肿瘤细胞治疗研究
英文原题：A CD19-Anti-ErbB2 scFv Engager Protein Enables CD19-Specific CAR T Cells to Eradicate ErbB2(+) Solid Cancer.
CD19特异性CAR T细胞治疗白血病/淋巴瘤的疗效，至少部分依赖于特定CAR的独特性质以及健康B细胞的存在，后者通过反复刺激增强靶细胞裂解和细胞因子分泌。
CD19特异性CAR T细胞治疗白血病/淋巴瘤的疗效，至少部分取决于特定CAR本身的性质，以及健康B细胞的存在；后者可通过反复刺激增强靶细胞裂解和细胞因子分泌。本研究尝试利用同一种CAR靶向ErbB2⁺等实体瘤。研究者使用一种融合蛋白将CD19 CAR T细胞重定向至ErbB2⁺细胞；该融合蛋白由赫赛汀来源的抗ErbB2单链可变片段（scFv）4D5与CD19胞外结构域连接而成。CD19-4D5scFv衔接蛋白使CD19 CAR T细胞能够识别ErbB2⁺癌细胞并抑制其肿瘤生长。ErbB2重定向的CD19 CAR T细胞具有与ErbB2 CAR T细胞相当的初始杀伤能力；加入CD19⁺ B细胞后，CD19 CAR T细胞的活化进一步增强，抗肿瘤活性也随之提高。此外，与ErbB2 CAR T细胞不同，ErbB2重定向的CD19 CAR T细胞靶向癌细胞相较健康成纤维细胞的选择性高出100倍。研究结果表明，CD19 CAR T细胞可被CD19-scFv衔接蛋白“劫持”，从而特异性攻击实体癌，使其应用范围扩展至B细胞恶性肿瘤之外。
The efficacy of CD19-specific CAR T cells in the treatment of leukemia/lymphoma relies, at least in part, on the unique properties of the particular CAR and the presence of healthy B cells that enhance the target cell lysis and cytokine secretion through repetitive stimulation. Here, we report to apply the same CAR to target solid tumors, such as ErbB2 + carcinoma. CD19 CAR T cells are redirected towards the ErbB2 + cells by a fusion protein that is composed of the herceptin-derived anti-ErbB2 scFv 4D5 linked to the CD19 exodomain. The CD19-4D5scFv engager enabled CD19 CAR T cells to recognize the ErbB2 + cancer cells and to suppress the ErbB2 + tumor growth. The primary killing capacity by the ErbB2-redirected CD19 CAR T cells was as efficient as by the ErbB2 CAR T cells, however, adding CD19 + B cells furthermore reinforced the activation of the CD19 CAR T cells, thereby improving the anti-tumor activities. The ErbB2-redirected CD19 CAR T cells, moreover, showed a 100-fold superior selectivity in targeting cancer cells versus healthy fibroblasts, which was not the case for the ErbB2 CAR T cells. The data demonstrate that the CD19 CAR T cells can be high-jacked by a CD19-scFv engager protein to attack specifically solid cancer, thereby expanding their application beyond the B cell malignancies.
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