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Modulating extracellular TCR-CD3 interactions to identify new melanoma immunotherapy targets

调节细胞外 TCR-CD3 相互作用以确定新的黑色素瘤免疫治疗靶点

基本信息

批准号：
10406370
负责人：
Aswin Natarajan
金额：
$ 19.41万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406370
关键词：
Affinity Amino Acids Antigen Targeting Antigens Binding Binding Sites Biological Assay CD3 Antigens CTLA4 gene Cell surface Clone Cells Complementarity Determining Regions Computing Methodologies Data Docking Effectiveness Exploratory/Developmental Grant Generations Goals HLA-A2 Antigen Human Immune Immune System Diseases Immune signaling Immune system Immunity Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Interferons Interleukin-2 Knowledge Laboratories Lead Libraries Major Histocompatibility Complex Malignant Neoplasms Mechanics Mediating Metastatic Melanoma Methodology Methods Mus Mutagenesis Mutate Mutation Nuclear Magnetic Resonance Outcome Pathway interactions Patients Peptides Phase I Clinical Trials Proteins Publishing Regimen Regulatory T-Lymphocyte Resistance SILV gene Signal Pathway Signal Transduction Site Skin Cancer Specificity Structure System T Cell Receptor Signaling Pathway T cell response T cell therapy T-Cell Receptor T-Lymphocyte Testing Thymus Gland Toxic effect Tumor Antigens adaptive immune response anti-CTLA4 anti-PD-1 base cross reactivity cytokine cytotoxicity design dimer engineered T cells extracellular fight against functional outcomes high reward high risk immune checkpoint blockade improved in silico in vivo in vivo Model innovation melanoma monomer mouse model mutant neoplastic cell novel novel strategies programmed cell death protein 1 programs protein complex receptor binding response screening small molecule tumor tumor initiation

项目摘要

ABSTRACT Melanoma is one of the deadliest and aggressive form of skin cancer. Main treatment options in metastatic melanoma involve T cell immunotherapy using checkpoint blockade (anti-PD-1, anti-CTLA-4 and others) or adoptive T cell therapy (ACT) with modified patient T cells. Although, durable response is only observed in a fraction of patients. Further progress can be made by studying and targeting different T cell signaling pathways. One such pathway is the T cell receptor (TCR) signaling pathway. T cell recognition of antigen by the TCR and the resulting proximal signaling through the surrounding CD3 subunits are key steps in the initiation of tumor-killing. Identification of the specific extracellular contacts between the TCR and CD3 subunits gives precise guidance for immunotherapeutic strategies that modulate T-cell immunity by targeting signaling through the TCR-CD3 complex. Previous studies that targeted the antigen binding site for enhancing T-cell responses to tumor antigens often lead to off-target effects and toxicity. Based on our recent TCR-CD3 structure, we mutated specific CD3 interacting TCR-residues that resulted in different T cell cytokine responses. Our hypothesis is that by modulating TCR-CD3 interactions in specific ways, immune-mediated cytotoxicity to tumor antigens can be increased without losing specificity for the cancer antigen. To test our hypothesis, in Aim 1, an in vitro retroviral TCR display method and a novel CD3-tetramer assay will be used to mutate specific TCR-residues and identify TCRs that interact with CD3 with increased affinity, resulting in T cells that mediate more effective functionality. In Aim 2, a structure-based TCR design will be used to identify TCR mutants with enhanced CD3 binding ability in silico. In both instances, identified mutations will be introduced into gp100-specific TCRs and their in vitro/in vivo tumor killing efficacy will be analyzed to validate the anti-tumor potential of new TCRs with the goal of developing new wave of effective T cell therapies against melanoma.

摘要