Engineered TCR-T Cell Therapy Targeting Driver Mutations in NSCLC

针对 NSCLC 驱动基因突变的工程化 TCR-T 细胞疗法

基本信息

批准号：
10258346
负责人：
Matthew James Spindler
金额：
$ 40万
依托单位：
GIGAMUNE, INC.
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：
2021-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258346
关键词：
Adoptive Cell Transfers Alleles Allogenic Antigens Autologous Avidity Biological Assay Biotechnology CAR T cell therapy CD19 gene CTAG1 gene Cancer Patient Catalogs Cell surface Cells Clinical Clinical Research Clinical Trials DNA sequencing Development Disease Doctor of Philosophy Eligibility Determination Engineering Epidermal Growth Factor Receptor Epitopes Event Expression Library FDA approved Gene Fusion Gene Mutation Genes Genetic Engineering Genomics HLA Antigens Hematologic Neoplasms Human Immunogenomics In Vitro Individual KRAS2 gene Libraries Malignant Neoplasms Microfluidics Mutate Mutation Nature Non-Small-Cell Lung Carcinoma Oncologist Patients Peptides Phase Publishing Recombinants Recurrent Malignant Neoplasm Sampling Small Business Innovation Research Grant Solid Neoplasm T cell therapy T-Cell Development T-Lymphocyte Technology Testing Testis Tumor Antigens Tumor-Infiltrating Lymphocytes WT1 gene cancer type cell killing chimeric antigen receptor T cells clinical efficacy driver mutation effective therapy efficacy study engineered T cells immunogenic immunogenicity in vivo interest melanoma neoantigens new therapeutic target novel novel therapeutics response safety study synovial sarcoma targeted treatment treatment response tumor tumor infiltrating lymphocyte therapy tumorigenesis

项目摘要

PROJECT SUMMARY Project Title: Engineered TCR-T Cell Therapy Targeting Driver Mutations in NSCLC Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Adoptive cell therapies (ACTs) including CAR-T, TCR-T, and TIL therapies have shown strong clinical responses for the treatment of cancer patients for hematological cancers and solid tumors. However, only anti- CD19 CAR-T cell therapies have been FDA approved and commercialized for the treatment of hematological cancers. Numerous TCR-T cell clinical trials are ongoing for the treatment of solid tumors, but these trials target only a handful of well-known cancer-testis and over expressed tumor antigens. Thus, there is a need to develop TCR-T cell therapies that target novel tumor antigens. Recurrent cancer driver mutations and fusion events in genes like KRAS, EGFR, and ALK drive tumorigenesis in numerous cancers including non-small cell lung cancer (NSCLC). Importantly, these mutations are homogenously present within the tumor and the generated neoantigens have shown immunogenicity in cancer patients and healthy individuals across common HLA types. This suggests that TCR-T cell therapies targeting driver mutations would be a safe and effective treatment for NSCLC. The Specific Aim of this Phase I SBIR project is to develop a catalog of natural human TCRs that target recurrent cancer driver gene mutations present in NSCLC patients for use in TCR-engineered autologous or allogeneic ACTs (TCR-T cells). GigaMune's unique technology uses microfluidics, genomics, and mammalian display to generate millions-diverse, natively paired TCRab repertoire libraries. The TCRab libraries are immortal, enabling repeated experimentation with a panel of antigens. This will expedite discovery of rare anti- driver mutation TCRs. The project is led by Dr. Matthew J. Spindler, an expert in immunogenomics and inventor of the GigaMune technology and supported by leading NSCLC oncologists Justin Gainor and Alice Shaw (Mass General). After completing this Phase I SBIR project, GigaMune will further develop promising TCRs as TCR-T cell therapies, through in vivo efficacy studies, in vitro safety studies, and manufacturing development.

项目概要项目名称：针对 NSCLC 驱动突变的工程化 TCR-T 细胞疗法组织：GigaMune Inc. PI：Matthew J Spindler 博士包括 CAR-T、TCR-T 和 TIL 疗法在内的过继细胞疗法 (ACT) 已显示出强大的临床效果癌症患者对血液癌症和实体瘤的治疗反应。然而，只有抗 CD19 CAR-T细胞疗法已获得FDA批准并商业化，用于治疗血液病癌症。目前正在进行大量 TCR-T 细胞治疗实体瘤的临床试验，但这些试验仅针对少数众所周知的癌症睾丸和过度表达的肿瘤抗原。因此，有必要开发针对新型肿瘤抗原的 TCR-T 细胞疗法。 KRAS、EGFR 和 ALK 等基因中的复发性癌症驱动突变和融合事件驱动肿瘤发生包括非小细胞肺癌 (NSCLC) 在内的多种癌症。重要的是，这些突变是同质存在于肿瘤内，产生的新抗原在癌症中表现出免疫原性常见 HLA 类型的患者和健康个体。这表明 TCR-T 细胞疗法靶向驱动突变将是一种安全有效的非小细胞肺癌治疗方法。第一阶段 SBIR 项目的具体目标是开发一个天然人类 TCR 目录，其目标是 NSCLC 患者中存在复发性癌症驱动基因突变，用于 TCR 工程自体或同种异体 ACT（TCR-T 细胞）。 GigaMune 的独特技术采用微流体学、基因组学和哺乳动物显示以生成数百万个多样化、本地配对的 TCRab 库。 TCRab 库是不朽，可以对一组抗原进行重复实验。这将加速罕见抗病毒药物的发现驱动突变 TCR。该项目由免疫基因组学专家、GigaMune 发明人 Matthew J. Spindler 博士领导技术并得到领先的 NSCLC 肿瘤学家 Justin Gainor 和 Alice Shaw（麻省总医院）的支持。后完成这一 I 期 SBIR 项目后，GigaMune 将进一步开发有前途的 TCR 作为 TCR-T 细胞疗法，通过体内功效研究、体外安全性研究和生产开发。