Regulation of gamma delta T cell immunoediting by novel phosphoantigens

新型磷酸抗原对 γδT 细胞免疫编辑的调节

基本信息

批准号：
9215652
负责人：
ANDREW J WIEMER
金额：
$ 37.78万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215652
关键词：
Address Adverse effects Affect Affinity American Antibodies Antibody Therapy Antigens Bacteria Binding Biological Cancerous Cells Chemicals Clinical Communicable Diseases Cytolysis Data Development Diphosphates Disease Dose Drug Kinetics Effectiveness Employee Strikes Exhibits Goals Growth Human Immune Immune response Immune system Immunity Immunotherapy In Vitro Infection Inflammatory Integrins Intravenous Libraries Lymphoma Lytic Malignant Neoplasms Mediating Metabolic Metabolism Modeling Molecular Target Osteoporosis Patients Peptides Permeability Pharmaceutical Preparations Phosphonic Acids Phosphorus Primates Production Public Health Receptor Cell Regulation Research Risedronate Risk Rodent Series Structure-Activity Relationship Syndrome T-Cell Receptor T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Index Time alpha-beta T-Cell Receptor analog base bisphosphonate bone cancer cell cancer immunotherapy cancer risk cancer therapy chemical stability compound 30 cytokine fighting humanized mouse in vivo isopentenyl pyrophosphate kinase inhibitor leukemia/lymphoma mouse model neoplastic cell novel phosphonate public health relevance receptor response small molecule tool trafficking tumor uptake γδ T cells

项目摘要

DESCRIPTION (provided by applicant): An attractive strategy for cancer treatment is to strengthen the ability of the patient's own immune system to detect and clear cancerous cells. However, current antibody-based or cell-based immunotherapies have limited effectiveness or high invasiveness. A small molecule drug that activates the immune system to fight cancer would be an attractive clinical option because it may not require the intravenous dosing associated with antibody therapies and it would be less invasive than cell based options. The objective of our research is to develop a drug that stimulates the immune response to cancer by activating cells known as the gamma delta T cells. Gamma delta T cells are early responders to malignancy, and as such, their activation holds great promise for cancer immunotherapy. In contrast to T cells that express the more prevalent alpha beta T cell receptor and respond to peptide antigens, T cells that express the V9V2 T cell receptor respond to small phosphorous-containing compounds known as phosphoantigens. As a side effect of treatment for osteoporosis, nitrogenous bisphosphonate drugs indirectly activate gamma delta T cells by enhancing accumulation of the phosphoantigen isopentenyl diphosphate, substantially reducing the risk of some cancers. However, no known direct activators of gamma delta T cells are available for human use. Here, we propose to test the central hypothesis that phosphonate phosphoantigens with enhanced metabolic stability will directly activate gamma delta T cells, in a way that is dependent upon cellular internalization and integrin- mediated cell contact. Development of a new class of phosphoantigens is essential because clinical use of bisphosphonate drugs to activate gamma delta T cells is limited by their narrow therapeutic index and high bone affinity, and clinical use of natural phosphoantigens is limited due to rapid diphosphate metabolism. We will synthesize a series of novel organophosphorous compounds with increased metabolic stability relative to known phosphoantigens and characterize their activation of gamma delta T cells. We also will prepare protected phosphoantigens, which will allow us to continue to investigate how enhanced cellular uptake promotes a stronger response. We will use these new chemical tools to address the fundamental unanswered question of how phosphoantigens activate gamma delta T cells to fight cancer. The ultimate goal is to identify a phosphoantigen that will be used for cancer treatment. These findings will come at a time when the biological understanding of anti- cancer immunity is far from complete, and thus have the potential for dramatic impact on the field of cancer immunotherapy.

描述（由申请人提供）：癌症治疗的一个有吸引力的策略是增强患者自身免疫系统检测和清除癌细胞的能力，然而，当前基于抗体或基于细胞的免疫疗法的有效性有限或侵袭性高。激活免疫系统来对抗癌症的小分子药物将是一种有吸引力的临床选择，因为它可能不需要与抗体疗法相关的静脉给药，并且比基于细胞的药物的侵入性更小。开发一种药物，通过激活γδT细胞来刺激对癌症的免疫反应，γδT细胞是恶性肿瘤的早期反应者，因此，与T细胞相比，它们的激活为癌症免疫治疗带来了巨大的希望。表达更普遍的 αβ T 细胞受体并对肽抗原作出反应，表达 V9V2 T 细胞受体的 T 细胞对称为磷酸抗原的小型含磷化合物作出反应。为了提高治疗骨质疏松症的效果，含氮双膦酸盐药物通过增强磷酸抗原异戊烯基二磷酸的积累来间接激活 γ δ T 细胞，从而显着降低某些癌症的风险。然而，尚无已知的γ δ T 细胞直接激活剂可供人类使用。，我们建议测试中心假设，即具有增强代谢稳定性的磷酸化磷酸抗原将直接激活 γ δ T 细胞，其方式依赖于细胞内化和整合素 -开发一类新的磷酸抗原至关重要，因为双磷酸盐药物激活γδT细胞的临床使用因其狭窄的治疗指数和高骨亲和力而受到限制，并且天然磷酸抗原的临床使用由于快速的二磷酸盐代谢而受到限制。我们将合成一系列相对于已知磷酸抗原具有更高代谢稳定性的新型有机磷化合物，并表征它们对 γ δ T 细胞的激活。我们还将制备受保护的磷酸抗原，这将使我们能够继续研究增强的细胞摄取如何促进更强的反应，我们将使用这些新的化学工具来解决磷酸抗原如何激活γδT细胞来对抗癌症的基本问题。这些发现将在抗癌免疫的生物学理解还远未完成的时候出现，因此有可能对癌症免疫治疗领域产生巨大影响。