Purpose: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. Experimental Design: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). Results: The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. Conclusions: We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.

中文翻译：

---

组蛋白去乙酰化酶抑制剂 Panobinostat 增强嵌合抗原受体 T 细胞对胰腺癌的抗肿瘤作用

目的：在本文中，我们描述了一种联合嵌合抗原受体 (CAR) T 细胞疗法，该疗法在两种免疫活性小鼠胰腺癌模型和一种人类胰腺癌异种移植模型中根除大部分肿瘤。实验设计：我们使用了双特异性鼠 CAR T 细胞，该细胞表达针对 Her2 肿瘤抗原的 CAR，以及对 gp100 特异的 T 细胞受体 (TCR)。由于 gp100 也称为 pMEL，因此将双特异性 CAR T 细胞表示为 CARaMEL 细胞。将含有编码 gp100 小基因 (VV-gp100) 的活痘苗病毒的疫苗施用于受体小鼠以刺激 CARaMEL 细胞。该治疗还包括组蛋白去乙酰化酶抑制剂帕比司他 (Pano)。结果：联合治疗能够显着抑制 Her2+ 胰腺癌，从而根除大多数肿瘤。除了诱导癌细胞凋亡外，Pano 还增强了 CAR T 细胞基因的可及性并促进 CAR T 细胞分化为中央记忆细胞。为了测试这种方法的转化潜力，我们建立了一种用抗 Her2 CAR 和 gp100-TCR 转导人类 T 细胞的方法。人类 T 细胞暴露于 Pano 促进了 T 细胞中枢记忆表型，人类 CARaMEL 细胞和 Pano 的联合治疗根除小鼠中的人类胰腺癌异种移植物。结论：我们建议胰腺癌患者可以使用包含双特异性 CAR T 细胞的方案进行治疗，这是一种通过 TCR 激活双特异性 CAR T 细胞的疫苗，