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Targeted antigen receptor treatment of cancer

癌症靶向抗原受体治疗

基本信息

批准号：
7271277
负责人：
ALAN N. HOUGHTON
金额：
$ 215.05万
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：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7271277
关键词：
Active Immunization Active Immunotherapy Address Alpha Particle Emitter Antibodies Antibody Formation Antibody Therapy Antigen Presentation Antigen Receptors Antigen Targeting Antigens Arts Autoantigens B-Lymphocytes Bacterial Infections Biological Biological Assay Biometry Biophysics Bioterrorism Blood Blood Circulation Blood Vessels Bone Marrow Bone Marrow Ablation Bone Marrow Transplantation Breast CD4 Positive T Lymphocytes CD8B1 gene CTAG1 gene Cancer Immunology Science Cell Therapy Cell physiology Cell surface Cells Chemicals Chronic Classification Clinical Clinical Immunology Clinical Research Clinical Trials Collaborations Colorectal Combined Modality Therapy Combined Vaccines Complement Cytoplasmic Granules DNA Sequence Rearrangement DNA Vaccines Data Development Differentiation Antigens Disadvantaged Discipline of Nuclear Medicine Disease Employee Strikes Environment Enzymes Evolution Experimental Models Extracellular Space Fab Immunoglobulins Family Fc Receptor Fibroblasts Force of Gravity Foundations Funding GPA33 gene Generations Genes Genetic Recombination Glycolipids Goals Graft-Versus-Tumor Induction Grant HIV Hematopoietic stem cells Heterogeneity Homeostasis Homologous Gene Human Humoral Immunities Image Imaging Techniques Immune Immune response Immune system Immunity Immunoglobulin G Immunoglobulins Immunologic Adjuvants Immunologic Monitoring Immunology Immunotherapy In Situ Individual Infection Investigation Investigational Therapies Label Laboratories Laboratory Research Large Intestine Carcinoma Lead Letters Link Liquid substance Literature Localized Lymphoma MS4A1 gene Malaria Malignant Childhood Neoplasm Malignant Neoplasms Measures Medical Medical Imaging Medical Oncologist Memorial Sloan-Kettering Cancer Center Methods Modality Modeling Molecular Molecular Target Monitor Monoclonal Antibodies Monophenol Monooxygenase Multicenter Trials Mus Nuclear Numbers Nurses Operative Surgical Procedures Optics Organ Organism Organization administrative structures Ovarian Ovarian Carcinoma Pancreas Parents Passive Immunotherapy Patient Care Patients Peptide Hydrolases Personal Satisfaction Pharmaceutical Preparations Pharmacology Pharmacy facility Phase Phase I Clinical Trials Phenotype Physicians Physics Polyvalent Vaccine Pre-Clinical Model Program Research Project Grants Progress Reports Prostate Proteins Publications Quality Control Radiochemistry Radioimmunotherapy Radioisotopes Range Rate Reagent Recording of previous events Recovery Regulatory Affairs Reliance Research Research Design Research Personnel Resistance Resources Role Solid Solid Neoplasm Somatic Mutation Specificity Spleen Staging Structure Surgeon System T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte Techniques Therapeutic Therapeutic Agents Therapeutic Studies Tissues Title Translating Translational Research Translations Transplantation Tumor Antibodies Tumor Antigens Tumor-Associated Vasculature Upper arm Vaccination Vaccine Antigen Vaccine Design Vaccines Validation Vascular System Viral Virus Virus Diseases Vision Work Wound Healing antigen binding base cancer immunology function cancer therapy cancer type chemotherapy clinical efficacy clinically relevant concept cytokine cytotoxic data management design disorder control dosimetry extracellular fibroblast-activating factor gene therapy immunogenic immunoglobulin receptor improved in vivo innovation interest leukemia lung Carcinoma melanoma miniaturize molecular imaging mutant novel novel strategies novel therapeutics oncology optical imaging particle pathogen practical application pre-clinical prevent programs quality assurance receptor research clinical testing response sarcoma sibrotuzumab statistics synthetic peptide tool tumor uptake vaccine development

