Local Activation of CD8 T Cells and Systemic Tumor Eradication without Toxicity via Slow Release and Local Delivery of Agonistic CD40 Antibody
Local Activation of CD8 T Cells and Systemic Tumor Eradication without Toxicity via Slow Release and Local Delivery of Agonistic CD40 Antibody
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DOI：
10.1158/1078-0432.ccr-10-2888
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发表时间：
2011-04-15
影响因子：
11.5
通讯作者：
Melief, Cornelis J. M.
中科院分区：
文献类型：
--
作者：
Fransen, Marieke F.;Sluijter, Marjolein;Melief, Cornelis J. M.
目的：抗CD 40激动性抗体抗肿瘤的免疫疗法已在临床前动物模型中广泛研究，最近也在临床试验中进行了研究。虽然已经获得了有希望的结果，但抗体（Ab）相关的毒性一直是限制因素。我们推断，通过刺激肿瘤区域中树突状细胞（DC）上的CD 40而排除全身刺激来严格局部激活肿瘤特异性CD 8 T细胞可能足以有效根除肿瘤并且可以限制全身毒性。免疫原性肿瘤的临床前体内模型用于研究递送无毒剂量的激动性抗肿瘤药物的潜力。结果：在缓释Montanide伊萨-51中配制的抗CD 40单克隆抗体的递送通过诱导局部而非全身DC活化来重编程CTL，导致有效的肿瘤特异性CTL应答，其根除局部和远处肿瘤。通过器官组织学和血液中的肝酶测定，局部抗CD 40 Ab给药后的不良副作用远低于全身给药。抗CD 40抗体的局部递送仅激活针对肿瘤引流区域中呈递的抗原的CTL，因为表达不同肿瘤抗原的不相关的远处肿瘤不能被根除。这些结果建立了一种新的治疗原理，即局部递送和缓慢释放激动性抗CD 40 Ab至肿瘤引流区域有效地激活局部肿瘤。特异性CD 8 T细胞成为全身效应物，而不引起全身毒性或非特异性CTL活化。这些发现对患者使用抗CD 40治疗具有重要意义。临床癌症研究; 17（8）; 2270-80。(C)2011年AACR。
Purpose: Immunotherapy against tumors with anti-CD40 agonistic antibodies has been extensively studied in preclinical animal models and recently also in clinical trials. Although promising results have been obtained, antibody (Ab)-related toxicity has been a limiting factor. We reasoned that strict local activation of tumor-specific CD8 T cells through stimulation of CD40 on the dendritic cells (DC) in the tumor area while excluding systemic stimulation might be sufficient for effective tumor eradication and can limit systemic toxicity.Experimental Design: Preclinical in vivo models for immunogenic tumors were used to investigate the potential of delivering a nontoxic dose of agonistic anti-CD40 Ab to the tumor region, including draining lymph node, in a slow-release formulation (montanide).Results: The delivery of anti-CD40 monoclonal Ab, formulated in slow-release Montanide ISA-51, reprograms CTLs by inducing local but not systemic DC activation, resulting in effective tumor-specific CTL responses that eradicate local and distant tumors. Adverse side effects, assayed by organ histology and liver enzymes in the blood, were much lower after local anti-CD40 Ab delivery than systemic administration. The local delivery of anti-CD40 Ab activates only CTLs against antigens presented in the tumor-draining area, because unrelated distant tumors expressing different tumor antigens were not eradicated.Conclusions: These results establish a novel therapeutic principle that local delivery and slow release of agonistic anti-CD40 Ab to the tumor-draining area effectively activates local tumor-specific CD8 T cells to become systemic effectors without causing systemic toxicity or nonspecific CTL activation. These findings have important implications for the use of anti-CD40 therapies in patients. Clin Cancer Res; 17(8); 2270-80. (C) 2011 AACR.