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Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models In Vitro Functional Studies and Cynomolgus Macaque Toxicology

机译:Ipilimumab和Nivolumab联合免疫疗法的临床前开发:小鼠肿瘤模型体外功能研究和食蟹猕猴毒理学

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摘要

The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.
机译:单克隆抗体ipilimumab(抗CTLA-4)和nivolumab(抗PD-1)在越来越多的癌症中显示出显着的抗肿瘤活性。结合使用,ipilimumab和nivolumab在转移性黑色素瘤患者中表现出更好的活性(CHECKMATE-067)。在这里,我们描述了预测这些临床结果的临床前开发策略。在小鼠MC38和CT26大肠肿瘤模型中观察到协同抗肿瘤活性,但同时发生CTLA-4和PD-1封锁,但未见连续封锁。在MC38模型中,使用固定剂量的抗CTLA-4抗体和减少剂量的抗PD-1抗体可以维持显着的抗肿瘤活性。免疫组织化学和流式细胞仪分析证实,联合治疗后,CD3 + T细胞积聚在肿瘤边缘并浸润肿瘤块,从而产生了有利的效应子和调节性T细胞比,促炎性增加细胞因子的分泌,以及肿瘤特异性T细胞的活化。类似地,结合ipilimumab和nivolumab的体外研究显示,在人类外周血淋巴细胞的超抗原刺激和混合淋巴细胞反应测定中,细胞因子分泌增强。在猕猴猕猴毒理学研究中,联合治疗观察到剂量依赖性免疫相关的胃肠道炎症。在以前的单剂食蟹猕猴研究中未观察到这种反应。这些体外测定法和体内模型共同构成了用于鉴定和开发高效抗肿瘤联合免疫疗法的临床前策略。

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