Dai Min, Yip Yuen Yee, Hellstrom Ingegerd, Hellstrom Karl Erik
University of Washington Harborview Medical Center, Department of Pathology, Seattle, Washington.
Clin Cancer Res. 2015 Mar 1;21(5):1127-38. doi: 10.1158/1078-0432.CCR-14-1339. Epub 2014 Aug 20.
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/CTLA-4 or CD137/PD-1/CTLA-4/CD19 were administrated intratumorally to mice with syngeneic tumors (B16 and SW1 melanoma, TC1 lung carcinoma), including tumors with a mean surface of approximately 80 mm(2). Survival and tumor growth were assessed. Immunologic responses were evaluated using flow cytometry and qRT-PCR.
More than 50% of tumor-bearing mice had complete regression and long-term survival after tumor injection with mAbs recognizing CD137/PD-1/CTLA-4/CD19 with similar responses in three models. Intratumoral injection was more efficacious than intraperitoneal injection in causing rejection also of untreated tumors in the same mice. The three-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/CTLA-4/CD19 can eradicate established tumors and reverse a Th2 response with tumor-associated CD19 cells to Th1 immunity, whereas a combination lacking anti-CD19 is less effective. There are several human cancers for which a similar approach may provide clinical benefit.
免疫调节性单克隆抗体可用于治疗癌症，但除小肿瘤外，治愈情况罕见。我们的目标是探索通过将具有不同作用模式的单克隆抗体联合并注射到肿瘤中，治疗窗口是否会扩大。
将针对CD137/PD-1/CTLA-4或CD137/PD-1/CTLA-4/CD19的单克隆抗体组合瘤内注射给患有同基因肿瘤（B16和SW1黑色素瘤、TC1肺癌）的小鼠，包括平均表面积约为80平方毫米的肿瘤。评估生存率和肿瘤生长情况。使用流式细胞术和定量逆转录聚合酶链反应评估免疫反应。
超过50%的荷瘤小鼠在瘤内注射识别CD137/PD-1/CTLA-4/CD19的单克隆抗体后实现了完全消退和长期存活，三种模型中的反应相似。瘤内注射在导致同一小鼠中未治疗肿瘤的排斥方面比腹腔注射更有效。三抗体组合也可诱导肿瘤消退，但效果较差。副作用很少，未观察到对治疗耐药的肿瘤。移植的肿瘤细胞迅速引发Th2反应，CD19细胞增加。成功的治疗将这种反应转变为Th1表型，CD19细胞减少，长期记忆CD8效应细胞和产生IFNγ和TNFα的T细胞数量增加。
瘤内注射识别CD137/PD-1/CTLA-4/CD19的单克隆抗体可根除已形成的肿瘤，并将与肿瘤相关的CD19细胞的Th2反应逆转至Th1免疫，而缺乏抗CD19的组合效果较差。有几种人类癌症采用类似方法可能会带来临床益处。
