Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens

项目摘要 项目名称：靶向1型糖尿病自身抗原的工程化TCR-Treg细胞疗法 Registrant Organization：liu hanlin PI：Matthew J Spindler，博士 包括CAR-T和TCR-T细胞疗法在内的工程化过继细胞疗法已显示出强大的临床应用前景。 接受五种FDA批准的CAR-T细胞疗法治疗血液癌症的癌症患者的反应， 许多TCR-T细胞治疗实体瘤的临床试验正在进行中。这些新药都利用了 工程化的细胞毒性T细胞，旨在直接杀死癌细胞。与细胞毒性T细胞相反，调节性T细胞 其功能是通过抗原特异性活性局部抑制免疫应答。TCR工程化调节性T细胞 细胞（TCR-TCR）可用于治疗自身免疫性疾病患者，而不是作为杀伤靶点 细胞，而不是防止细胞被杀死。然而，为了开发工程化的TCR-Treg细胞， 因此，在免疫治疗中，迫切需要鉴定自身抗原反应性TCR以特异性地将Treg活性引导至靶细胞。 胰岛，在那里它们可以局部抑制引起疾病病理学的自身反应性细胞毒性T细胞。 1型糖尿病（T1 D）自身抗原，包括前胰岛素原、IA-2和GAD 65，是理想的TCR-Treg细胞靶点 因为它们在胰岛和β（B）细胞中特异性表达。这些自身抗原通常是 T1 D患者中的CD 4和CD 8 T细胞靶向的肽表位跨许多HLA等位基因呈递。 重要的是，最近的研究表明，从CD 8 + T细胞分离的TCR克隆型可以重定向Treg， 对I类HLA呈递肽的抑制活性。这表明靶向T1 D的工程化TCR-Tcl 3 自身抗原可以抑制胰岛内的自身反应性细胞毒性T细胞。因此， 靶向跨越不同HLA等位基因的T1 D自身抗原的TCR-Treg细胞疗法将提供广泛的免疫治疗。 有效治疗T1 D患者。 该第一阶段SBIR项目的具体目标是开发靶向T1 D的天然人类TCR目录 用于TCR工程化Treg细胞疗法的自身抗原。GigaMune的独特技术使用微流体， 基因组学和哺乳动物展示，以产生数百万种不同的天然配对的TCRab库。的 TCRab库是不朽的，能够用一组抗原进行重复实验。这将加速 发现罕见的抗T1 D TCR。 该项目由免疫基因组学专家、GigaMune的发明者Matthew J. Spindler博士领导 该公司由连续创业者和联合创始人大卫约翰逊（GigaGen）支持。完成后 在第一阶段SBIR项目中，GigaMune将进一步开发有前景的TCR作为TCR-Treg细胞疗法， 体内功效研究、体外安全性研究和生产开发。

PROJECT SUMMARY Project Title: Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Engineered adoptive cell therapies including CAR-T and TCR-T cell therapies have shown strong clinical responses in cancer patients with five FDA approved CAR-T cell therapies for hematological cancers and numerous TCR-T cell clinical trials ongoing for the treatment of solid tumors. These new drugs have all leveraged engineered cytotoxic T cells and are designed to directly kill cancer cells. In contrast to cytotoxic T cells, Tregs function to locally suppress immune responses through antigen-specific activity. TCR engineered regulatory T cells (TCR-Tregs) could be used for the treatment of patients with autoimmune disorders, not for killing target cells but rather for preventing cells from being killed. However, in order to develop engineered TCR-Treg cell therapies, there is a critical need in identifying autoantigen reactive TCRs to specifically direct Treg activity into pancreatic islets where they can locally suppress the autoreactive cytotoxic T cells causing disease pathology. Type 1 diabetes (T1D) autoantigens, including preproinsulin, IA-2, and GAD65, are ideal TCR-Treg cell targets as they are specifically expressed in pancreatic islets and beta (b)-cells. These autoantigens are commonly targeted by CD4 and CD8 T cells in T1D patients with peptide epitopes presented across many HLA alleles. Importantly, recent studies have demonstrated that TCR clonotypes isolated from CD8+ T cells can redirect Treg suppressive activity to class I HLA presented peptides. This suggests that engineered TCR-Tregs targeting T1D autoantigens could suppress autoreactive cytotoxic T cells within the pancreatic islets. Therefore, a catalog of TCR-Treg cell therapies targeting T1D autoantigens across different HLA alleles would provide a broadly effective treatment for T1D patients. The Specific Aim of this Phase I SBIR project is to develop a catalog of natural human TCRs that target T1D autoantigens for use in TCR-engineered Treg cell therapies. 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-T1D TCRs. The project is led by Dr. Matthew J. Spindler, an expert in immunogenomics and inventor of the GigaMune technology and supported by serial entrepreneur and co-founder David Johnson (GigaGen). After completing this Phase I SBIR project, GigaMune will further develop promising TCRs as TCR-Treg cell therapies, through in vivo efficacy studies, in vitro safety studies, and manufacturing development.