Combination immunotherapy including OncoVEXmGMCSF creates a favorable tumor immune micro-environment in transgenic BRAF murine melanoma.
Combination immunotherapy including OncoVEXmGMCSF creates a favorable tumor immune micro-environment in transgenic BRAF murine melanoma.
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包括 OncoVEXmGMCSF 在内的联合免疫疗法在转基因 BRAF 小鼠黑色素瘤中创造了有利的肿瘤免疫微环境。
DOI：
10.1007/s00262-021-03088-y
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发表时间：
2022
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作者：
Gartrell,RobynD;Blake,Zoë;Rizk,EmanuelleM;Perez-Lorenzo,Rolando;Weisberg,StuartP;Simoes,Ines;Esancy,Camden;Fu,Yichun;Davari,DanielleR;Barker,Luke;Finkel,Grace;Mondal,Manas;Minns,HannaE;Wang,SamuelW;Fullerton,BenjaminT;
Talimogene Laherparepvec(OncoVEXmGMCSF)是一种溶瘤病毒，免疫检查点抑制物抗程序性细胞死亡蛋白1(anti-PD1)和BRAF抑制物(BRAF)都已被临床批准用于治疗黑色素瘤患者，并通过不同的作用机制有效。就个体而言，这些疗法也对肿瘤免疫微环境(时间)产生影响。在时间上评估这三种疗法的联合效果有助于确定何时联合治疗最适合进一步研究。在这项研究中，我们使用转基因小鼠黑色素瘤模型(Tyr：：Creer；BRAFCA/+；PTENflx/Flox)，评估BRAFi、抗PD1和OncoVEXmGMCSF组合的反应时间。我们发现，与单独使用BRAFI相比，三重组合BRAFI + 抗PD1 + OncoVEXmGMCSF治疗的小鼠肿瘤生长减少，与对照组相比延长了生存时间。流式细胞仪分析显示，与未接受肿瘤治疗的小鼠相比，接受肿瘤治疗的小鼠的CD8 + /CD3 + 细胞毒性T淋巴细胞(CTL)百分比增加，FOXP3 + /CD4 + T调节细胞(Tregs)百分比下降。治疗后30d的免疫基因组分析显示，接受OncoVEXmGMCSF+ BRAFI治疗的小鼠Th1和干扰素相关基因增加。综上所述，BRAFI + 抗PD1GMCSF联合治疗在控制肿瘤生长方面比任何单一治疗更有效，并且在该时间内接受OncoVEXmGMCSF治疗的组有更多的CTL的肿瘤浸润和较少的肿瘤内Tregs。本研究为联合靶向药物、溶瘤病毒治疗和检查点抑制剂治疗黑色素瘤提供了合理的依据。
Talimogene Laherparepvec (OncoVEXmGMCSF), an oncolytic virus, immune checkpoint inhibitor anti-programmed cell death protein 1 (anti-PD1), and BRAF inhibition (BRAFi), are all clinically approved for treatment of melanoma patients and are effective through diverse mechanisms of action. Individually, these therapies also have an effect on the tumor immune microenvironment (TIME). Evaluating the combination effect of these three therapies on the TIME can help determine when combination therapy is most appropriate for further study. In this study, we use a transgenic murine melanoma model (Tyr::CreER; BRAFCA/+; PTENflox/flox), to evaluate the TIME in response to combinations of BRAFi, anti-PD1, and OncoVEXmGMCSF. We find that mice treated with the triple combination BRAFi + anti-PD1 + OncoVEXmGMCSFhave decreased tumor growth compared to BRAFi alone and prolonged survival compared to control. Flow cytometry shows an increase in percent CD8 + /CD3 + cytotoxic T Lymphocytes (CTLs) and a decrease in percent FOXP3 + /CD4 + T regulatory cells (Tregs) in tumors treated with OncoVEXmGMCSFcompared to mice not treated with OncoVEXmGMCSF. Immunogenomic analysis at 30d post-treatment shows an increase in Th1 and interferon-related genes in mice receiving OncoVEXmGMCSF+ BRAFi. In summary, treatment with combination BRAFi + anti-PD1 + OncoVEXmGMCSFis more effective than any single treatment in controlling tumor growth, and groups receiving OncoVEXmGMCSFhad more tumoral infiltration of CTLs and less intratumoral Tregs in the TIME. This study provides rational basis to combine targeted agents, oncolytic viral therapy, and checkpoint inhibitors in the treatment of melanoma.