Changes of CD4+ Lymphocyte Profile in Patients with Renal Cell Carcinoma and its

肾细胞癌及其相关疾病患者CD4淋巴细胞谱的变化

• 批准号: 7481056
• 负责人: Walter J. Storkus
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7481056
• 关键词: Animals; Antigen Presentation; Antigen Presentation Pathway; Antigens; Antitumor Response; Apoptosis; Autologous; Autologous Dendritic Cells; CD4 Positive T Lymphocytes; Cell Line; Cell physiology; Clinical; Clinical Trials; Clinical Trials Design; Country; Data; Defect; Dendritic Cell Vaccine; Dendritic Cells; Development; Disease; Environment; Epitopes; Equilibrium; Exhibits; Functional disorder; Generations; Goals; Head and Neck Squamous Cell Carcinoma; Health; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Surveillance; Immunosuppression; Immunotherapy; In Vitro; Incidence; Incubated; Interleukin-15; Intralesional Injections; Investigation; Laboratories; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Modeling; Molecular; Molecular Target; Mus; Nature; No Evidence of Disease; Pathway interactions; Patients; Peptide/MHC Complex; Peptides; Phase; Predisposition; Process; Production; Randomized; Regulation; Renal Cell Carcinoma; Research Personnel; Resistance; Role; Safety; Staging; Stimulus; System; Testing; Therapeutic; Therapeutic immunosuppression; Time; Translating; Tumor Antigens; Tumor Cell Line; Tumor-Derived; Vaccination; Vaccines; Viral; antigen processing; base; cancer therapy; clinically significant; cytokine; design; flu; in vivo; insight; melanoma; mouth squamous cell carcinoma; neoplastic cell; next generation; peripheral blood; programs; response; tumor; uptake

We have previously observed a strong bias in the functional polarization of tumor-specific CD4+ T cell responses in the peripheral blood of patients with advanced stage renal cell carcinoma (RCC), cervical cancer or melanoma. Notably, patients with active disseminated disease were typically characterized by predominant Th2- or T regulatory-type immunity to tumor antigen-derived Th epitopes, while those patients successfully treated and exhibiting no evidence of disease (NED) at the time of analysis, displayed principally Th1-type immune reactivity to these same epitopes. Virtually all patients retained Th1-type immunity to viral (EBV, Flu) Th epitopes, regardless of disease stage, supporting the tumor-specific nature of immune deviation in the CD4+ T cell compartment of these cancer-bearing patients. In the current proposal, we will determine mechanism(s) underlying Th immune deviation in patients with RCC, resolve means by which to correct such deficiencies in vitro and then translate corrective therapies into a phase l/ll clinical trial designed to treat patients with advanced stage RCC. Specifically, we will: Aim 1. Test the hypothesis that tumor-specific Th1-type immune deviation in patients with advanced stage RCC involves tumor-induced alterations in the balance of DC functional subsets or DC-expressed costimulatory molecues. Aim 2. Test the hypothesis that tumor-specific Th1-type immune dysfunction in RCC patients with active disease involves the preferential apoptosis of Th1-type, but not Th2- or T regulatory-type CD4+ T cells. Aim 3. Test the hypothesis that aDC1-based vaccines can correct dysfunctional, antigen-specific Type-1 immunity in vitro. Aim 4. Test the hypothesis that aDC1/tumor peptide-based vaccination of RCC patients with advanced disease will correct dysfunctional anti-RCC Type-1 CD4+ T cell responses in a phase l/ll clinical trial.

我们之前已经观察到肿瘤特异性的CD4+T细胞的功能极化存在强烈的偏向 晚期宫颈肾癌患者外周血中的反应 癌症或黑色素瘤。值得注意的是，活动性播散性疾病患者的典型特征是 主要的Th2或T调节型免疫对肿瘤抗原衍生的Th表位，而这些患者 已成功治疗且在分析时未显示任何疾病证据(NED)，显示 主要是针对这些相同表位的Th1型免疫反应性。几乎所有患者都保留了Th1型 对病毒(EBV、流感)Th表位的免疫，不分疾病阶段，支持肿瘤特异性 这些癌症患者的CD4+T细胞间的免疫偏离。在目前的提案中， 我们将通过以下途径来确定肾癌患者Th免疫偏离的潜在机制(S)，解决办法 在体外纠正这些缺陷，然后将纠正疗法转化为L/11期临床试验 专为治疗晚期肾癌患者而设计。具体来说，我们会： 目的1.验证晚期患者肿瘤特异性Th1型免疫偏离的假设 肾癌涉及肿瘤引起的DC功能亚群平衡或DC表达的改变 共刺激分子。 目的2.验证活动期肾细胞癌患者肿瘤特异性Th1型免疫功能障碍的假说 疾病涉及Th1型细胞的优先凋亡，但不涉及Th2或T调节型CD4+T细胞的凋亡。 目的3.验证基于aDC1的疫苗可以纠正功能失调的、抗原特异性的1型疫苗的假设 体外免疫。 目的4.验证晚期肾细胞癌患者应用aDC1/肿瘤多肽疫苗的假说 疾病将在L/11期临床试验中纠正功能失调的抗RCC1型CD4+T细胞反应。