Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade.
Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade.
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静脉注射溶瘤牛痘病毒使胰腺神经内分泌肿瘤和转移瘤对免疫检查点阻断敏感。
DOI：
10.1016/j.omto.2021.12.016
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发表时间：
2022-03-17
期刊：
影响因子：
--
通讯作者：
McDonald DM
中科院分区：
文献类型：
--
作者：
Inoue M;Kim M;Inoue T;Tait M;Byrne T;Nitschké M;Murer P;Cha H;Subramanian A;De Silva N;Chiaverotti T;McDonald DM
本研究确定了静脉内（i.v.）溶瘤牛痘病毒mpJX-594（mpJX）对抗程序性死亡受体-1抗体（aPD 1）在功能性和转移性胰腺神经内分泌肿瘤（PanNET）中的抗肿瘤活性的影响。将一剂静脉注射的mpJX（为具有与临床病毒Pexa-Vec相同的质粒设计的小鼠而设计）单独或与aPD 1（mpJX + aPD 1）重复给药一起给予两种对比的PanNET遗传模型：一种发生良性胰岛素分泌肿瘤（RIP1-Tag2; C57 BL/6J小鼠），另一种发生肝转移（RIP1-Tag2; AB6F1小鼠）。实验表明，aPD 1与mpJX在PanNET中对CD8 + T细胞和自然杀伤（NK）细胞的流入、凋亡和增殖抑制具有协同作用。在mpJX + aPD 1后，凋亡增加53倍（5天）和增殖减少85%（20天）超过了单独给予mpJX和aPD 1的总和。mpJX + aPD 1还稳定了具有功能性PanNET的小鼠的血液胰岛素和葡萄糖，使具有侵袭性PanNET的小鼠的肝转移消退，并延长了两者的存活期。研究结果显示，mpJX + aPD 1将“冷”PanNET转化为免疫原性肿瘤，具有广泛的细胞毒性T细胞流入，肿瘤细胞杀伤和增殖抑制。功能性PanNET的肿瘤胰岛素分泌减少延长了生存期，对侵袭性PanNET的抗转移作用将转移负荷降低至低于治疗前。这些发现支持了具有aPD 1的牛痘病毒对功能性和转移性PanNET的功效。静脉内给予患有胰腺神经内分泌肿瘤的小鼠的牛痘病毒mpJX-594通过将免疫学上的"冷"肿瘤转变为"热"肿瘤来增加抗PD1抗体的抗肿瘤应答。治疗组合的协同作用放大了细胞毒性T细胞流入，并导致较小的、功能较低的原发性肿瘤和转移灶消退。
This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs). One i.v. dose of mpJX, engineered for mice with the same plasmid design as clinical virus Pexa-Vec, was administered alone or with repeated dosing of aPD1 (mpJX+aPD1) to two contrasting genetic models of PanNET: one developing benign insulin-secreting tumors (RIP1-Tag2;C57BL/6J mice) and the other developing liver metastases (RIP1-Tag2;AB6F1 mice). Experiments revealed that aPD1 had synergistic actions with mpJX on CD8+ T cell and natural killer (NK) cell influx, apoptosis, and suppression of proliferation in PanNETs. After mpJX+aPD1, the 53-fold increase in apoptosis (5 days) and 85% reduction in proliferation (20 days) exceeded the sum of mpJX and aPD1 given separately. mpJX+aPD1 also stabilized blood insulin and glucose in mice with functional PanNETs, regressed liver metastases in mice with aggressive PanNETs, and prolonged survival of both. The findings revealed that mpJX+aPD1 converted “cold” PanNETs into immunogenic tumors with widespread cytotoxic T cell influx, tumor cell killing, and suppression of proliferation. Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs. Vaccinia virus mpJX-594 administered intravenously to mice with pancreatic neuroendocrine tumors increases the antitumor response of an anti-PD1 antibody by turning immunologically “cold” tumors into “hot” tumors. Synergistic actions of the treatment combination amplify cytotoxic T cell influx and lead to smaller, less functional primary tumors and to the regression of metastases.
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影响因子：
7
作者：
Brown KE;Freeman GJ;Wherry EJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
17.1
作者：
Allen E;Jabouille A;Rivera LB;Lodewijckx I;Missiaen R;Steri V;Feyen K;Tawney J;Hanahan D;Michael IP;Bergers G
通讯作者：
Bergers G
影响因子：
--
作者：
Contractor T;Kobayashi S;da Silva E;Clausen R;Chan C;Vosburgh E;Tang LH;Levine AJ;Harris CR
通讯作者：
Harris CR
影响因子：
64.8
作者：
HANAHAN, D
通讯作者：
HANAHAN, D