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

• 批准号: 8549710
• 负责人: Christina N Johnson
• 金额: $ 4.25万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549710
• 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

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.

描述（由申请人提供）：多发性骨髓瘤（MM）是骨髓浆细胞癌，死亡率大于50％1。 根据美国癌症注册机构的国家癌症统计数据，非裔美国人的发病率和死亡率大约是其他族裔人口中的两倍。 因此，重要的是要检查这些人群所特有的因素，这可能导致与该疾病相关的发病率和死亡率不平等。 在自体和同种异体造血干细胞移植后，主要观察到了MM的可用治疗方法，主要观察到缓解3,4。 也已经制定了免疫疗法策略。 例如，已证明人白细胞抗原（HLA）-A2限制了与多发性骨髓瘤细胞中过表达的MM相关蛋白HM1.24，已被证明可以通过骨髓瘤特异性细胞毒性T淋巴细胞（CTLS）刺激干扰素γ表达。 但是，目前，仅这些治疗方法并不能始终如一地在体外或体内研究中引起抗肿瘤细胞毒性作用8,9。 这部分是由于缺乏对TE因子的理解，这些因子在很大程度上耐受性肿瘤设置（例如同性恋性）中有助于T细胞的激活。 但是，非裔美国人中HLA多态性的较大多样性为询问HLA限制的生物物理基础提供了独特的资源，该疾病（如MM）限制了HLA限制。 该提案中详细详细介绍的项目的一般目标是确定HLA-A2中同种异体变化对HM1.24抗原的免疫主导肽诱导的诱导的影响。 非裔美国人和高加索人之间某些HLA-A2等位基因的患病率可能有所不同，并且这些差异有可能导致针对HLA-A2限制性肿瘤相关抗原的不同反应。 因此，在AIM 1中，将确定非裔美国人人口中最普遍的HLA-A类等位基因。 对于这些等位基因的MM HM1.24的免疫原性肽将通过计算机分析确定。 这将在AIM 2中用于设计和构建通过分子建模和分子生物学技术的HLA-A2-HM1.24复合物的结构同种异体变体。 最后，在AIM 3中，为了研究同种异体变化对CTL响应的影响，将使用慢病毒载体系统的新应用将复合物传递到抗原呈递细胞中。 然后，APC将与HLA-A2限制的HM1.24特异性CTL在CTL效应子测定中共同培养。 被检验的假设是，可以对此MM相关的HLA肽复合物的同种异体变体进行设计以增强CTL响应。 该项目利用生物信息学，分子生物学和组织培养技术来解决HLA-A2肽复合物的生物物理和遗传成分如何有助于T细胞的同种异体反应。 最终，该项目试图为目前用于开发MM等疾病的免疫疗法的知识库做出贡献，特别是在证明有据可查的健康差异的人群中。