A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors.
A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors.
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DOI：
10.1158/1078-0432.ccr-20-2487
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Fan S
中科院分区：
文献类型：
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作者：
Lei X;Ou Z;Yang Z;Zhong J;Zhu Y;Tian J;Wu J;Deng H;Lin X;Peng Y;Li B;He L;Tu Z;Chen W;Li Q;Liu N;Zhang H;Wang Z;Fang Z;Yamada T;Lv X;Tian T;Pan G;Wu F;Xiao L;Zhang L;Cai T;Wang X;Tannous BA;Li J;Kontos F;Ferrone S;Fan S
嵌合抗原受体（CAR） T细胞治疗实体恶性肿瘤的有限疗效促使我们测试表观遗传治疗是否可以增强B7-H3 CAR T细胞治疗几种实体癌症类型的抗肿瘤活性。我们评估了B7-H3在许多人类实体癌和正常组织样本中的表达。B7-H3联合治疗的疗效。CAR-T细胞和去乙酰化酶抑制剂SAHA与几种实体癌症类型及其潜在的潜在机制通过体外和离体实验进行了表征。B7-H3在大多数人实体瘤样本中表达，但在正常组织中表达受限。B7-H3。CAR-T细胞选择性杀伤体外表达B7-H3的人癌细胞系。低剂量的SAHA在转录水平和B7-H3水平上调几种实体癌细胞中B7-H3的表达。CAR在人转基因T细胞膜上的表达。相反，经SAHA处理后，T细胞表达的免疫抑制分子，如CTLA-4和TET2下调。低剂量SAHA显著增强B7-H3的抗肿瘤活性。体外和体外实体癌CAR-T细胞，包括原位PDX和转移性模型，用自体CAR-T细胞输注治疗。我们的研究结果表明，我们的新策略是将SAHA和B7-H3结合起来。CAR-T细胞增强了它们对实体癌的治疗效果，并证明了其转化为临床环境的合理性。
The limited efficacy of chimeric antigen receptor (CAR) T cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3 CAR T cells with several solid cancer types. We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR-T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments. B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR-T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic T cell membrane. In contrast, the expression of immunosuppressive molecules, such as CTLA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR-T cells with solid cancers in vitro and ex vivo, including orthotopic PDX and metastatic models treated with autologous CAR-T cell infusions. Our results show that our novel strategy which combines SAHA and B7-H3.CAR-T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.