Optimized Peptide Vaccines Eliciting Extensive CD8 T-Cell Responses with Therapeutic Antitumor Effects
Optimized Peptide Vaccines Eliciting Extensive CD8 T-Cell Responses with Therapeutic Antitumor Effects
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DOI：
10.1158/0008-5472.can-09-2019
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Celis, Esteban
中科院分区：
文献类型：
--
作者：
Cho, Hyun-Il;Celis, Esteban
开发有效的癌症治疗疫苗的一个主要挑战是克服对恶性细胞和正常组织上表达的肿瘤相关抗原的免疫耐受。在此，我们描述了一种新的疫苗接种方法 TriVax，该方法使用代表 CD8 T 细胞表位的合成肽、作为有效免疫佐剂的 Toll 样受体激动剂和共刺激抗 CD40 抗体来产生大量能够识别和杀死肿瘤细胞的高亲和力抗原反应性 T 细胞。我们的结果表明，TriVax 诱导大量持久的抗原特异性 CD8 T 细胞，在体内表现出显着的抗肿瘤作用。施用含有源自黑素体抗原 (Trp2(180-188)) 的 CD8 T 细胞表位的 TriVax 制剂可引发抗原特异性 CD8 T 细胞，从而诱导全身性自身免疫（白癜风）。更重要的是，TriVax 免疫可有效引发有效的保护性抗肿瘤免疫，并对已确定的 B16 黑色素瘤具有显着的治疗效果。这种治疗作用是由 CD8 T 细胞通过穿孔素介导的裂解介导的，并且需要 I 型 IFN 的参与，而不是 IFN γ 的参与。这些结果表明，类似的策略适用于设计有效的疫苗接种，以在癌症患者中进行临床研究。 [癌症研究 2009;69(23):9012-9]
A major challenge for developing effective therapeutic vaccines against cancer is overcoming immunologic tolerance to tumor-associated antigens that are expressed on both malignant cells and normal tissues. Herein, we describe a novel vaccination approach, TriVax, that uses synthetic peptides representing CD8 T-cell epitopes, Toll-like receptor agonists that function as potent immunologic adjuvants and costimulatory anti-CD40 antibodies to generate large numbers of high-avidity antigen-reactive T cells capable of recognizing and killing tumor cells. Our results show that TriVax induced huge numbers of long-lasting antigen-specific CD8 T cells that displayed significant antitumor effects in vivo. The administration of a TriVax formulation containing a CD8 T-cell epitope derived from a melanosomal antigen (Trp2(180-188)) elicited antigen-specific CD8 T cells that induced systemic autoimmunity (vitiligo). More important, TriVax immunization was effective in eliciting potent protective antitumor immunity as well as remarkable therapeutic effects against established B16 melanoma. This therapeutic effect was mediated by CD8 T cells via perforin-mediated lysis and required the participation of type-I IFN but not IFN gamma. These results suggest that similar strategies would be applicable for the design of effective vaccination for conducting clinical studies in cancer patients. [Cancer Res 2009;69(23):9012-9]