Kwilas Anna R, Donahue Renee N, Tsang Kwong Y, Hodge James W
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Cancer Cell Microenviron. 2015;2(1). doi: 10.14800/ccm.677.
Combination therapy for the treatment of cancer is becoming increasingly essential as we gain improved understanding of the complexity of cancer progression and the mechanisms by which cancer cells become resistant to single-agent therapy. Recent studies, both clinical and preclinical, have suggested that immunotherapy is a promising approach to the treatment of cancer; however, strategies to improve its clinical efficacy are still needed. A number of recent studies have indicated that antiangiogenic tyrosine kinase inhibitors (TKIs) target multiple components of the tumor microenvironment and are an ideal class of agents for synergizing with cancer immunotherapy. TKIs are well known to modulate tumor endothelial cells, leading to vascular normalization; however, these agents have also been recently shown to decrease tumor compactness and tight junctions, thereby reducing solid tumor pressure and allowing for improved perfusion of collapsed vessels and increased tumor oxygenation. In addition, some TKIs are capable of inducing immunogenic modulation, whereby tumor cells are sensitized to killing by T lymphocytes. Moreover, a number of TKIs have been shown to be involved in immune subset conditioning, increasing the frequency and function of effector immune elements, while decreasing the number and function of immune suppressor cells. The alteration of the immune landscape, direct modification of tumor cells, and improved vascular perfusion leads to improved antitumor efficacy when antiangiogenic TKIs are combined with immunotherapy. Collectively, the data presented in this review support the clinical combination of multi-targeted antiangiogenic TKIs, including but not limited to cabozantinib, sunitinib, and sorafenib, as well as to other antiangiogenic therapies, such as the anti-VEGF antibody bevacizumab, with cancer vaccines for improved treatment of solid tumors.
随着我们对癌症进展的复杂性以及癌细胞对单药治疗产生耐药性的机制有了更深入的了解，癌症的联合治疗变得越来越重要。近期的临床和临床前研究均表明，免疫疗法是一种很有前景的癌症治疗方法；然而，仍需要提高其临床疗效的策略。最近的多项研究表明，抗血管生成酪氨酸激酶抑制剂（TKIs）可靶向肿瘤微环境的多个成分，是与癌症免疫疗法协同作用的理想药物类别。众所周知，TKIs可调节肿瘤内皮细胞，导致血管正常化；然而，最近还发现这些药物可降低肿瘤紧实度和紧密连接，从而降低实体瘤压力，改善塌陷血管的灌注并增加肿瘤氧合。此外，一些TKIs能够诱导免疫原性调节，使肿瘤细胞对T淋巴细胞杀伤敏感。而且，已表明多种TKIs参与免疫亚群调节，增加效应免疫元件的频率和功能，同时减少免疫抑制细胞的数量和功能。当抗血管生成TKIs与免疫疗法联合使用时，免疫格局的改变、肿瘤细胞的直接修饰以及血管灌注的改善可提高抗肿瘤疗效。总体而言，本综述中呈现的数据支持将多靶点抗血管生成TKIs（包括但不限于卡博替尼、舒尼替尼和索拉非尼）以及其他抗血管生成疗法（如抗VEGF抗体贝伐单抗）与癌症疫苗联合用于实体瘤的改善治疗。
