Optimization of MART-1 TCR Gene Transfer for Anti-Melanoma Immunity

MART-1 TCR 基因转移抗黑色素瘤免疫的优化

基本信息

批准号：
8239560
负责人：
Pin Wang
金额：
$ 29.16万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8239560
关键词：
Adoptive Transfer Affinity Animal Model Biology Cell physiology Cell surface Cells Clinical Clinical Trials Codon Nucleotides Engineering Enhancers Gene Silencing Gene Transfer Genetic Goals Hematopoietic stem cells Human Immunity In Vitro Investigation Learning Lentivirus Vector Light Matrix Attachment Regions Mature T-Lymphocyte Metastatic Melanoma Modality Modification Operative Surgical Procedures Outcome Patients Population Program Research Project Grants RNA Interference Regimen Series Signal Transduction Stem cells System T-Cell Activation T-Lymphocyte Techniques Testing Therapeutic Translating Treatment Efficacy Tumor Immunity Vertebral column Work abstracting cancer immunotherapy cellular engineering embryonic stem cell genetic element improved in vivo man melanoma novel novel strategies pre-clinical promoter response success

项目摘要

PROJECT 5: OPTIMIZATION OF MART-1 TCR GENE TRANSFER FOR ANTI-MELANOMA IMMUNITY ABSTRACT TCR gene transfer is a feasible approach for treating metastatic melanoma and greatly expands the scope of adoptive transfer for cancer immunotherapy. In light of the low clinical response rate to standard therapies, further optimization of this therapeutic modality is urgently needed. Our long-term goal is to optimize the components involved in TCR gene transfer so that this treatment can be translated into a reliable therapeutic modality. Our preliminary studies have identified a high affinity MART-1 TCR from a patient with an unusually high population of high affinity MART-1 specific T cells. The experimental focus of this proposal is to evaluate various strategies to improve TCR gene transfer. The first specific aim is to optimize the MART-1 TCR for an enhanced anti-melanoma response. Success of this aim will enable us to overcome the intrinsic problem of TCR mispairing and obtain an engineered MART-1 TCR with improved affinity. The second specific aim is to optimize T cells that have been modified by a MART-1 TCR to yield an enhanced anti-melanoma response, which will allow us to validate the proposed genetic modification strategies for building better T cells and develop a novel means to generate optimal MART-1 T cells in vitro for adoptive transfer. The third specific aim is to optimize a lentiviral delivery system for TCR gene transfer. Accomplishment of this aim will provide us with new versions of lentiviral vectors with superior abilities to genetically modify mature T cells, hematopoietic stem cells and embryonic stem cells. Taken together, these novel studies will contribute significantly to the further success of the next wave of investigation into TCR gene transfer.

项目5：针对抗黑素瘤免疫的Mart-1 TCR基因转移的优化抽象的 TCR基因转移是一种可行的方法，用于治疗转移性黑色素瘤，并大大扩大了范围癌症免疫疗法的收养转移。鉴于对标准疗法的临床缓解率低，迫切需要进一步优化这种治疗方式。我们的长期目标是优化 TCR基因转移涉及的成分，因此可以将这种治疗转化为可靠的治疗性方式。我们的初步研究已经确定了异常患者的高亲和力mart-1 TCR 高亲和力MART-1特异性T细胞的高种群。该建议的实验重点是评估改善TCR基因转移的各种策略。第一个具体目的是优化mart-1 TCR 增强的抗黑色素瘤反应。这个目标的成功将使我们能够克服 TCR误导并获得具有改善亲和力的工程MART-1 TCR。第二个具体目的是优化已通过MART-1 TCR修饰的T细胞，以产生增强的抗黑色素瘤反应，这将使我们能够验证提出的遗传修饰策略，以构建更好的T细胞和开发一种新型手段，以产生最佳的MART-1 T细胞体外进行过继转移。第三个特定目标是优化用于TCR基因转移的慢病毒输送系统。实现这一目标将为我们提供具有卓越能力的慢病毒载体的新版本可以改变成熟的T细胞，造血茎细胞和胚胎干细胞。综上下一波研究对TCR基因转移的成功。