The Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
Cancer Res. 2019 Mar 1;79(5):899-904. doi: 10.1158/0008-5472.CAN-18-3158. Epub 2019 Jan 8.
Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells and . Curative effects were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR-T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. SIGNIFICANCE: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
嵌合抗原受体 (CAR) 与细胞表面靶标结合时，能够传递类似于激活的 T 细胞受体的信号。针对 CD19 的 CAR 表达 T 细胞可在白血病和淋巴瘤中产生治愈效果，已被批准用于临床应用。然而，目前尚无用于实体瘤的 CAR-T 疗法获得批准。我们假设，通过类似的方法可以克服实体瘤对 CAR-T 的耐药性，例如通过细胞因子或免疫检查点阻断来重新激活肿瘤浸润性 T 淋巴细胞 (TIL)。在这里，我们证明针对 HER2 的 CAR-T 细胞可以杀死葡萄膜和皮肤黑色素瘤细胞 和 。仅在转染人 IL2 的 NOD/SCID IL2 受体 γ (NOG) 基因敲除小鼠异种移植中观察到治愈效果。该效果具有靶向特异性，因为 CRISPR/Cas9 介导的黑色素瘤细胞中 HER2 的破坏消除了 CAR-T 细胞的杀伤作用。CAR-T 细胞还能够杀死对自体 TIL 的过继 T 细胞转移 (ACT) 产生耐药性的黑色素瘤细胞。因此，CAR-T 疗法为那些对 ACT 治疗或免疫检查点阻断无反应的患者提供了一种选择。此外，我们的数据强调了使用转染人 IL2 的 NOG 小鼠作为模型来证明 CAR-T 细胞对 TIL 治疗或免疫检查点阻断无反应的葡萄膜和皮肤黑色素瘤的疗效，甚至可能以个性化的方式证明疗效。意义：这些发现表明，一种新型的人源化小鼠模型可以帮助将针对 TIL 治疗或免疫检查点阻断无反应的葡萄膜和皮肤黑色素瘤的 CAR-T 细胞进行临床转化。