项目摘要

DESCRIPTION (provided by applicant): The Clinical Immunotherapy Program is a highly interactive research effort that has a rich history of bringing targets discovered in the laboratory through preclinical models into early stage clinical trials with the goal of selecting experimental therapies for late stage clinical testing. The present proposal continues this tradition through targeting tissue-specific antigens for cancer therapy using antigen receptors. The rationale is based on the remarkable specificity of the antigen receptors on T cells and B cells. Shared themes include targeting differentiation antigens and tumor stroma, specificity of antigen receptors, enhancement of potency of antigen receptor-based therapies, modulation of immunity, overcoming heterogeneity in the tumor, and the application of sophisticated methods for imaging and quantitation. Two strategies for therapy are explored active immunotherapy (vaccines) to generate antibody and T-cell responses and passive immunotherapy with antibodies (monoclonal antibodies, mAb). The Program has four projects that use new approaches (e.g., single chain Fv mAb fragments, alpha emitters, nanogenerators, optical imaging, heteroclitic DNA vaccines, T-cell homeostasis for vaccination) for: 1) Increasing antibody potency by arming with alpha particle emitters with extraordinary energy over a very short range. 2) Overcoming limitations of targeting antibodies to solid tumors using novel miniaturized antigen-binding domains of antibodies to penetrate tumors more effectively. 3) Overcoming tolerance against tissue-specific self antigens in cancers for active immunization by increasing potency through rationally designed antigen mutants to enhance antigen presentation. 4) Enhancing and skewing immune responses toward tumor antigens following active immunization during recovery of immune homeostasis after bone marrow ablation. An Administrative Core provides biostatistics, data management, nursing, and pharmacy support. The Biophysics and Nuclear Medicine Core provides state-of-the-art optical and nuclear imaging, dosimetry, radiochemistry, and advanced molecular imaging. The Immune Monitoring Core measures cytokines, antibodies and T-cells, including quantitation, specificities and phenotype. The ultimate goal is to establish new principles and strategies for antigen receptor-based therapies, and more specifically develop synergistic treatments that combine antibodies and T cells directed at different and overlapping cellular and tissue compartments.

临床免疫治疗计划是一项高度互动的研究工作，具有将实验室中通过临床前模型发现的靶点带入早期临床试验的丰富历史，目的是为后期临床试验选择实验性疗法。本发明通过使用抗原受体靶向用于癌症治疗的组织特异性抗原来延续这一传统。基本原理是基于T细胞和B细胞上抗原受体的显著特异性。共同的主题包括靶向分化抗原和肿瘤基质，抗原受体的特异性，增强基于抗原受体的治疗的效力，免疫调节，克服肿瘤的异质性，以及复杂的成像和定量方法的应用。两种治疗策略是主动免疫治疗（疫苗），以产生抗体和T细胞反应和被动免疫治疗抗体（单克隆抗体，mAb）。该方案有四个项目采用新的方法（例如，单链抗体片段，α发射体，纳米发生器，光学成像，异向DNA 疫苗，用于疫苗接种的T细胞内稳态）用于：1）通过在非常短的范围内装备具有非凡能量的α粒子发射体来增加抗体效力。2)使用抗体的新型小型化抗原结合结构域克服将抗体靶向实体瘤的限制以更有效地穿透肿瘤。3)通过合理设计的抗原突变体增强抗原呈递，提高效力，克服癌症中对组织特异性自身抗原的耐受性，用于主动免疫。4)骨髓消融后免疫稳态恢复期间主动免疫后对肿瘤抗原的免疫应答增强和偏斜。行政核心提供生物统计，数据管理，护理和药房支持。生物物理学和核医学核心提供最先进的光学和核成像，剂量测定，放射化学和先进的分子成像。免疫监测核心测量细胞因子，抗体和T细胞，包括定量，特异性和表型。最终目标是为基于抗原受体的疗法建立新的原则和策略，更具体地说，开发协同治疗，将联合收割机抗体和针对不同和重叠的细胞和组织区室的T细胞相结合。