Use of Allogenicity to Stimulate Effector Responses Against Multiple Myeloma

利用同种异体刺激针对多发性骨髓瘤的效应反应

基本信息

批准号：
8319972
负责人：
Christina N Johnson
金额：
$ 4.72万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-17 至 2015-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319972
关键词：
Address Affect Affinity African American Alleles Allogenic Allogenicity Amino Acids Antigen-Presenting Cells Antigens Autologous Binding Bioinformatics Biological Assay Bone Marrow Cancerous Caucasians Caucasoid Race Cell Line Cells Coculture Techniques Complex Computer Simulation Cytotoxic T-Lymphocytes Death Rate Development Disease Disease remission Engineering Exhibits Gene Frequency Genetic Genetic Polymorphism Genetic Variation Goals HLA Antigens Hematopoietic stem cells Immune response Immunotherapy In Vitro Incidence Interferon Type II Lentivirus Vector Malignant Neoplasms Methodology Modeling Molecular Molecular Biology Molecular Biology Techniques Molecular Models Morbidity - disease rate Multiple Myeloma Peptides Plasma Cells Population Prevalence Proteins Recombinants Resources Site-Directed Mutagenesis Subfamily lentivirinae System T cell response T-Cell Activation T-Lymphocyte Techniques Testing Therapeutic Tissue Culture Techniques Tumor Antigens United States Variant cancer statistics cytotoxic design and construction health disparity immunogenic in vivo knowledge base model design molecular modeling mortality neoplasm registry novel overexpression programs response tumor vector

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a bone marrow plasma cell cancer with a mortality rate greater than 50%1. According to the National Program of Cancer Registries United States Cancer Statistics, both incidence and death rates among African-Americans were approximately twice that seen in the other ethnic populations2. It is therefore important to examine those factors unique to this population which may contribute to the unequal rates of morbidity and mortality associated with this disease. Of the available treatments for MM, remission has primarily been observed following autologous and allogeneic hematopoietic stem cell transplantation3,4. Immunotherapy strategies have also been developed. For example, the human leukocyte antigen (HLA)-A2 restricted MM-associated protein HM1.24, which is overexpressed in Multiple myeloma cells, has been shown to stimulate interferon gamma expression by myeloma-specific cytotoxic T lymphocytes (CTLs)7. However, at present, these therapeutic approaches alone do not consistently elicit antitumor cytotoxic effects in in vitro or in vivo studies8,9. This is due, in part, to the lack of understanding of te factors which contribute to T cell activation in the largely tolerizing tumor setting, such as allogenicity. However, the greater diversity of HLA polymorphisms in African-Americans provides a unique resource for interrogating the biophysical underpinnings of HLA restriction in targeted tumor immunotherapies for diseases such as MM. The general objective of the project detailed in this proposal is to determine the effect of allogeneic variation in HLA-A2 on the induction of CTLs to immunodominant peptides of the HM1.24 antigen. The prevalence of certain HLA-A2 alleles may differ between African-Americans and Caucasians, and it is possible that these differences contribute to different responses against HLA-A2-restricted tumor associated antigens. Thus, in Aim 1, the most prevalent HLA-A class I alleles within the African-American population will be identified. Immunogenic peptides of MM HM1.24 specific for those alleles will be determined by in silico analysis. This will be used in Aim 2 to design and construct structurally allogeneic variants of HLA-A2-HM1.24 complexes by molecular modeling and molecular biology techniques. Finally, in Aim 3, to investigate the impact of allogeneic variation on CTL responses, the complexes will be delivered to antigen presenting cells using a novel application of the lentiviral vector system. The APCs will then be co-cultured with HLA-A2-restricted, HM1.24-specific CTLs in CTL effector assays. The hypothesis being tested is that allogeneic variants of this MM associated HLA-peptide complex can be engineered to augment CTL responses. This project utilizes bioinformatics, molecular biology, and tissue culture techniques to address how biophysical and genetic components of HLA-A2-peptide complexes contribute to the allogeneic responses of T cells. Ultimately, this project seeks to contribute to the knowledge base currently being used to develop immunotherapies for diseases such as MM, specifically in populations which demonstrate well-documented health disparities. PUBLIC HEALTH RELEVANCE: Multiple myeloma is a destructive plasma cell cancer which disproportionately affects African-Americans and for which no definitive cure exists. This project may contribute a putative model for designing and optimizing vectors which uses the genetic variation within the African-American population to promote anti-cancer immune responses. This model could perhaps be used to develop personalized therapies for diseases such as Multiple myeloma, which exhibit health disparities in unique populations.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种骨髓浆细胞癌，死亡率大于 50%1。根据美国癌症登记国家计划的癌症统计数据，非洲裔美国人的发病率和死亡率大约是其他种族人群的两倍2。因此，重要的是检查该人群特有的因素，这些因素可能导致与该疾病相关的发病率和死亡率不平等。在 MM 的可用治疗中，主要在自体和异体造血干细胞移植后观察到缓解3,4。免疫治疗策略也已被开发出来。例如，人类白细胞抗原 (HLA)-A2 限制性 MM 相关蛋白 HM1.24 在多发性骨髓瘤细胞中过度表达，已被证明可以刺激骨髓瘤特异性细胞毒性 T 淋巴细胞 (CTL)7 的干扰素 γ 表达。然而，目前，在体外或体内研究中，这些治疗方法本身并不能始终如一地引起抗肿瘤细胞毒性作用8,9。这在一定程度上是由于缺乏对在很大程度上耐受的肿瘤环境中促进 T 细胞激活的因素的了解，例如同种异体。然而，非洲裔美国人中 HLA 多态性的多样性为探究 MM 等疾病的靶向肿瘤免疫疗法中 HLA 限制的生物物理学基础提供了独特的资源。该提案中详述的项目的总体目标是确定 HLA-A2 中的同种异体变异对诱导 CTL 生成 HM1.24 抗原的免疫显性肽的影响。非洲裔美国人和白种人之间某些 HLA-A2 等位基因的流行率可能有所不同，这些差异可能导致针对 HLA-A2 限制性肿瘤相关抗原的不同反应。因此，在目标 1 中，将鉴定非裔美国人群体中最常见的 HLA-A I 类等位基因。将通过计算机分析确定对这些等位基因特异的 MM HM1.24 的免疫原性肽。这将用于目标 2，通过分子建模和分子生物学技术设计和构建 HLA-A2-HM1.24 复合物的结构同种异体变体。最后，在目标 3 中，为了研究同种异体变异对 CTL 反应的影响，将使用慢病毒载体系统的新应用将复合物递送至抗原呈递细胞。然后，在 CTL 效应器测定中，APC 将与 HLA-A2 限制性、HM1.24 特异性 CTL 共培养。正在测试的假设是，这种 MM 相关 HLA-肽复合物的同种异体变体可以被设计来增强 CTL 反应。该项目利用生物信息学、分子生物学和组织培养技术来研究 HLA-A2 肽复合物的生物物理和遗传成分如何促进 T 细胞的同种异体反应。最终，该项目旨在为目前用于开发针对多发性骨髓瘤等疾病的免疫疗法的知识库做出贡献，特别是在有详细记录的健康差异的人群中。公共健康相关性：多发性骨髓瘤是一种破坏性浆细胞癌，对非裔美国人影响尤为严重，而且尚无明确的治愈方法。这个项目可能会为设计和优化载体提供一个推定模型，该模型利用非裔美国人群体中的遗传变异来促进抗癌免疫反应。该模型或许可以用于开发针对多发性骨髓瘤等疾病的个性化疗法，这些疾病在独特人群中表现出健康差异。