Rossetti Rafaela, Brand Heloísa, Lima Sarah Caroline Gomes, Furtado Izadora Peter, Silveira Roberta Maraninchi, Fantacini Daianne Maciely Carvalho, Covas Dimas Tadeu, de Souza Lucas Eduardo Botelho
Center for Cell-Based Therapy, Blood Center of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
Biotechnology Nucleus - Blood Center of Ribeirão Preto, Butantan Institute, São Paulo, Brazil.
Immunother Adv. 2022 Jan 25;2(1):ltac005. doi: 10.1093/immadv/ltac005. eCollection 2022.
Immune checkpoint (IC) blockade using monoclonal antibodies is currently one of the most successful immunotherapeutic interventions to treat cancer. By reinvigorating antitumor exhausted T cells, this approach can lead to durable clinical responses. However, the majority of patients either do not respond or present a short-lived response to IC blockade, in part due to a scarcity of tumor-specific T cells within the tumor microenvironment. Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) provide the necessary tumor-specific immune cell population to target cancer cells. However, this therapy has been considerably ineffective against solid tumors in part due to IC-mediated immunosuppressive effects within the tumor microenvironment. These limitations could be overcome by associating adoptive cell transfer of genetically engineered T cells and IC blockade. In this comprehensive review, we highlight the strategies and outcomes of preclinical and clinical attempts to disrupt IC signaling in adoptive T-cell transfer against cancer. These strategies include combined administration of genetically engineered T cells and IC inhibitors, engineered T cells with intrinsic modifications to disrupt IC signaling, and the design of CARs against IC molecules. The current landscape indicates that the synergy of the fast-paced refinements of gene-editing technologies and synthetic biology and the increased comprehension of IC signaling will certainly translate into a novel and more effective immunotherapeutic approaches to treat patients with cancer.
使用单克隆抗体的免疫检查点（IC）阻断是目前治疗癌症最成功的免疫治疗干预措施之一。通过重振抗肿瘤耗竭性T细胞，这种方法可带来持久的临床反应。然而，大多数患者对IC阻断要么无反应，要么反应短暂，部分原因是肿瘤微环境中缺乏肿瘤特异性T细胞。过继转移经基因工程改造以表达嵌合抗原受体（CAR）或工程化T细胞受体（TCR）的T细胞，可提供靶向癌细胞所需的肿瘤特异性免疫细胞群体。然而，这种疗法对实体瘤相当无效，部分原因是肿瘤微环境中IC介导的免疫抑制作用。将基因工程改造T细胞的过继性细胞转移与IC阻断相结合可克服这些限制。在这篇综述中，我们重点介绍了在过继性T细胞转移治疗癌症中破坏IC信号传导的临床前和临床尝试的策略及结果。这些策略包括联合给予基因工程改造T细胞和IC抑制剂、对工程化T细胞进行内在修饰以破坏IC信号传导，以及设计针对IC分子的CAR。当前的情况表明，基因编辑技术和合成生物学的快速改进与对IC信号传导的深入理解相结合，必将转化为治疗癌症患者的新颖且更有效的免疫治疗方法。
