Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas.
Cancer Immunol Res. 2019 Apr;7(4):528-533. doi: 10.1158/2326-6066.CIR-18-0888.
Although T cells genetically modified with chimeric antigen receptors became the first immune effector product to obtain FDA approval, T-cell products that recognize their antigenic targets through their native receptors have also produced encouraging responses. For instance, T cells recognizing immunogenic viral antigens are effective when infused in immunosuppressed patients. A large number of tumor antigens are also expressed on nonviral tumors, but these antigens are less immunogenic. Many tumors can evade a transferred immune response by producing variants, which have lost the targeted antigens, or inhibitory molecules that recruit suppressive cells, impeding persistence and function of immune effectors. Nevertheless, infusion of antigen-specific T cells has been well-tolerated, and clinical responses have been consistently associated with immune activity against tumor antigens and epitope spreading. To overcome some of the obstacles mentioned above, current research is focused on defining culture conditions that promote persistence and activity of infused antigen-specific T cells. Combinations with immune checkpoint inhibitors or epigenetic modifiers to improve T-cell activity are also being evaluated in the clinic. Antigen-specific T cells may also be manufactured to overcome tumor evasion mechanisms by targeting multiple antigens and engineered to be resistant to inhibitory factors, such as TGFβ, or to produce the cytokines that are essential for T-cell expansion and sustained antitumor activity. Here, we discuss the use of T cells specific to tumor antigens through their native receptors and strategies under investigation to improve antitumor responses.
尽管嵌合抗原受体基因修饰的 T 细胞成为第一个获得 FDA 批准的免疫效应产物，但通过天然受体识别其抗原靶标的 T 细胞产品也产生了令人鼓舞的反应。例如，输注识别免疫原性病毒抗原的 T 细胞在免疫抑制患者中有效。大量非病毒肿瘤也表达肿瘤抗原，但这些抗原的免疫原性较低。许多肿瘤可以通过产生丢失靶向抗原的变体或募集抑制细胞的抑制分子来逃避转移的免疫反应，从而阻碍免疫效应物的持久性和功能。然而，输注抗原特异性 T 细胞已被很好地耐受，临床反应与针对肿瘤抗原的免疫活性和表位扩展一致。为了克服上述一些障碍，目前的研究集中于定义促进输注的抗原特异性 T 细胞持久性和活性的培养条件。还在临床中评估与免疫检查点抑制剂或表观遗传修饰剂联合使用以提高 T 细胞活性。也可以制造抗原特异性 T 细胞以通过靶向多个抗原来克服肿瘤逃逸机制，并设计为对抑制因子（如 TGFβ）具有抗性，或产生对于 T 细胞扩增和持续抗肿瘤活性至关重要的细胞因子。在这里，我们讨论了通过天然受体利用针对肿瘤抗原的 T 细胞以及正在研究的提高抗肿瘤反应的策略。
