Onodi Fanny, Maherzi-Mechalikh Chahrazed, Mougel Alice, Ben Hamouda Nadine, Taboas Charlotte, Gueugnon Fabien, Tran Thi, Nozach Herve, Marcon Elodie, Gey Alain, Terme Magali, Bouzidi Ahmed, Maillere Bernard, Kerzerho Jérôme, Tartour Eric, Tanchot Corinne
INSERM U970, PARCC (Paris-Cardiovascular Research Center), Paris, France.
Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Front Oncol. 2018 Nov 13;8:517. doi: 10.3389/fonc.2018.00517. eCollection 2018.
The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4 and CD8 T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4 and CD8 T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8 and multifunctional Th1 CD4 T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4 and CD8 T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development.
抗肿瘤疫苗的疗效既取决于所靶向抗原的选择，也取决于其设计。肿瘤抗原生存素是开发治疗性癌症疫苗的一个有吸引力的靶点，因为它在大多数人类肿瘤中过度表达且具有重要功能。因此，已经开展了多项针对不同癌症适应症中生存素的临床试验。其中大多数依赖基于短肽的疫苗，显示出有前景但有限的临床结果。在本研究中，我们调查了一种基于新型长合成肽（LSP）的靶向肿瘤抗原生存素（SVX）的癌症疫苗的免疫原性和治疗效果。这种SVX疫苗由三种包含多个CD4和CD8 T细胞表位的长合成肽组成，这些肽可与多种HLA II类和I类分子结合。在健康个体中的研究表明，无论个体的HLA类型如何，SVX肽在人体中都具有CD4和CD8 T细胞免疫原性。重要的是，在各种癌症患者的血液中也检测到了针对SVX肽的高频率自发T细胞前体，这表明对这些肽不存在耐受性。然后，我们证明了SVX疫苗对四种不同的已建立的小鼠肿瘤模型具有高治疗效果，这与其产生特异性细胞毒性CD8和多功能Th1 CD4 T细胞反应的能力相关。当肿瘤被根除时，产生的记忆T细胞反应可防止再次攻击，从而实现对复发的长期保护。还发现用SVX疫苗治疗可通过增加CD4和CD8 T细胞而非调节性T细胞的肿瘤浸润来重塑肿瘤微环境，因此使平衡向高效免疫反应倾斜。这些结果突出表明，这种基于LSP的SVX疫苗似乎是一种有前景的癌症疫苗，值得进一步开展临床研究。
