Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma.
Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma.
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DOI：
10.1158/1078-0432.ccr-18-3626
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发表时间：
2020-05-01
期刊：
影响因子：
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通讯作者：
Roy EJ
中科院分区：
文献类型：
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作者：
Tang B;Guo ZS;Bartlett DL;Yan DZ;Schane CP;Thomas DL;Liu J;McFadden G;Shisler JL;Roy EJ
我们假设，局部刺激激活肿瘤特异性T细胞和抗免疫抑制药的结合将改善胶质瘤的治疗。以病毒编码的IL15Rα-IL15为T细胞激活刺激因子，前列腺素合成抑制剂为抗免疫抑制因子，过继转移肿瘤特异性T细胞。两种溶瘤痘病毒，vvDD痘苗病毒和粘液瘤病毒，分别表达融合蛋白IL15Rα-IL15和一个荧光蛋白。病毒基因(YFP或tdTomato Red)在小鼠胶质瘤GL261细胞中的表达得到证实。用vvDD-IL15Rα-YFP痘苗病毒或vMyx-IL15Rα-TdTr联合免疫C57BL/6J小鼠的GL261肿瘤，包括GL261的新抗原GARC-1肽疫苗接种、雷帕霉素、塞来昔布和过继T细胞治疗。VvDD-IL15R、α-YFP和vMyx-IL15R、α-TdTr分别感染和杀伤GL261细胞。在体内，由于IL15Rα-IL15的表达，肿瘤中的NK细胞和CD8+T细胞增加。联合治疗的每个组成部分都有助于延长生存期：溶瘤病毒、病毒表达的IL15Rα-IL15、T细胞来源(无论是通过预防接种还是过继转移)，以及前列腺素抑制，所有这些都协同作用，在大多数小鼠中消除了胶质瘤。VvDD-IL15Rα-YFP偶尔会引起脑室-脑膜炎，但vMyx-IL15Rα-TdTr是安全有效的，可引起肿瘤特异性T细胞的强烈渗透，并在83%的治疗小鼠中消除胶质瘤。携带IL15Rα-IL15的溶瘤痘病毒与过继T细胞治疗、雷帕霉素和塞来昔布联合使用时，可提供强大的抗肿瘤作用。
We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. Virally encoded IL15Rα-IL15 as the T-cell activating stimulus and a prostaglandin synthesis inhibitor as the anti-immunosuppressant were combined with adoptive transfer of tumor-specific T cells. Two oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein IL15Rα-IL15 and a fluorescent protein. Viral gene expression (YFP or tdTomato Red) was confirmed in the murine glioma GL261 in vitro and in vivo. GL261 tumors in immunocompetent C57BL/6J mice were treated with vvDD-IL15Rα-YFP vaccinia virus or vMyx-IL15Rα-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T-cell therapy. vvDD-IL15Rα-YFP and vMyx-IL15Rα-tdTr each infected and killed GL261 cells in vitro. In vivo, NK cells and CD8+ T cells were increased in the tumor due to the expression of IL15Rα-IL15. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15Rα-IL15 expressed by the virus, a source of T cells (whether by prevaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDD-IL15Rα-YFP occasionally caused ventriculitis-meningitis, but vMyx-IL15Rα-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice. IL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib.