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

结构相关的自肽对 T 细胞介导的治疗的影响

• 批准号: 8958983
• 负责人: David M. Kranz
• 金额: $ 16.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958983
• 关键词: Address; Adverse effects; Affinity; Alanine; Antigens; Autoimmunity; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cessation of life; Clinical Trials; Collection; Computer Simulation; Engineering; Frequencies; Goals; HLA-A2 Antigen; Human; Immune; Immune system; Immunization; In Vitro; Letters; Malignant Neoplasms; Mediating; Mus; Normal tissue morphology; Pathologist; Pathology; Patients; Peptides; Peripheral; Probability; Proteome; Published Comment; Risk; Safety; Sensitivity and Specificity; Specificity; Staining method; Stains; System; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transgenic Mice; Transgenic Organisms; Vaccines; Variant; Virus; WT1 gene; Work; base; cancer cell; cancer therapy; cross reactivity; interest; mouse model; public health relevance; response; survivin; tumor

 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.

 描述（由申请人提供）：癌症逃避免疫系统，部分原因是患者的T细胞已对潜在抗原产生耐受性。两种基于免疫的策略试图克服这个问题：一种涉及用作疫苗的癌肽抗原，另一种涉及将癌症抗原特异性T细胞受体（TCR）引入患者的体内 T细胞，离体活化（即过继性T细胞疗法）。TCR与自身抗体的交叉反应性 与癌肽抗原结构相似的肽将影响这两种方法。我们最近进行了人体蛋白质组的计算机分析，以检查已知癌症抗原集合中每种肽的结构相似的HLA-A2结合肽的数量。我们的分析表明，在癌症肽中，这种结构相似的肽的数量存在100倍的差异。对小鼠蛋白质组的分析表明，40-60%的这些结构相似的肽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HLA-A2转基因小鼠模型来实验性地测试与这两种基于免疫的癌症疗法直接相关的两种假设。首先，对于特定的癌抗原，结构相似的自身肽的频率将影响T细胞耐受性的程度。第二，蛋白质组中结构相似的自身肽的较高频率将增加过继性T细胞方法中脱靶交叉反应性的可能性，特别是对于较高亲和力的TCR。确定HLA-A2肽结合蛋白质组对CD 8 + T细胞库和耐受性的影响。目标2.确定TCR亲和力与肽交叉反应性之间的关系。目标3.在HLA-A2转基因小鼠中进行TCR转导的T细胞的安全性和有效性评估。