Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
JCI Insight. 2018 Apr 5;3(7). doi: 10.1172/jci.insight.99573.
Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA.
胰腺导管腺癌 (PDA) 的特点是其高度免疫抑制的肿瘤微环境 (TME)，限制了 T 细胞浸润并诱导 T 细胞功能低下。间皮素导向嵌合抗原受体 T 细胞 (meso-CAR T 细胞) 治疗在临床试验中显示出一定的疗效，但抗肿瘤疗效仍然有限。我们假设联合间皮素 CAR T 细胞与表达 TNF-α 和 IL-2 的溶瘤腺病毒 (Ad5/3-E2F-D24-TNFa-IRES-IL2，或 OAd-TNFa-IL2) 将提高疗效。OAd-TNFa-IL2 增强了人源性 PDA 异种移植免疫缺陷小鼠中间皮素 CAR T 细胞的抗肿瘤疗效，疗效与大量增加的肿瘤浸润淋巴细胞 (TILs)、增强和延长的 T 细胞功能有关。用亲本 OAd 联合间皮素 CAR T 治疗的小鼠即使原发性肿瘤得到控制，也会发展为肺转移。然而，没有一只用联合 OAd-TNFa-IL2 和间皮素 CAR T 治疗的小鼠死于肿瘤转移。我们还通过联合表达鼠 TNF-α 和 IL-2 的腺病毒 (Ad-mTNFa-mIL2) 和鼠 CAR T 细胞在同种小鼠肿瘤模型中评估了这种方法。这种方法诱导了高度侵袭性和免疫抑制性 PDA 肿瘤小鼠的显著肿瘤消退。Ad-mTNFa-mIL2 增加了 CAR T 细胞和宿主 T 细胞向肿瘤的浸润，并通过巨噬细胞的 M1 极化和树突状细胞成熟改变了宿主肿瘤免疫状态。这些发现表明，联合细胞因子武装溶瘤腺病毒增强 CAR T 细胞治疗的疗效是克服 PDA 治疗中免疫抑制性 TME 的一种有前途的方法。
