Peptide Vaccination after T-Cell Transfer Causes Massive Clonal Expansion, Tumor Eradication, and Manageable Cytokine Storm
Peptide Vaccination after T-Cell Transfer Causes Massive Clonal Expansion, Tumor Eradication, and Manageable Cytokine Storm
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DOI：
10.1158/0008-5472.can-10-2288
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
van Hall, Thorbald
中科院分区：
文献类型：
--
作者：
Ly, Long V.;Sluijter, Marjolein;van Hall, Thorbald
连续性T细胞转移（ACT）成功地应用于基于肿瘤特异性T细胞的活化和效应功能的癌症治疗。在这里，我们目前的结果从一个小鼠模型中，ACT是与一个长的肽为基础的疫苗，包括gp 100 T细胞表位相结合。在肽疫苗接种后，转移的CD 8（+）T细胞扩增高达1，000倍，导致白色血细胞计数增加3倍，并且抗原特异性记忆T细胞的产生频率非常高，其产生往往与有效的抗肿瘤应答相关。大量效应T细胞广泛分布到不同的组织，包括皮肤和免疫特权眼，它们在那里介导肿瘤根除。重要的是，这些惊人的T细胞动力学发生在免疫功能正常的小鼠中，而没有预先进行血液学调节。通过疫苗接种持续激活特异性T细胞库导致强烈的T细胞介导的细胞因子风暴和由于多器官衰竭的致死性。然而，这种免疫病理学可以通过控制肽的快速生物分布或通过使用弱激动肽来预防。总之，这些结果确定了一种肽疫苗接种策略，可以有效地加强有效的ACT在非淋巴细胞耗竭的主机。Cancer Res; 70（21）; 8339-46. (C)2010年AACR。
Adoptive T-cell transfer (ACT) is successfully applied as a cancer treatment that is based on the activation and effector functions of tumor-specific T cells. Here, we present results from a mouse model in which ACT is combined with a long peptide-based vaccine comprising gp100 T-cell epitopes. Transferred CD8(+) T cells expanded up to 1,000-fold after peptide vaccination, leading to a 3-fold increase in white blood cell count and a very high frequency in the generation of antigen-specific memory T cells, the generation of which tended to correlate with effective antitumor responses. An enormous pool of effector T cells spread widely to different tissues, including the skin and the immune-privileged eye, where they mediate tumor eradication. Importantly, these striking T-cell dynamics occurred in immunocompetent mice without prior hematologic conditioning. Continued activation of the specific T-cell pool by vaccination led to strong T-cell-mediated cytokine storm and lethality due to multi-organ failure. However, this immunopathology could be prevented by controlling the rapid biodistribution of the peptide or by using a weakly agonistic peptide. Together, these results identify a peptide vaccination strategy that can potently accentuate effective ACT in non-lymphodepleted hosts. Cancer Res; 70(21); 8339-46. (C) 2010 AACR.