Mirshahidi Saied, Kramer Victor G, Whitney James B, Essono Sosthène, Lee Sandra, Dranoff Glenn, Anderson Karen S, Ruprecht Ruth M
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, United States.
Vaccine. 2009 Mar 13;27(12):1825-33. doi: 10.1016/j.vaccine.2009.01.089. Epub 2009 Feb 6.
Peptide-based vaccines, one of several anti-tumor immunization strategies currently under investigation, can elicit both MHC Class I-restricted (CD8(+)) and Class II-restricted (CD4(+)) responses. However, the need to identify specific T-cell epitopes in the context of MHC alleles has hampered the application of this approach. We have tested overlapping synthetic peptides (OSP) representing a tumor antigen as a novel approach that bypasses the need for epitope mapping, since OSP contain all possible epitopes for both CD8(+) and CD4(+) T cells. Here we report that vaccination of inbred and outbred mice with OSP representing tumor protein D52 (TPD52-OSP), a potential tumor antigen target for immunotherapy against breast, prostate, and ovarian cancer, was safe and induced specific CD8(+) and CD4(+) T-cell responses, as demonstrated by development of specific cytotoxic T cell (CTL) activity, proliferative responses, interferon (IFN)-gamma production and CD107a/b expression in all mice tested. In addition, TPD52-OSP-vaccinated BALB/c mice were challenged with TS/A breast carcinoma cells expressing endogenous TPD52; significant survival benefits were noted in vaccine recipients compared to unvaccinated controls (p<0.001). Our proof-of-concept data demonstrate the safety and efficacy of peptide library-based cancer vaccines that obviates the need to identify epitopes or MHC backgrounds of the vaccinees. We show that an OSP vaccination approach can assist in the disruption of self-tolerance and conclude that our approach may hold promise for immunoprevention of early-stage cancers in a general population.
基于肽的疫苗是目前正在研究的几种抗肿瘤免疫策略之一，它可以引发主要组织相容性复合体（MHC）I类限制性（CD8(+)）和II类限制性（CD4(+)）反应。然而，在MHC等位基因背景下识别特定T细胞表位的需求阻碍了这种方法的应用。我们测试了代表肿瘤抗原的重叠合成肽（OSP），作为一种绕过表位映射需求的新方法，因为OSP包含CD8(+)和CD4(+) T细胞的所有可能表位。在此我们报告，用代表肿瘤蛋白D52（TPD52 - OSP）的OSP对近交和远交小鼠进行疫苗接种是安全的，并诱导了特异性CD8(+)和CD4(+) T细胞反应，在所有测试小鼠中，通过特异性细胞毒性T细胞（CTL）活性的发展、增殖反应、干扰素（IFN）-γ产生和CD107a/b表达得以证明。此外，用TS/A乳腺癌细胞对内源性表达TPD52的接种了TPD52 - OSP的BALB/c小鼠进行攻击；与未接种疫苗的对照相比，疫苗接种小鼠有显著的生存获益（p<0.001）。我们的概念验证数据证明了基于肽库的癌症疫苗的安全性和有效性，该疫苗无需识别接种者的表位或MHC背景。我们表明OSP疫苗接种方法可以帮助打破自身耐受性，并得出结论，我们的方法可能对普通人群早期癌症的免疫预防具有前景。
