Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens

针对 1 型糖尿病自身抗原的工程化 TCR-Treg 细胞疗法

• 批准号: 10545634
• 负责人: Matthew James Spindler
• 金额: $ 30万
• 依托单位: GIGAMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545634
• 关键词: Adaptive Immune System; Adoptive Cell Transfers; Alleles; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Responses; B-Lymphocytes; Beta Cell; Biological Assay; Biological Markers; Biotechnology; Blood Glucose; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cancer Patient; Catalogs; Cell Therapy; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Cytotoxic T-Lymphocytes; DNA sequencing; Development; Diabetes Mellitus; Disease; Disease Progression; Disease remission; Doctor of Philosophy; Eligibility Determination; Engineering; Epitopes; Eragrostis; Expression Library; FDA approved; Genes; Genomics; Glucose; Hematologic Neoplasms; Human; Immune; Immune mediated destruction; Immune response; Immune system; Immunogenomics; Immunosuppression; Immunotherapy; In Vitro; Insulin; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Libraries; MHC Class I Genes; Microfluidics; Nature; Newly Diagnosed; Pathology; Patients; Peptides; Phase; Publishing; Recombinants; Regulatory T-Lymphocyte; Replacement Therapy; Sampling; Self Tolerance; Small Business Innovation Research Grant; Solid Neoplasm; T cell therapy; T-Lymphocyte; Technology; Testing; Therapeutic; Toxic effect; Treatment Efficacy; autoreactive T cell; autoreactivity; beta cell replacement; cancer cell; chronic autoimmune disease; design; diabetes mellitus therapy; diabetes pathogenesis; effective therapy; effector T cell; efficacy study; glucose monitor; immunoregulation; in vivo; infection risk; interest; mouse model; novel therapeutics; peripheral blood; pre-clinical; preclinical study; preproinsulin; prevent; response; safety study; symptom management; targeted treatment

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.

项目总结