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：
8448003
负责人：
Pin Wang
金额：
$ 27.41万
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/8448003
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：优化 MART-1 TCR 基因转移以实现抗黑色素瘤免疫抽象的 TCR基因转移是治疗转移性黑色素瘤的可行方法，大大扩展了治疗范围癌症免疫治疗的过继转移。鉴于对标准疗法的临床反应率较低，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参与 TCR 基因转移的成分，以便该治疗可以转化为可靠的治疗方法情态。我们的初步研究已从患有异常疾病的患者身上鉴定出高亲和力的 MART-1 TCR。大量高亲和力 MART-1 特异性 T 细胞。该提案的实验重点是评估改善 TCR 基因转移的各种策略。第一个具体目标是优化 MART-1 TCR 增强抗黑色素瘤反应。这一目标的成功将使我们能够克服以下内在问题： TCR 错配并获得亲和力提高的工程化 MART-1 TCR。第二个具体目标是优化经过 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所提出的基因改造策略，以构建更好的 T 细胞和开发一种在体外生成最佳 MART-1 T 细胞用于过继转移的新方法。第三个具体目标旨在优化TCR基因转移的慢病毒递送系统。这一目标的实现将为我们提供新版本的慢病毒载体具有卓越的基因修饰成熟T细胞、造血干细胞的能力细胞和胚胎干细胞。总而言之，这些新颖的研究将为进一步的研究做出重大贡献。下一波 TCR 基因转移研究的成功。