Immune responses to gene-modified, autologous dendritic cell vaccines in melanoma

黑色素瘤中基因修饰的自体树突状细胞疫苗的免疫反应

基本信息

批准号：
7244117
负责人：
James William Young
金额：
$ 31.47万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244117
关键词：
Alleles Antigen Presentation Antigens Autoantigens Autologous Autologous Dendritic Cells Biological Assay CD34 gene Cell Cycle Cell surface Cells Cessation of life Class Clinical Clinical Trials Coupling Cytomegalovirus Data Dendritic Cell Vaccine Dendritic Cells Dermal Epitopes Evaluation Flow Cytometry Flu matrix protein Gene-Modified Genes Genetic Goals HLA A*0201 antigen Hematopoietic stem cells Human Immune Immune Tolerance Immune response Immunity Immunization Immunologic Monitoring Influenza Keyhole Limpet Hemocyanin Langerhans cell Length MHC Class I Genes MHC Class II Genes Malignant Neoplasms Modeling Modification Monitor Monophenol Monooxygenase Mutation Outcome Patients Peptide/MHC Complex Peptides Phase I Clinical Trials Physiologic pulse Population Process Pulse taking Relative (related person)Retroviral Vector Risk Safety Solutions Staging Standards of Weights and Measures T-Lymphocyte Testing Therapeutic Time Toxic effect Transgenes Tumor Antigens Vaccines Viral Antigens Zalcitabine base cancer cell comparative cytokine flu immunogenic improved in vivo interest interstitial melanoma monocyte pre-clinical progenitor response retroviral transduction tumor tyrosinase peptide

项目摘要

DESCRIPTION (provided by applicant): Advances in our understanding of human dendritic cells have resolved many important unknowns about the onset of immunity and how dendritic cells could control these responses against cancer. Tumor antigens are poor immunogens by themselves, because they are either self or altered-self antigens. Hence the bar to overcoming tolerance toward cancer-self antigens, while attainable, is quite high. Dendritic cells can circumvent many of these barriers by presenting tumor antigens in association with all the other requisite molecules that elicit immune reactivity. Genetic strategies offer potential advantages in coupling tumor antigens to dendritic cells. Compared with standard peptide-pulsing, multiple epitopes can be expressed by genetically modified dendritic cells, which can be processed and tailored to a variety of MHC alleles. Sustained antigen-presentation is more likely and can be monitored over time. We have generated substantial preclinical data using common viral antigens (influenza, CMV) as models, in lieu of tumor antigens. We have successfully transduced CD34+ progenitors, however, that differentiate into Langerhans- type dendritic cells and express full-length human tyrosinase, an important melanoma antigen. We now propose a human clinical trial in patients with advanced melanoma (stages III-IV). We will compare Langerhans-type dendritic cells genetically modified by retroviral transduction to express full-length human tyrosinase with Langerhans cells pulsed with the HLA-A*0201 -restricted tyrosinase peptide. Safety and toxicity will be assessed in this phase I trial. Additional response assessments include detailed immune monitoring by ELISpot. tetramer reactivity, and flow cytometry-based cytokine secretion assays, comparing post-vaccine responses with pre-treatment baselines. These studies will provide proof of principle for any advantage to sustained presentation of multiple class I and II MHC epitopes over presentation of a single class I MHC peptide to stimulate adaptive tumor-specific immunity. (LAY SUMMARY: Genetic alterations of specialized Langerhans-type dendritic cells will be tested for safety, toxicity, and the stimulation of tumor- specific immunity in patients with advanced stage III-IV melanoma.)

描述（由申请人提供）：我们对人类树突状细胞理解的进步已经解决了关于免疫的发生以及树突状细胞如何控制这些针对癌症的反应的许多重要的未知数。肿瘤抗原本身是较差的免疫原，因为它们要么是自身抗原，要么是改变的自身抗原。因此，克服对癌症自身抗原的耐受性的障碍虽然可以实现，但相当高。树突状细胞可以通过呈递肿瘤抗原以及引发免疫反应的所有其他必需分子来绕过许多这些障碍。遗传策略在肿瘤抗原与树突状细胞偶联方面提供了潜在的优势。与标准肽脉冲相比，转基因树突状细胞可以表达多个表位，并且可以针对各种 MHC 等位基因进行加工和定制。持续的抗原呈递更有可能，并且可以随着时间的推移进行监测。我们使用常见病毒抗原（流感、CMV）作为模型代替肿瘤抗原，生成了大量临床前数据。然而，我们已经成功转导了 CD34+ 祖细胞，它们分化为朗格汉斯型树突细胞并表达全长人酪氨酸酶（一种重要的黑色素瘤抗原）。我们现在提议对晚期黑色素瘤（III-IV 期）患者进行人体临床试验。我们将比较通过逆转录病毒转导进行基因修饰以表达全长人酪氨酸酶的朗格汉斯型树突细胞与用 HLA-A*0201 限制性酪氨酸酶肽脉冲的朗格汉斯细胞。安全性和毒性将在第一阶段试验中进行评估。其他反应评估包括通过 ELISpot 进行详细的免疫监测。四聚体反应性和基于流式细胞术的细胞因子分泌测定，将疫苗后反应与治疗前基线进行比较。这些研究将为持续呈递多个 I 类和 II 类 MHC 表位相对于呈递单一 I 类 MHC 肽来刺激适应性肿瘤特异性免疫的优势提供原理证明。（简单总结：将测试特化朗格汉斯型树突状细胞的基因改变的安全性、毒性以及对晚期 III-IV 期黑色素瘤患者肿瘤特异性免疫的刺激作用。）