Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors
Peptide vaccine given with a Toll-like receptor agonist is effective for the treatment and prevention of spontaneous breast tumors
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DOI：
10.1158/0008-5472.can-06-3290
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发表时间：
2007-02-01
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：
Nava-Parada, Pilar;Forni, Guido;Celis, Esteban
我们的目标是开发肽疫苗，刺激针对常见癌症的肿瘤抗原特异性T细胞反应。先前的工作已经表明，为了产生有效的T细胞应答，肽必须与强佐剂如Toll样受体激动剂组合施用。然而，大多数用于研究肽疫苗的动物肿瘤模型系统并不能真正代表人类的恶性疾病，因为它们仅使用可移植的肿瘤系，并且使用高免疫原性的外源蛋白，而不是真正的肿瘤抗原。在这里，我们描述了一种肽疫苗接种策略，这是非常有效的延迟或预防自发性乳腺肿瘤的发生。携带活化的大鼠HER-2/neu癌基因的转基因雌性BALB-neuT小鼠用来自大鼠HER-2/neu基因产物的合成肽与Toll样受体激动剂佐剂组合接种，所述合成肽代表CTL的表位。我们的研究结果表明，为了获得肿瘤抗原特异性CTL应答和抗肿瘤效应，疫苗必须重复施用，或者必须用抗CD 25抗体治疗来阻断CD 4/CD 25调节性T细胞的功能。用这种方法接种的小鼠保持无肿瘤或能够控制自发肿瘤生长，并表现出持久的CTL应答，不仅针对免疫肽，而且针对衍生自大鼠HER-2/neu产物的其他肽（即，表位扩展）。这些结果表明，在患者中进行临床研究时应遵循类似的策略。
Our goal is to develop peptide vaccines that stimulate tumor antigen-specific T-cell responses against frequently found cancers. Previous work has shown that to generate effective T-cell responses, peptides have to be administered in combination with strong adjuvants such as Toll-like receptor agonists. However, most animal tumor model systems used to study peptide vaccines were not truly representative of malignant diseases in humans because they solely used transplantable tumor lines, and instead of true tumor antigens, they used highly immunogenic foreign proteins. Here, we describe a peptide vaccination strategy, which is highly effective in delaying or preventing the occurrence of spontaneous breast tumors. Transgenic female BALB-neuT mice that carry the activated rat HER-2/neu oncogene were vaccinated with a synthetic peptide from the rat HER-2/neu gene product, which represents an epitope for CTLs in combination with a Toll-like receptor agonist adjuvant. Our results show that to obtain tumor antigen-specific CTL responses and antitumor effects, the vaccine had to be administered repetitively, or the function of CD4/CD25 T regulatory cells had to be blocked with anti-CD25 antibody therapy. Mice that were vaccinated with this approach remained tumor-free or were able to control spontaneous tumor growth and exhibited long-lasting CTL responses, not only against the immunizing peptide but also against other peptides derived from rat HER-2/neu product (i.e., epitope spreading). These results suggest that similar strategies should be followed for conducting clinical studies in patients.