Klampatsa Astero, Leibowitz Michael S, Sun Jing, Liousia Maria, Arguiri Evguenia, Albelda Steven M
Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Ther Oncolytics. 2020 Jul 15;18:360-371. doi: 10.1016/j.omto.2020.07.005. eCollection 2020 Sep 25.
The therapeutic efficacy of adoptive transfer of T cells transduced with chimeric antigen receptors (CARs) has been limited in the treatment of solid cancers, partly due to tumor antigen heterogeneity. Overcoming lack of universal tumor antigen expression would be achieved if CAR T cells could induce bystander effects. To study this process, we developed a system where CAR T cells targeting mesothelin could cure tumors containing 100% antigen-positive cells in immunocompetent mice. Using this model, we found that the CAR T cells were unable to cure tumors, even when only 10% of the tumor cells were mesothelin negative. A bystander effect was not induced by co-administration of anti-PD-1, anti-CTLA-4, or anti-TGF-β (transforming growth factor β) antibodies; agonistic CD40 antibodies; or an IDO (indoleamine 2,3-dioxygenase) inhibitor. However, pretreatment with a non-lymphodepleting dose of cyclophosphamide (CTX) prior to CAR T cells resulted in cures of tumors with up to 25% mesothelin-negative cells. The mechanism was dependent on endogenous CD8 T cells but not on basic leucine zipper transcription factor ATF-like 3 (BATF3)-dependent dendritic cells. These data suggest that CAR T cell therapy of solid tumors, in which the targeted antigen is not expressed by the vast majority of tumor cells, will not likely be successful unless combination strategies to enhance bystander effects are used.
嵌合抗原受体（CAR）转导的T细胞过继性转移在实体癌治疗中的疗效有限，部分原因是肿瘤抗原的异质性。如果CAR T细胞能够诱导旁观者效应，那么缺乏普遍肿瘤抗原表达的问题就能得到解决。为了研究这一过程，我们开发了一个系统，其中靶向间皮素的CAR T细胞能够治愈免疫活性小鼠体内含有100%抗原阳性细胞的肿瘤。利用这个模型，我们发现即使只有10%的肿瘤细胞间皮素呈阴性，CAR T细胞也无法治愈肿瘤。联合使用抗PD-1、抗CTLA-4或抗TGF-β（转化生长因子β）抗体、激动性CD40抗体或IDO（吲哚胺2,3-双加氧酶）抑制剂均未诱导旁观者效应。然而，在CAR T细胞之前用非淋巴细胞清除剂量的环磷酰胺（CTX）进行预处理，可治愈含有高达25%间皮素阴性细胞的肿瘤。其机制依赖于内源性CD8 T细胞，而不依赖于碱性亮氨酸拉链转录因子ATF样3（BATF3）依赖性树突状细胞。这些数据表明，对于绝大多数肿瘤细胞不表达靶向抗原的实体瘤，除非采用增强旁观者效应的联合策略，CAR T细胞疗法不太可能成功。
