BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.
BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy.
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DOI：
10.1158/0008-5472.can-11-2837
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发表时间：
2012-08-15
期刊：
影响因子：
11.2
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Koya RC;Mok S;Otte N;Blacketor KJ;Comin-Anduix B;Tumeh PC;Minasyan A;Graham NA;Graeber TG;Chodon T;Ribas A
将免疫治疗与靶向治疗相结合，阻断致癌的BRAFV600，可能会改善晚期黑色素瘤的治疗。在这里，我们开发了一种由BRAFV600E驱动的黑色素瘤小鼠模型SM1，它与完全免疫功能的小鼠是同源的。SM1细胞暴露于BRAF抑制剂维莫拉非尼(PLX4032)后，由于MAPK信号通路的抑制，在体内外表现出部分敏感性。维莫拉非尼联合过继细胞转移(ACT)治疗SM1-OVA肿瘤表达的识别鸡卵蛋白(OVA)的T细胞受体(TCR)转基因淋巴细胞或识别SM1内源性表达gp100的PMEL-1 TCR转基因淋巴细胞的联合治疗，与单独治疗相比，具有更好的抗肿瘤效果。T细胞分析表明，维莫拉非尼没有显著改变过继转移细胞的扩张、分布或肿瘤聚集。然而，维莫拉非尼矛盾地增加了MAPK信号、体内细胞毒活性和过继转移细胞的瘤内细胞因子分泌。总之，我们的发现来自两个独立的结合BRAF靶向治疗和免疫治疗的模型，支持在BRAFV600突变转移性黑色素瘤患者中测试这种治疗组合。
Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. Here, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer (ACT) therapy with lymphocytes genetically modified with a T cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors, or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1, resulted in superior antitumor responses compared with either therapy alone. T cell analysis demonstrated that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased MAPK signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Together, our findings, derived from two independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma.