Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies.
Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies.
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DOI：
10.1158/1078-0432.ccr-14-1339
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发表时间：
2015-03-01
期刊：
影响因子：
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通讯作者：
Hellstrom KE
中科院分区：
文献类型：
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作者：
Dai M;Yip YY;Hellstrom I;Hellstrom KE
免疫调节单克隆抗体可以治疗癌症，但除了小肿瘤外，治愈率很低。我们的目的是探索是否通过将具有不同作用模式的mAb组合并将其注射到肿瘤中来增加治疗窗。将针对CD 137/PD-1/CTLA 4或CD 137/PD-1/CTLA 4/CD 19的mAb的组合肿瘤内施用至具有同基因肿瘤（B16和SW 1黑素瘤、TC 1肺癌）的小鼠，包括平均表面积为~ 80 mm 2的肿瘤。评估存活率和肿瘤生长。使用流式细胞术和qRT-PCR评价免疫应答。超过50%的荷瘤小鼠在肿瘤注射识别CD 137/PD-1/CTLA 4/CD 19的mAb后完全消退并长期存活，在3种模型中具有相似的反应。瘤内注射比腹膜内注射更有效地引起相同小鼠中未治疗肿瘤的排斥反应。3 mAb组合也可诱导消退，但效力较低。副作用少，未观察到耐药肿瘤。移植的肿瘤细胞迅速引起Th 2应答，CD 19细胞增加。成功的治疗将这种应答转移到Th 1表型，减少了CD 19细胞，增加了长期记忆CD 8效应细胞和产生IFNγ和TNFα的T细胞的数量。肿瘤内注射识别CD 137/PD-1/CTLA 4/CD 19的mAb可以根除已建立的肿瘤，并逆转肿瘤相关CD 19细胞对Th 1免疫的Th 2应答，而缺乏抗CD 19的组合效果较差。有几种人类癌症，其中类似的方法可以提供临床益处。
Immunomodulatory mAbs can treat cancer, but cures are rare except for small tumors. Our objective was to explore whether the therapeutic window increases by combining mAbs with different modes of action and injecting them into tumors. Combinations of mAbs to CD137/PD-1/CTLA4 or CD137/PD-1/CTLA4/CD19 were administrated intratumorally to mice with syngeneic tumors (B16 and SW1 melanoma, TC1 lung carcinoma), including tumors with a mean surface of ~80mm2. Survival and tumor growth were assessed. Immunological responses were evaluated using flow cytometry and qRT-PCR. Over 50% of tumor-bearing mice had complete regression and long-term survival after tumor injection with mAbs recognizing CD137/PD-1/CTLA4/CD19 with similar responses in 3 models. Intratumoral injection was more efficacious than i.p. injection to cause rejection also of untreated tumors in the same mice. The 3 mAb combination could also induce regression but was less efficacious. There were few side-effects and therapy resistant tumors were not observed. Transplanted tumor cells rapidly caused a Th2 response with increased CD19 cells. Successful therapy shifted this response to the Th1 phenotype with decreased CD19 cells and increased numbers of long term memory CD8 effector cells and T cells making IFNγ and TNFα. Intratumoral injection of mAbs recognizing CD137/PD-1/CTLA4/CD19 can eradicate established tumors and reverse a Th2 response with tumor-associated CD19 cells to Th1 immunity while a combination lacking anti-CD19 is less effective. There are several human cancers where a similar approach may provide clinical benefit.