Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology.
Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology.
复制标题
ipilimumab和Nivolumab组合免疫疗法的临床前开发：小鼠肿瘤模型，体外功能研究和cynomolgus猕猴毒理学。
DOI：
10.1371/journal.pone.0161779
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Korman AJ
中科院分区：
文献类型：
--
作者：
Selby MJ;Engelhardt JJ;Johnston RJ;Lu LS;Han M;Thudium K;Yao D;Quigley M;Valle J;Wang C;Chen B;Cardarelli PM;Blanset D;Korman AJ
单克隆抗体易普利姆玛（抗CTLA-4）和纳武单抗（抗PD-1）在越来越多的癌症中显示出显著的抗肿瘤活性。当组合时，伊匹单抗和纳武单抗在患有转移性黑素瘤的患者中显示出上级活性（PDIKMATE-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MC 38和CT 26结肠直肠肿瘤模型中，在同时而非顺序CTLA-4和PD-1阻断的情况下观察到协同抗肿瘤活性。在MC 38模型中，使用固定剂量的抗CTLA-4抗体和降低剂量的抗PD-1抗体维持了显著的抗肿瘤活性。免疫组织化学和流式细胞术分析证实，CD 3 + T细胞聚集在肿瘤边缘，并浸润肿瘤块，以响应联合治疗，导致有利的效应和调节T细胞比例，增加促炎细胞因子分泌，并激活肿瘤特异性T细胞。类似地，使用组合的易普利姆玛和纳武单抗的体外研究显示在人外周血淋巴细胞的超抗原刺激中和在混合淋巴细胞应答测定中增强的细胞因子分泌。在一项食蟹猴毒理学研究中，在联合治疗中观察到剂量依赖性免疫相关胃肠道炎症;在既往食蟹猴单药研究中未观察到该应答。总之，这些体外试验和体内模型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。
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.
登录
查看更多内容
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
28.2
作者：
Llosa, Nicolas J.;Cruise, Michael;Housseau, Franck
通讯作者：
Housseau, Franck
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS