Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell-Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects
Controlled Local Delivery of CTLA-4 Blocking Antibody Induces CD8+ T-Cell-Dependent Tumor Eradication and Decreases Risk of Toxic Side Effects
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DOI：
10.1158/1078-0432.ccr-12-0781
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发表时间：
2013-10-01
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.;van der Sluis, Tetje C.;Melief, Cornelis J. M.
目的：在临床前模型和临床试验中，通过抗体阻断CTLA-4增强了抗肿瘤T细胞应答。然而，用CTLA-4阻断抗体治疗与自身免疫和炎症副作用相关。在这项研究中，我们提出了一种新的管理方法CTLA-4阻断抗体作为单一疗法。实验设计：我们使用不同的临床前小鼠癌症模型，研究局部管理CTLA-4阻断抗体及其对癌症进展和抗肿瘤T细胞反应的影响。通过在肿瘤区域注射皮下缓释递送制剂中的抗体，我们表明，低八倍剂量的抗体在诱导肿瘤根除方面与全身递送一样有效。较低剂量和缓慢释放的抗体导致血清中抗体水平降低千倍，减少不良事件和自身免疫风险。在所研究的肿瘤模型中，CTLA-4阻断治疗的主要靶细胞和效应细胞是肿瘤特异性内源性CD 8（+）T细胞，其也能够根除远处肿瘤，而CD 4（+）T细胞在抗体介导的肿瘤根除中不起显著作用。将CTLA-4阻断抗体以缓释制剂注射到肿瘤附近是激活抗肿瘤T细胞应答的有效方式。这种给药方法与非常低的血清抗体水平相关，这降低了治疗诱导的副作用的风险。这些结果要求在临床环境中探索类似的输送原理。(C)2013年AACR。
Purpose: Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy.Experimental Design: We use different preclinical mouse models of cancer to investigate the local administration of CTLA-4 blocking antibody and its effect on cancer progression and the antitumor T-cell response.Results: By injecting the antibodies in a subcutaneous slow-release delivery formulation in the tumor area, we show that an eight-fold lower dose of antibody is as effective in inducing tumor eradication as systemic delivery. A lower dose and slow release of the antibody results in thousand-fold decreased levels of antibody in the serum, reducing adverse events and the risk of autoimmunity. The main target and effector cells of the CTLA-4 blockade treatment in the studied tumor models are tumor-specific endogenous CD8(+) T cells that are capable of eradicating also distant tumors, whereas CD4(+) T cells do not play a prominent role in the antibody-mediated tumor eradication.Conclusions: Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects. These results call for exploration of a similar delivery principle in clinical settings. (C) 2013 AACR.