Kato Daiki, Yaguchi Tomonori, Iwata Takashi, Morii Kenji, Nakagawa Takayuki, Nishimura Ryohei, Kawakami Yutaka
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine.
Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo.
Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(1):68-77. doi: 10.2177/jsci.40.68.
Immune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.
免疫检查点阻断（ICB）以及采用抗原受体基因工程改造的T细胞的过继性细胞疗法（ACT）已被证明对少数实体瘤患者有效。ICB治疗的应答者通常具有T细胞炎症性肿瘤。因此，开发将非T细胞炎症性肿瘤转化为T细胞炎症性肿瘤的策略很重要。尽管靶向血液系统恶性肿瘤的嵌合抗原受体转导T（CAR-T）细胞疗法显示出持久的临床应答，但实体瘤中缺乏独特抗原、癌细胞中的抗原丢失以及实体瘤的免疫抑制性肿瘤微环境（TME）阻碍了基因工程改造的T细胞疗法在实体瘤中的成功。然而，基因工程改造的T细胞具有强大的杀伤活性和细胞因子产生能力，可诱导抗原扩散并调节ICB治疗无应答者中所见的非T细胞炎症性肿瘤的TME。针对癌症的免疫反应高度异质性，不仅在肿瘤类型之间存在差异，而且在患者体内或同一类型癌症的不同患者之间也存在差异，这表明应根据个体患者的免疫状态采用个性化免疫疗法。在此，我们基于ACT和ICB疗法，为实体瘤的个性化联合免疫疗法提供我们的观点。
