A Potent Vaccination Strategy That Circumvents Lymphodepletion for Effective Antitumor Adoptive T-cell Therapy
A Potent Vaccination Strategy That Circumvents Lymphodepletion for Effective Antitumor Adoptive T-cell Therapy
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DOI：
10.1158/0008-5472.can-11-3246
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发表时间：
2012-04-15
期刊：
影响因子：
11.2
通讯作者：
Celis, Esteban
中科院分区：
文献类型：
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作者：
Cho, Hyun-Il;Reyes-Vargas, Eduardo;Celis, Esteban
使用肿瘤反应性T淋巴细胞的诱导细胞疗法是治疗晚期癌症的有希望的方法。成功的肿瘤根除主要取决于过继转移的T细胞的扩增和存活。使用全身照射（TBI）和施用高剂量白细胞介素（IL）-2的细胞耗竭已经与过继细胞疗法一起使用以促进T细胞扩增和存活，以实现最大的治疗效果。然而，TBI和高剂量IL-2增加了影响总生存率的主要并发症的风险。在这里，我们描述了TBI和高剂量IL-2的替代方法，用于优化过继细胞治疗，从而对小鼠中已建立的黑色素瘤产生显著的治疗效果。在过继性细胞治疗后给予有效的非感染性肽疫苗显著增加了抗原特异性T细胞的数量，从而提高了荷黑色素瘤小鼠的存活率。此外，肽疫苗接种与PD 1阻断或IL-2/抗IL-2抗体复合物的组合导致接受过继性细胞治疗的具有大肿瘤的小鼠的完全疾病根除和长期存活。我们的研究结果表明，PD 1阻断和IL-2/抗IL-2复合物增强了过继细胞治疗后肽疫苗接种诱导的T细胞应答的定量和定性方面。这些发现可能有助于优化癌症患者的过继细胞治疗，而无需毒性辅助程序。癌症研究; 72（8）; 1986-95。(C)2012年AACR。
Adoptive cell therapy using tumor-reactive T lymphocytes is a promising approach for treating advanced cancer. Successful tumor eradication depends primarily on the expansion and survival of the adoptively transferred T cells. Lymphodepletion using total body irradiation (TBI) and administering high-dose interleukin (IL)-2 have been used with adoptive cell therapy to promote T-cell expansion and survival to achieve maximal therapeutic effects. However, TBI and high-dose IL-2 increase the risk for major complications that impact overall survival. Here we describe an alternative approach to TBI and high-dose IL-2 for optimizing adoptive cell therapy, resulting in dramatic therapeutic effects against established melanomas in mice. Administration of a potent, noninfectious peptide vaccine after adoptive cell therapy dramatically increased antigen-specific T-cell numbers leading to enhancement in the survival of melanoma-bearing mice. Furthermore, combinations of peptide vaccination with PD1 blockade or IL-2/anti-IL-2 antibody complexes led to complete disease eradication and long-term survival in mice with large tumors receiving adoptive cell therapy. Our results indicate that PD1 blockade and IL-2/anti-IL-2 complexes enhance both the quantitative and qualitative aspects of the T-cell responses induced by peptide vaccination after adoptive cell therapy. These findings could be useful for the optimization of adoptive cell therapy in cancer patients without the need of toxic adjunct procedures. Cancer Res; 72(8); 1986-95. (C) 2012 AACR.