PO.IM01.02 · 免疫学
利用工程化溶瘤单纯疱疹病毒调控肿瘤微环境以促进强效抗肿瘤应答
Modulating the tumor microenvironmentwith an engineered oncolytic herpesvirus facilitates potent antitumor response
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
溶瘤病毒（OV）是一种有前景的癌症治疗方法，减毒病毒可选择性地感染并杀伤肿瘤，同时保留健康细胞。受感染细胞释放的肿瘤抗原和细胞因子可致敏并激活免疫系统，从而产生持久的抗肿瘤应答。这会使肿瘤微环境炎症化，并可能与免疫检查点抑制剂（ICI）治疗形成互补。然而，这种协同作用尚未得到证实：在一项随机、双盲的III期试验中，基于HSV的talimogene laherparepvec（TVEC）联合抗PD1 ICI治疗，相较于单用抗PD1治疗，未能改善无进展生存期和总生存期。这可能归因于病毒因子部分通过抑制抗肿瘤免疫成分来促进肿瘤选择性复制。因此，临床上存在着对能够克服现有疗法局限性的OV的未满足需求。我们此前开发了一种新型溶瘤HSV——DN146，其经过优化以实现最大程度的免疫刺激，同时不损害肿瘤选择性复制。对DN146中gamma 1 34.5基因的重新工程化改造，使病毒能够高效复制并杀伤肿瘤细胞，同时强效激活STING和RIG-I。在体内，与临床类似物相比，DN146在三阴性乳腺癌小鼠模型中表现出强烈的免疫刺激和树突状细胞成熟，以及对转移灶的强效清除。我们为DN146装载了一种工程化的高亲和力SIRPalpha，通过阻断SIRPalpha-CD47免疫检查点来进一步增强其抗肿瘤效应。该检查点的拮抗剂可改善巨噬细胞吞噬作用并促进T细胞向TME募集。此外，CD47阻断可改善肿瘤抗原向CD8+ T细胞的交叉呈递。这些效应应与DN146产生的STING激活协同作用，从而广泛重编程肿瘤微环境。当在双侧小鼠结直肠癌模型中进行测试时，该病毒实现了对局部注射肿瘤和远端未注射肿瘤的清除，表明其具有强大的局部和全身抗肿瘤效应。
查看英文原文 English abstract
Oncolytic viruses (OV) are a promising approach to cancer treatment, whereby attenuated viruses selectively infect and kill tumors, while sparing healthy cells. Tumor antigens and cytokines released from infected cells prime and activate the immune system to generate durable antitumor responses. This inflames the tumor microenvironment and may complement immune checkpoint inhibitor (ICI) therapy. However, this synergy is yet to be demonstrated: in a randomized, double blind, phase III trial, the HSV based talimogene laherparepvec (TVEC) in combination with anti-PD1 ICI therapy failed to improve both progression free survival and overall survival relative to anti-PD1 therapy alone. This may be attributable to viral factors that promote tumor selective replication in part by suppressing antitumor immune elements. Consequently, there is an unmet need for OVs that overcome the limitations of current therapies. We previously developed a novel oncolytic HSV, DN146, optimized for maximum immune stimulation without compromising tumor selective replication. Re-engineering of the gamma 1 34.5 gene in DN146 permits efficient viral replication and tumor cell killing, while robustly activating STING and RIG-I. In vivo , DN146 exhibits strong immune stimulation and dendritic cell maturation, and robust clearance of metastatic lesions as compared to clinical analogues in a mouse model of triple negative breast cancer. We armed DN146 with an engineered high affinity SIRPalpha to further potentiate its antitumor effects by blocking the SIRPalpha-CD47 immune checkpoint. Antagonists of this checkpoint improve macrophage phagocytosis and T-cell recruitment to the TME. Further, CD47 blockade can improve cross presentation of tumor antigens to CD8+ T-cells. Together, these effects should cooperate with STING activation from DN146 to broadly reprogram the tumor microenvironment. When tested in a bilateral, murine colorectal cancer model, this virus achieves clearance of both locally injected and distal un-injected tumors, indicating strong local and systemic antitumor effects.
利益披露 Disclosure
J. Najjar, None..
G. Geetanjali, None..
C. Kangas, None..
B. He, None.