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

基本信息

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
项目类别：
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

项目摘要

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.

该项目测试了改进的直流疫苗，旨在促进体内交叉演示和决定因素扩散。根据我们以前的试验的结果，我们做出了一些重要的改进：使用3个全长定义的肿瘤抗原来激活DC 多个CD8*和CD4'^ T细胞克隆（减少了对抗原损失变体的关注）；提供抗原演讲DC的生活；为CD4+ T细胞提供同源CD4* T细胞帮助（“帮助” CTL）；使用成熟的直流（专门匹配腺病毒（ADV）转导信号的鸡尾酒）；激活通过NK细胞迁移和激活的先天免疫；并用全身IFN alpha提升（用于内源性 DC 1型偏斜，改善了交叉染色和对T细胞的直接影响）。在一起，这种疫苗策略应更有效地激活多种多种抗肿瘤响应我们预测的自适应和先天效应子将导致较高的患者频率仅激活疫苗编码的抗原特异性T细胞反应，但也会发展出决定因素扩散和明显的临床反应。这三个目标是：目标1：完成Advtmm2/DC +/- IFN alpha临床试验 1.A. IV阶段患者的临床结果； 1.B.免疫结局（来自血液和TIL；基线，疫苗后和IFN后alpha）; 1.c。 ADV特定的细胞和体液反应目标2：临床反应的机制和生物标志物 2.A.直流疫苗的转录分析（+/-成熟，+/- advtmm2）; 2.B.肿瘤转录分析（基线，疫苗后和IFN后alpha）； 2.C。 IFNα引起的外周血信号传导（统计）; 2.D.血清分析（自身免疫性抗体，LDH，CRP细胞因子）； 2.e。分子模仿支原体（基线记忆对支原体的影响）； 2.F。种系DNA SNP分析 AIM 3：抗黑色素瘤免疫力中NK细胞“激活”的机制体外研究以扩大我们在ADV/DC-NK细胞串扰中与银行黑色素瘤患者的发现血液和肿瘤（原发性肿瘤扩展到细胞系）： 3.A.直接NK细胞与黑色素瘤肿瘤细胞的相互作用（细胞毒性，细胞因子）； 3B：辅助/类型1 在塑造自适应CD*和CD4* T细胞响应中偏斜的作用； 3C：黑色素瘤对NK细胞的影响功能。