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通过拮抗 Th2 炎症,实现已建立的小鼠肿瘤的持久完全消退。

Long-lasting complete regression of established mouse tumors by counteracting Th2 inflammation.

机构信息

Department of Pathology, Harborview Medical Center, University of Washington, Seattle, WA 98104-2499, USA.

出版信息

J Immunother. 2013 May;36(4):248-57. doi: 10.1097/CJI.0b013e3182943549.

Abstract

Mice with intraperitoneal ID8 ovarian carcinoma or subcutaneous SW1 melanoma were injected with monoclonal antibodies (mAbs) to CD137PD-1CTLA4 7-15 days after tumor initiation. Survival of mice with ID8 tumors tripled and >40% of mice with SW1 tumors remained healthy >150 days after last treatment and are probably cured. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4 cells and involved CD8 cells and NK cells to a less extent. The 3 mAb combination significantly decreased CD19 cells at tumor sites, increased IFN-γ and TNF-α producing CD4 and CD8 T cells and mature CD86 dendritic cells (DC), and it increased the ratios of effector CD4 and CD8 T cells to CD4Foxp3 regulatory T (Treg) cells and to CD11bGr-1 myeloid suppressor cells (MDSC). This is consistent with shifting the tumor microenvironment from an immunosuppressive Th2 to an immunostimulatory Th1 type and is further supported by PCR data. Adding an anti-CD19 mAb to the 3 mAb combination in the SW1 model further increased therapeutic efficacy. Data from ongoing experiments show that intratumoral injection of a combination of mAbs to CD137PD-1CTLA4CD19 can induce complete regression and dramatically prolong survival also in the TC1 carcinoma and B16 melanoma models, suggesting that the approach has general validity.

摘要

在肿瘤起始后 15 天内,将抗 CD137、PD-1、CTLA-4 单克隆抗体(mAb)注入患有腹腔 ID8 卵巢癌或皮下 SW1 黑色素瘤的小鼠体内。ID8 肿瘤小鼠的存活率增加了两倍,超过 40%的 SW1 肿瘤小鼠在最后一次治疗后>150 天仍然健康,可能已被治愈。治疗效果与具有记忆和抗原特异性的全身性免疫反应有关,需要 CD4 细胞,并在一定程度上涉及 CD8 细胞和 NK 细胞。3 种 mAb 联合治疗显著减少了肿瘤部位的 CD19 细胞,增加了 IFN-γ 和 TNF-α 产生的 CD4 和 CD8 T 细胞以及成熟的 CD86 树突状细胞(DC),并增加了效应 CD4 和 CD8 T 细胞与 CD4Foxp3 调节性 T(Treg)细胞和 CD11bGr-1 髓样抑制细胞(MDSC)的比例。这与将肿瘤微环境从免疫抑制性 Th2 型转变为免疫刺激性 Th1 型一致,PCR 数据进一步支持了这一观点。在 SW1 模型中,将抗 CD19 mAb 加入到 3 种 mAb 联合治疗中,进一步提高了治疗效果。正在进行的实验数据表明,肿瘤内注射 CD137、PD-1、CTLA-4、CD19 单克隆抗体联合治疗可诱导 TC1 癌和 B16 黑色素瘤模型中的完全消退,并显著延长生存时间,这表明该方法具有普遍的有效性。

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