Multiple Antigen-Engineered DC Immunization and IFNalpha-2b Boost for Metastatic

多重抗原工程 DC 免疫和 IFNα-2b 增强治疗转移性

• 批准号: 8554630
• 负责人: Lisa Helene Butterfield
• 金额: $ 22.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-26 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554630
• 关键词: Adenoviruses; Antibodies; Antibody Formation; Antigen Presentation; Antigens; Autoimmunity; Autologous; Biological Markers; Blood; Blood Vessels; CD4 Positive T Lymphocytes; CD8B1 gene; CTAG1 gene; Cell Communication; Cell Line; Cell physiology; Cellular Immunity; Clinical; Clinical Trials; Combined Modality Therapy; Cross Presentation; Cross-Priming; DNA; Dendritic Cell Vaccine; Dendritic Cells; Engineering; Frequencies; Gene Expression; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunologics; In Vitro; Infiltration; Interferon-alpha; Lead; Length; Life; Memory; Molecular Mimicry; Monophenol Monooxygenase; Mycoplasma; NK Cell Activation; Natural Immunity; Natural Killer Cells; Outcome; Patients; Phenotype; Primary Neoplasm; Production; Prognostic Marker; Regulatory T-Lymphocyte; Role; Serum; Shapes; Signal Transduction; Skin Cancer; Staging; T cell response; T-Lymphocyte; Testing; Tumor Antibodies; Tumor Antigens; Tumor Biology; Tumor Suppression; Tumor-Derived; Vaccine Antigen; Vaccines; Variant; Viral Proteins; base; calreticulin; cell motility; cell type; cytokine; cytotoxicity; design; improved; in vivo; interleukin-12 subunit p40; melanoma; neoplastic cell; neutralizing antibody; novel; pathogen; peripheral blood; response; tumor

This project tests an improved DC vaccine which is designed to promote in vivo cross presentation and determinant spreading. Based on results from our previous trials, we have made several important improvements: engineering the DC with 3 full-length, defined, tumor antigens to activate multiple CD8* and CD4'^ T cell clones (reducing the concern for antigen loss variants); providing antigen presentation for the life of the DC; providing cognate CD4* T cell help to the CD8+ T cells ("helped" CTL); using a matured DC (a cocktail specifically matched to adenovirus (AdV) transduction signals); activating innate immunity via NK cell migration and activation; and boosting with systemic IFN alpha (for endogenous DC type 1 skewing, improved cross-priming and direct effects on T cells). Together, this vaccine strategy should more potently activate a polyclonal anti-tumor response incorporating multiple adaptive and innate effectors which we predict will lead to a higher frequency of patients who not only activate vaccine-encoded antigen-specific T cell responses, but also develop determinant spreading and a significant clinical response. The three aims are: Aim 1: Completion of the AdVTMM2/DC +/- IFN alpha clinical trial 1.a. Clinical outcomes in the stage IV patients; 1.b. Immunologic outcomes (from blood and TIL; baseline, post-vaccine and post-IFN alpha);1.c. AdV-specific cellular and humoral responses Aim 2: Mechanism and biomarkers of clinical response 2.a. DC Vaccine Transcriptional Profiling (+/- maturation, +/- AdVTMM2); 2.b. Tumor Transcriptional Profiling (baseline, post-vaccine and post-IFN alpha); 2.c. Peripheral blood signaling induced by IFN alpha (STATs); 2.d. Serum profiling (autoimmunity antibodies, LDH, CRP cytokines); 2.e. Molecular mimicry with mycoplasma (impact of baseline memory to mycoplasma); 2.f. Germline DNA SNP analysis Aim 3: Mechanism of NK cell "activation" in anti-melanoma immunity In vitro studies to expand our recent findings in AdV/DC-NK cell cross-talk with banked melanoma patient blood and tumor (primary tumor expanded to cell lines): 3.a. Direct NK cell interactions with melanoma tumor cells (cytotoxicity, cytokines); 3b: Helper/type 1 skewing role in shaping adaptive CDS* and CD4* T cell responses; 3c: Melanoma tumor impact on NK cell function.

该项目测试一种改进的DC疫苗，该疫苗旨在促进体内交叉 呈现和决定因素传播。根据我们之前的试验结果，我们已经做出了 几个重要的改进：用3个全长、已定义的肿瘤抗原来激活树突状细胞 多个CD8*和CD4‘^T细胞克隆(减少对抗原丢失变体的担忧)；提供抗原 介绍DC的生命；为CD8+T细胞提供同源的CD4*T细胞帮助(“帮助”的CTL)； 使用成熟的DC(与腺病毒(ADV)转导信号特异性匹配的鸡尾酒)；激活 通过NK细胞迁移和激活的先天免疫；以及系统干扰素α(针对内源性)的增强 DC 1型偏斜、改进的交叉启动和对T细胞的直接作用)。总而言之，这种疫苗 策略应该更有效地激活多克隆抗肿瘤反应 适应性和先天效应器，我们预测这将导致更高频率的患者 不仅激活疫苗编码的抗原特异性T细胞反应，而且还开发决定簇 扩散和显著的临床反应。 这三个目标是： 目标1：完成AdVTMM2/DC+/-干扰素α临床试验 1.a.IV期患者的临床结局；1.免疫结果(来自血液和TIL； 基线、疫苗后和干扰素后)；腺病毒特异性细胞和体液反应 目的2：临床反应的机制和生物标志物 2.a.DC疫苗转录图谱(+/-成熟，+/-AdVTMM2)；2.b.肿瘤转录本 简介(基线、疫苗接种后和干扰素α治疗后)；干扰素α诱导的外周血信号转导 (统计数据)；2.d.血清学分析(自身免疫抗体、LDH、CRP细胞因子)；分子模拟与 支原体(基线记忆对支原体的影响)；生殖系DNA SNP分析 目的3：NK细胞活化在抗黑色素瘤免疫中的作用机制 体外研究以扩大我们最近在ADV/DC-NK细胞与银行黑色素瘤患者的相互作用中的发现 血液和肿瘤(原发肿瘤扩大到细胞系)： 3.a.NK细胞与黑色素瘤细胞的直接相互作用(细胞毒性、细胞因子)；3b：辅助细胞/1型 扭曲在形成适应性CDS*和CD4*T细胞反应中的作用；3c：黑色素瘤对NK细胞的影响 功能。