Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington.
Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.
Int J Radiat Oncol Biol Phys. 2021 Feb 1;109(2):396-412. doi: 10.1016/j.ijrobp.2020.09.016. Epub 2020 Sep 15.
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.
新型疗法联合放疗在妇科癌症的发展治疗模式中仍然具有重要意义。免疫疗法在肿瘤学中的临床应用通过临床试验迅速改变了治疗领域、选择、模式和结果。免疫疗法已成为治疗实体瘤的治疗支柱，通过改变或增强免疫系统，与放疗和放化疗联合具有协同活性。在实体瘤中，放疗诱导树突状细胞迁移、T 细胞激活和增殖，并增加肿瘤浸润淋巴细胞。这些免疫调节作用与免疫检查点阻断联合，目前正在辅助、明确和转移性治疗中进行积极研究。早期阶段试验的结果表明，联合治疗模式具有有前途的疗效和总体可耐受的毒性特征。在过去 30 年中，标准治疗方法一直是放化疗，人们对优化局部晚期宫颈癌患者的治疗方法产生了浓厚的兴趣。大多数宫颈癌是在高危型人乳头瘤病毒持续感染后出现的，病毒癌蛋白导致细胞变化和永生化。因此，可能会产生免疫耐受，从而导致癌症。对人乳头瘤病毒相关致癌机制的认识表明，免疫疗法或检查点阻断可以重新激活抗肿瘤免疫反应。目前正在进行临床试验以探索这些方法的治疗潜力。子宫癌根据其驱动突变、突变负担和拷贝数改变分为 4 个分子亚类。在这些亚组中，聚合酶 epsilon 突变和微卫星不稳定可能代表多达 40%的子宫内膜癌，并且已经显示出免疫原性。由于这些 MSI 高肿瘤具有固有免疫原性，因此正在探索包括化疗、放疗和免疫治疗以及免疫检查点抑制剂治疗在内的联合免疫调节策略，以改善治疗结果。在这篇综述中，我们通过正在进行的临床试验探索了免疫调节和多模态治疗方法在宫颈癌和子宫癌治疗中的应用，这些试验研究了免疫疗法与放疗联合应用。
