Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Clin Cancer Res. 2020 May 1;26(9):2216-2230. doi: 10.1158/1078-0432.CCR-18-3626. Epub 2020 Feb 4.
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 and . 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 . , 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.
我们假设，联合应用激活肿瘤特异性 T 细胞的局部刺激物和免疫抑制剂将改善脑肿瘤的治疗效果。病毒编码的 IL15Rα-IL15 作为 T 细胞激活刺激物，以及前列腺素合成抑制剂作为免疫抑制剂，与肿瘤特异性 T 细胞过继转移联合应用。
两种溶瘤痘病毒，vvDD 痘苗病毒和兔痘病毒，均被工程改造表达融合蛋白 IL15Rα-IL15 和荧光蛋白。病毒基因表达（YFP 或 tdTomato Red）在免疫活性的 C57BL/6J 小鼠的鼠胶质母细胞瘤 GL261 中得到证实。GL261 肿瘤在免疫活性的 C57BL/6J 小鼠中用 vvDD-IL15Rα-YFP 痘苗病毒或 vMyx-IL15Rα-tdTr 联合其他治疗方法治疗，包括 GARC-1 肽（GL261 的新抗原）疫苗接种、雷帕霉素、塞来昔布和过继性 T 细胞治疗。
vvDD-IL15Rα-YFP 和 vMyx-IL15Rα-tdTr 均感染并杀死 GL261 细胞。由于表达了 IL15Rα-IL15，肿瘤中 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 细胞的来源（无论是通过预接种还是过继转移）以及前列腺素抑制均协同作用，使大多数小鼠的脑肿瘤得到消除。vvDD-IL15Rα-YFP 偶尔会引起脑室炎-脑膜炎，但 vMyx-IL15Rα-tdTr 是安全有效的，可引起肿瘤特异性 T 细胞的强烈浸润，83%的治疗小鼠的脑肿瘤得到消除。
当与过继性 T 细胞治疗、雷帕霉素和塞来昔布联合应用时，IL15Rα-IL15 武装的溶瘤痘病毒对脑肿瘤具有强大的抗肿瘤作用。
