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表达双特异性 T 细胞衔接器的溶瘤痘苗病毒增强了 EpCAM 阳性实体瘤中的免疫反应。

Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors.

机构信息

Affiliated Yancheng No.1 People's Hospital, Medical School of Nanjing University, Yancheng, China.

Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.

出版信息

Front Immunol. 2022 Nov 14;13:1017574. doi: 10.3389/fimmu.2022.1017574. eCollection 2022.

DOI:10.3389/fimmu.2022.1017574
PMID:36451817
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9702515/
Abstract

Insufficient intratumoral T-cell infiltration and lack of tumor-specific immune surveillance in tumor microenvironment (TME) hinder the progression of cancer immunotherapy. In this study, we explored a recombinant vaccinia virus encoding an EpCAM BiTE (VV-EpCAM BiTE) to modulate the immune suppressive microenvironment to enhance antitumor immunity in several solid tumors. VV-EpCAM BiTE effectively infected, replicated and lysed malignant cells. The EpCAM BiTE secreted from infected malignants effectively mediated the binding of EpCAM-positive tumor cells and CD3ϵ on T cells, which led to activation of naive T-cell and the release of cytokines, such as IFN-γ and IL-2. Intratumoral administration of VV-EpCAM BiTE significantly enhanced antitumor activity in malignancies with high other than with low EpCAM expression level. In addition, immune cell infiltration was significantly increased in TME upon VV-EpCAM BiTE treatment, CD8 T cell exhaustion was reduced and T-cell-mediated immune activation was markedly enhanced. Taken together, VV-EpCAM BiTE sophistically combines the antitumor advantages of bispecific antibodies and oncolytic viruses, which provides preclinical evidence for the therapeutic potential of VV-EpCAM BiTE.

摘要

肿瘤微环境（TME）中浸润的 T 细胞不足和缺乏肿瘤特异性免疫监视，阻碍了癌症免疫治疗的进展。在这项研究中，我们探索了一种编码 EpCAM BiTE 的重组痘病毒（VV-EpCAM BiTE），以调节免疫抑制微环境，增强几种实体瘤中的抗肿瘤免疫。VV-EpCAM BiTE 能有效地感染、复制和裂解恶性细胞。从感染的恶性细胞中分泌的 EpCAM BiTE 有效地介导了 EpCAM 阳性肿瘤细胞与 T 细胞上的 CD3ϵ 的结合，导致了幼稚 T 细胞的激活和细胞因子如 IFN-γ 和 IL-2 的释放。VV-EpCAM BiTE 的瘤内给药在 EpCAM 表达水平高的恶性肿瘤中显著增强了抗肿瘤活性，而在 EpCAM 表达水平低的恶性肿瘤中则没有。此外，VV-EpCAM BiTE 治疗后 TME 中的免疫细胞浸润显著增加，CD8 T 细胞耗竭减少，T 细胞介导的免疫激活显著增强。总之，VV-EpCAM BiTE 巧妙地结合了双特异性抗体和溶瘤病毒的抗肿瘤优势，为 VV-EpCAM BiTE 的治疗潜力提供了临床前证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/293780d3dbf2/fimmu-13-1017574-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/ee27b352018f/fimmu-13-1017574-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/fc2b612fb648/fimmu-13-1017574-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/4e2b5430c434/fimmu-13-1017574-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/901391568990/fimmu-13-1017574-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/5cb559fe20fd/fimmu-13-1017574-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/293780d3dbf2/fimmu-13-1017574-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/ee27b352018f/fimmu-13-1017574-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/fc2b612fb648/fimmu-13-1017574-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/4e2b5430c434/fimmu-13-1017574-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/901391568990/fimmu-13-1017574-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/5cb559fe20fd/fimmu-13-1017574-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce28/9702515/293780d3dbf2/fimmu-13-1017574-g006.jpg

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Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients.新辅助静脉内溶瘤痘苗病毒治疗促进患者的抗癌免疫。
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