Perelman School of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States.
Front Immunol. 2019 Feb 5;10:128. doi: 10.3389/fimmu.2019.00128. eCollection 2019.
Chimeric antigen receptor (CAR) T cells, T cells that have been genetically engineered to express a receptor that recognizes a specific antigen, have given rise to breakthroughs in treating hematological malignancies. However, their success in treating solid tumors has been limited. The unique challenges posed to CAR T cell therapy by solid tumors can be described in three steps: finding, entering, and surviving in the tumor. The use of dual CAR designs that recognize multiple antigens at once and local administration of CAR T cells are both strategies that have been used to overcome the hurdle of localization to the tumor. Additionally, the immunosuppressive tumor microenvironment has implications for T cell function in terms of differentiation and exhaustion, and combining CARs with checkpoint blockade or depletion of other suppressive factors in the microenvironment has shown very promising results to mitigate the phenomenon of T cell exhaustion. Finally, identifying and overcoming mechanisms associated with dysfunction in CAR T cells is of vital importance to generating CAR T cells that can proliferate and successfully eliminate tumor cells. The structure and costimulatory domains chosen for the CAR may play an important role in the overall function of CAR T cells in the TME, and "armored" CARs that secrete cytokines and third- and fourth-generation CARs with multiple costimulatory domains offer ways to enhance CAR T cell function.
嵌合抗原受体 (CAR) T 细胞是经过基因工程改造表达能够识别特定抗原的受体的 T 细胞,在治疗血液恶性肿瘤方面取得了突破性进展。然而,它们在治疗实体瘤方面的成功受到了限制。实体瘤对 CAR T 细胞治疗提出的独特挑战可以分三个步骤来描述:在肿瘤中找到、进入和存活。同时识别多个抗原的双 CAR 设计和 CAR T 细胞的局部给药都是用于克服肿瘤定位障碍的策略。此外,免疫抑制性肿瘤微环境对 T 细胞的分化和耗竭功能有影响,将 CAR 与检查点阻断或耗尽微环境中的其他抑制因子相结合,已经显示出非常有前景的结果,可以减轻 T 细胞耗竭的现象。最后,识别和克服与 CAR T 细胞功能障碍相关的机制对于产生能够增殖并成功消除肿瘤细胞的 CAR T 细胞至关重要。CAR 选择的结构和共刺激结构域可能在 CAR T 细胞在 TME 中的整体功能中发挥重要作用,分泌细胞因子的“装甲”CAR 和具有多个共刺激结构域的第三代和第四代 CAR 为增强 CAR T 细胞功能提供了途径。
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