Influence of structurally related self-peptides on T cell-mediated therapies

 描述(由申请人提供)：癌症逃避免疫系统的部分原因是患者的T细胞已经对潜在的抗原产生了耐受。两种基于免疫的策略试图克服这一问题：一种是将癌症多肽抗原用作疫苗，另一种是将癌症抗原特异性T细胞受体(TCR)引入患者的 T细胞，体外激活(即过继T细胞疗法)。TCRs与自身的交叉反应性 与癌症多肽抗原结构相似的多肽将对这两种方法产生影响。我们最近对人类蛋白质组进行了电子分析，以检查已知癌症抗原集合中每个肽的结构相似的、与HLA-A2结合的多肽的数量。我们的分析表明，不同的癌症多肽在结构相似的多肽的数量上存在100倍的差异。对小鼠蛋白质组的分析表明，这些结构相似的多肽中有40%-60%在两个物种中是相同的。基于这些发现，我们相信我们可以使用人类白细胞抗原A2转基因小鼠模型来实验测试与这两种基于免疫的癌症疗法直接相关的两个假说。首先，针对特定癌症抗原的结构相似的自体多肽的频率将影响T细胞耐受的程度。其次，蛋白质组中结构相似的自体多肽的频率越高，在过继T细胞方法中，特别是对于亲和力较高的TCR，将增加脱靶交叉反应的可能性。具体目的是：1.确定与人类白细胞抗原-A2多肽结合的蛋白质组对CD8+T细胞谱系和耐受性的影响。目的2.确定TCR亲和力与多肽交叉反应的关系。目的3.评价TCR转导的T细胞在人类白细胞抗原A2转基因小鼠体内的安全性和有效性。

 DESCRIPTION (provided by applicant): Cancer evades the immune system in part because a patient's T cells have been tolerized against potential antigens. Two immune-based strategies attempt to overcome this problem: one involves cancer peptide antigens used as vaccines and the other involves introduction of a cancer-antigen specific T cell receptor (TCR) into a patient's T cells, activated ex vivo (i.e. adoptive T cell therapies). The cross-reactivity of TCRs with self peptides that are structurally similar to the cancer peptide antigen will impact both of these approaches. We have recently conducted an in silico analysis of the human proteome to examine the number of structurally similar, HLA-A2-binding peptides, for each peptide among a collection of known cancer antigens. Our analysis revealed that that there was a 100-fold range of differences among cancer peptides in the number of such structurally similar peptides. Analysis of the mouse proteome showed that 40-60% of these structurally similar peptides were identical in both species. Based on these findings, we believe that we can use HLA-A2 transgenic mouse models to experimentally test two hypotheses that are directly relevant to these two immune-based cancer therapies. First, that the frequency of structurally similar self-peptides for a particular cancer antigen will influence the extent of T cell tolerance. Second, tha a higher frequency of structurally similar self-peptides in a proteome will increase the potential for off-target cross-reactivity in adoptive T cell approaches, especially with higher affinity TCRs The specific aims are: Aim 1. To determine the impact of the HLA-A2-peptide binding proteome on CD8+ T cell repertoires and tolerance. Aim 2. To determine the relationship between TCR affinity and peptide cross-reactivity. Aim 3. To perform a safety and efficacy assessment of TCR-transduced T cells in HLA-A2 transgenic mice.