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Clinical Development of anti-OX40 and OX40L

抗OX40和OX40L的临床开发

基本信息

批准号：
7247976
负责人：
BRENDAN D CURTI
金额：
$ 27.66万
依托单位：
PROVIDENCE PORTLAND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7247976
关键词：
Address Agonist Animal Model Animals Antibodies Antibody Formation Antibody Therapy Antigen Presentation Antigens Appendix Applications Grants Arts Autoimmune Diseases Autoimmunity Basic Science Biological Biological Assay Biology Breast CD8B1 gene Cancer Patient Cell Count Cell Death Cellular Immunity Chile Clinical Clinical Trials Clinical Trials Cooperative Group Colon Color Cytomegalovirus Data Development Disease Disease regression Doctor of Medicine Dose Drug Kinetics End Point Ensure Enzyme-Linked Immunosorbent Assay Exposure to Failure Flow Cytometry Future Generations Genus Cola Goals Head and Neck Cancer Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune Immune response Immunologic Memory Immunologic Monitoring Immunology Immunosuppression Immunotherapy In Vitro Keyhole Limpet Hemocyanin Knowledge Laboratories Malignant Neoplasms Manipulative Therapies Measures Mechanics Mediating Memory Methods Modeling Monitor Multiple Sclerosis Mus Non-Hodgkin&apos s Lymphoma Nursing Research Pathway interactions Patients Peripheral Personal Satisfaction Phase Phase I Clinical Trials Phenotype Pre-Clinical Model Prevention Problem Solving Production Prostate Rate Recombinant Proteins Recruitment Activity Renal Cell Carcinoma Reporter Research Research Institute Research Personnel Resources Rheumatoid Arthritis Role Safety Sampling Signal Transduction Surface T memory cell T-Cell Development T-Cell Proliferation T-Lymphocyte TNFSF4 gene Techniques Tern Testing Tetanus Therapeutic immunosuppression Toxic effect Translations Tumor Antigens Tumor Necrosis Factor Receptor Tumor-Infiltrating Lymphocytes Vaccines anticancer research base bench to bedside cancer immunotherapy cancer therapy cytokine cytotoxic data management design gene therapy gp34 antigen in vivo lymph nodes malignant breast neoplasm melanoma member memory CD4 T lymphocyte migration neoplastic cell nonhuman primate pre-clinical programs receptor binding research study response tumor tumor immunology tumor necrosis factor ligand superfamily member 4 tumor necrosis factor receptor superfamily member 4

项目摘要

DESCRIPTION (provided by applicant): Immunotherapy has shown great potential in the treatment of a variety of cancers such as breast cancer, melanoma, renal cell carcinoma and non-Hodgkin's lymphoma; however, the full potential of immunotherapy has not been achieved despite new antigen-specific vaccines, cellular therapy, antibodies, and cytokines. The reasons for the low response rate in cancer immunotherapy are many, but one of the most fundamental issues is that cancer patients develop progressive immunosuppression characterized by decreased T-cell effector and memory function. Experiments in the laboratory of Dr. Andrew Weinberg have described an immunological regulatory molecule present on T cells called OX40. The consequences of OX40 engagement relevant to the proposed research include generation of memory T cells, increased migration of effector T cells into the periphery, enhanced cytokine production by effector T cells, and the ability to break peripheral T-cell tolerance in vivo. OX40+ T cells are present in a wide variety of human tumors and in tumor-involved lymph nodes. OX40-based therapy causes tumor regression in a variety of animal tumor models, and was well-tolerated in murine and non-human primate pre-clinical experiments. This research will be the first to study OX40-based cancer therapy in humans. The specific aims of the proposed research are to define a well-tolerated dose of anti-OX40 for use in future clinical trials in humans by performing a phase I clinical trial, characterize the primary and recall immune responses to reporter antigens after anti-OX40 treatment using established immunological monitoring techniques such as ELISA and cytokine flow cytometry, and to produce a soluble form of the human OX40 ligand that contains the receptor-binding domain and matches or exceeds the biologic activity of the OX40 agonist antibody.

描述（由申请人提供）：免疫疗法在治疗多种癌症如乳腺癌、黑色素瘤、肾细胞癌和非霍奇金淋巴瘤方面显示出巨大潜力;然而，尽管有新的抗原特异性疫苗、细胞疗法、抗体和细胞因子，但免疫疗法的全部潜力尚未实现。癌症免疫治疗应答率低的原因很多，但最根本的问题之一是癌症患者发展出以T细胞效应子和记忆功能降低为特征的进行性免疫抑制。Andrew温伯格博士实验室的实验描述了一种存在于T细胞上的免疫调节分子，称为OX 40。与所提出的研究相关的OX 40参与的后果包括产生记忆T细胞，增加效应T细胞向外周的迁移，增强效应T细胞的细胞因子产生，以及打破体内外周T细胞耐受性的能力。0X 40 + T细胞存在于多种人类肿瘤和肿瘤涉及的淋巴结中。基于0X 40的疗法在多种动物肿瘤模型中引起肿瘤消退，并且在鼠和非人灵长类动物临床前实验中耐受良好。这项研究将是第一个研究基于OX 40的人类癌症治疗的研究。拟议研究的具体目的是通过进行I期临床试验来确定用于未来人体临床试验的抗OX 40的良好耐受剂量，使用已建立的免疫监测技术（如ELISA和细胞因子流式细胞术）表征抗OX 40治疗后对报告抗原的初次和回忆免疫应答，并产生可溶形式的人OX 40配体，其含有受体结合结构域并匹配或超过OX 40激动性抗体的生物活性。