Engineered TCR-T Cell Therapy Targeting Driver Mutations in NSCLC

项目总结 项目标题：针对非小细胞肺癌驱动因素突变的工程化TCR-T细胞治疗 组织：GigaMune Inc. 派：马修·J·斯宾德勒，博士。 包括CAR-T、TCR-T和TIL治疗在内的过继细胞疗法(ACTs)已经显示出很强的临床效果 对血液系统肿瘤和实体瘤患者的治疗反应。然而，只有反- CD19 CAR-T细胞疗法已获得FDA批准，并已商业化用于血液病的治疗 癌症。许多TCR-T细胞治疗实体瘤的临床试验正在进行中，但这些试验 只针对少数著名的癌症-睾丸和过度表达的肿瘤抗原。因此，有必要 开发针对新的肿瘤抗原的TCR-T细胞疗法。 KRAS、EGFR和ALK等基因中复发的癌症驱动因素突变和融合事件推动肿瘤发生 在包括非小细胞肺癌(NSCLC)在内的多种癌症中。重要的是，这些突变是 在肿瘤中均一存在，产生的新抗原在癌症中显示出免疫原性。 患者和健康个体跨越常见的人类白细胞抗原类型。这表明TCR-T细胞疗法具有靶向性 驱动基因突变将是治疗非小细胞肺癌安全有效的方法。 这个第一阶段SBIR项目的具体目标是开发一个针对以下目标的天然人类TCR目录 NSCLC患者中存在复发癌症驱动基因突变，用于TCR工程自体或 同种异体移植(TCR-T细胞)。GigaMune的独特技术使用了微流体、基因组学和哺乳动物 显示以生成数百万种不同的、本地配对的TCRab曲目库。TCRab库包括 永生的，可以用一组抗原重复实验。这将加速发现罕见的反 驱动程序突变TCR。 该项目由免疫基因组学专家、GigaMune发明者Matthew J.Spindler博士领导 技术，并得到领先的NSCLC肿瘤学家贾斯汀·盖纳和爱丽丝·肖(麻省总医院)的支持。之后 在完成这一第一阶段SBIR项目后，GigaMune将进一步开发有前景的TCR作为TCR-T细胞疗法， 通过体内疗效研究、体外安全性研究和制造开发。

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.