INVARIANT CHAIN BASED VACCINE STRATEGIES

我们实验室最近的研究已经确定了一种独特的T细胞识别抗原的模式，这种模式可能适用于增强对肿瘤相关抗原的特异性识别。我们的研究表明，来自环孢素诱导的自体移植物抗宿主病的自身反应性T细胞识别MHC II类不变链中的一种多肽，称为CLIP。虽然自身反应性T细胞部分地通过经典机制识别CLIP，但在CLIP的N末端侧翼区域之间似乎也存在一种功能性的超抗原样相互作用，该作用延伸到MHC II类分子的多肽结合槽和T细胞受体的Vbeta片段之外。初步研究表明，将CLIP的这一侧翼区域添加到标称抗原肽上，可增强其免疫原性。因此，这一建议的中心假设是，通过增加CLIP的N-末端侧翼区域来修饰肿瘤多肽将增强它们的免疫原性，并激发强大的抗肿瘤免疫反应。目前的研究将集中在癌基因C-erb B-2，也被称为HER-2/neu的多肽作为模型系统。这种癌基因在乳腺癌患者中会引起微弱但无效的免疫反应。由于大鼠与人类HER-2/neu有显著的同源性，将利用大鼠模型来检验这一假说。HER-2/neu与CLIP的N端侧翼区的嵌合构建物将被用作疫苗。最佳剂量和疫苗配方(佐剂、多肽负载肿瘤细胞、多肽负载树突状细胞)将被确定，以评估抗体产生和CD4+和CD8+依赖的细胞免疫，以及该疫苗策略是否引起有效的抗肿瘤反应。这些研究将确定新的策略来增强肿瘤多肽的免疫原性，这些多肽可能广泛适用于许多不同类型的癌症。

Recent studies in our laboratory have identified a unique mode of antigen recognition by T cells that may be adapted to augment specific recognition of tumor-associated antigens. Our studies have shown that the autoreactive T cells from Cyclosporine-induced autologous graft-vs-host disease recognize a peptide from the MHC class II invariant chain termed CLIP. Although the autoreactive T cells recognize CLIP, in part, via a classic mechanism, there also appears to be a functional superantigen-like interaction betwteen the N-terminal flanking region of CLIP that extends beyond the peptide binding groove of MHC class II and the Vbeta segment of the T cell receptor. Preliminary studies show that the addition of this flanking region of CLIP onto nominal antigenic peptides enhances their immunogenicity. The central hypothesis of this proposal, therefore, is that modification of tumor peptides by adding the N-terminal flanking region of CLIP will augment their immunogenicity and evoke a potent antitumor immune response. The present studies will focus on peptides from the oncogene, C-erbB-2 also known as Her-2/neu as a model system. This oncogene evokes a weak but ineffective immune response in patients with breast cancer. A rat model will be utilized to test this hypothesis since there is significant homology between rat and human Her-2/neu. Chimeric constructs of Her-2/neu with the N-terminal flanking region of CLIP will be utilized as a vaccine. The optimal dose and vaccine formulation (adjuvant, peptide loaded tumor cells, peptide loaded dendritic cells) that elicit the maximum immune response will be identified assessing antibody production and CD4+ and CD8+ dependent cellular immunity and whether this vaccine strategy evokes a potent antitumor response. These studies will identify novel strategies to enhance the immunogenicity of tumor peptides that may be broadly applicable to many different types of cancer.