Immunomodulatory Monoclonal Antibodies Combined with Peptide Vaccination Provide Potent Immunotherapy in an Aggressive Murine Neuroblastoma Model
Immunomodulatory Monoclonal Antibodies Combined with Peptide Vaccination Provide Potent Immunotherapy in an Aggressive Murine Neuroblastoma Model
复制标题
免疫调节单克隆抗体与肽疫苗联合为侵袭性小鼠神经母细胞瘤模型提供有效的免疫治疗
作者：
E. Williams;Stuart N. Dunn;S. James;Peter W. M. Johnson;M. Cragg;M. Glennie;J. Gray
目的：神经母细胞瘤是儿童最常见的颅外肿瘤之一。大多数患者存在转移性疾病，其预后仍然很差。免疫治疗是一种有吸引力的治疗方法，许多神经母细胞瘤肿瘤抗原已被确定。在这里，我们研究了结合免疫调节单克隆抗体（mAb）与肽疫苗接种在小鼠神经母细胞瘤模型中的治疗潜力。实验设计：携带神经母细胞瘤的小鼠单独使用靶向4-1BB、CD40和CTLA-4的单抗治疗，或与肿瘤抗原survivin （GWEDPPNDI）衍生的肽联合治疗。观察survivin特异性免疫反应和治疗效果。结果：在Neuro2a模型中，用抗4- 1bb、抗cd40或抗ctla -4单抗治疗已建立的肿瘤可导致40%至60%的小鼠肿瘤消退和长期生存。这依赖于自然杀伤细胞（NK）和CD8+ T细胞，并与肿瘤CD8+淋巴细胞浸润有关。只有在肿瘤形成后给予小鼠单克隆抗体才能获得成功的治疗，这表明依赖于足够的肿瘤来提供抗原。在更具侵袭性的AgN2a和NXS2模型中，单药mAb治疗无效。然而，如果单抗（抗ctla -4）与生存素肽疫苗联合使用，则可实现60%的长期生存率。这与生存素特异性t细胞免疫的产生有关，这种免疫同样只在肿瘤抗原存在的情况下表现出来。结论：这些数据表明，抗原和共刺激单抗的组合可能提供有效的免疫治疗神经母细胞瘤，并可能特别用于最小残留疾病的设置。临床癌症研究；19 (13);3545 - 55。AACR©2013。
Purpose: Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models. Experimental Design: Neuroblastoma-bearing mice were treated with mAb targeting 4-1BB, CD40, and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy were assessed. Results: In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8+ T cells and is associated with tumor CD8+ lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single-agent mAb therapy provides ineffective therapy. However, if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination, then 60% long-term survival is achieved. This is associated with the generation of survivin-specific T-cell immunity, which again is only shown in the presence of tumor antigen. Conclusions: These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting. Clin Cancer Res; 19(13); 3545–55. ©2013 AACR.
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DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
影响因子：
11.2
作者：
F. Hirano;K. Kaneko;H. Tamura;Haidong Dong;Shengdian Wang;Masao Ichikawa;C. Rietz;D. Flies
通讯作者：
F. Hirano;K. Kaneko;H. Tamura;Haidong Dong;Shengdian Wang;Masao Ichikawa;C. Rietz;D. Flies
DOI：
10.1056/nejmoa0911123
发表时间：
2010-09-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Yu AL;Gilman AL;Ozkaynak MF;London WB;Kreissman SG;Chen HX;Smith M;Anderson B;Villablanca JG;Matthay KK;Shimada H;Grupp SA;Seeger R;Reynolds CP;Buxton A;Reisfeld RA;Gillies SD;Cohn SL;Maris JM;Sondel PM;Children's Oncology Group
通讯作者：
Children's Oncology Group
DOI：
10.1016/j.uct.2007.06.001
发表时间：
2007-06-01
期刊：
Update on cancer therapeutics
影响因子：
--
作者：
Khalil, Magi;Vonderheide, Robert H
通讯作者：
Vonderheide, Robert H