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.
Public Health Relevance Statement: PROJECT NARRATIVE Project Title: Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Type 1 diabetes (T1D) is a chronic autoimmune disorder that destroys pancreatic islet beta cells leading to lifelong insulin deficiency that requires frequent glucose monitoring and insulin replacement therapy to control blood glucose levels. Recent studies using immune modulation have produced exciting results with new therapies that rely on regulatory T cells (Tregs) to suppress the autoimmune response. We are using microfluidics and DNA sequencing to capture disease-modulating T cells from patients. T1D reactive genes from these T cells are then engineered into healthy Tregs to create a TCR-engineered Treg cell therapy.
Project Terms: Alleles; Allelomorphs; Epitopes; Antigenic Determinants; Binding Determinants; Antigens; immunogen; Autoantibodies; autoimmune antibody; autoreactive antibody; self reactive antibody; Autoantigens; Autologous Antigens; Self-Antigens; Autoimmune Diseases; autoimmune condition; autoimmune disorder; Autoimmune Responses; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biological Assay; Assay; Bioassay; Biologic Assays; Biotechnology; Biotech; Blood Glucose; Blood Sugar; Cells; Cell Body; Clinical Research; Clinical Study; Clinical Trials; Diabetes Mellitus; diabetes; Insulin-Dependent Diabetes Mellitus; Brittle Diabetes Mellitus; IDDM; Juvenile-Onset Diabetes Mellitus; Ketosis-Prone Diabetes Mellitus; Sudden-Onset Diabetes Mellitus; T1 DM; T1 diabetes; T1D; T1DM; Type 1 Diabetes Mellitus; Type 1 diabetes; Type I Diabetes Mellitus; insulin dependent diabetes; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; type I diabetes; type one diabetes; Disease; Disorder; Eligibility Determination; Eligibility; Protocol Screening; Engineering; Genes; MHC Class I Genes; Class I Genes; MHC Class I; Glucose; D-Glucose; Dextrose; Human; Modern Man; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Insulin; Humulin R; Novolin R; Regular Insulin; Islets of Langerhans; B9 endocrine pancreas; Endocrine Pancreas; Islands of Langerhans; Nesidioblasts; Pancreatic Islets; Pars endocrina pancreatis; islet progenitor; Libraries; Pathology; Patients; Peptides; Publishing; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Cell-Mediated Lympholytic Cells; Cytolytic T-Cell; Cytotoxic T Cell; killer T cell; Cytotoxic T-Lymphocytes; Treg; regulatory T-cells; Regulatory T-Lymphocyte; Technology; Testing; preproinsulin; pre-proinsulin; Chronic; Clinical; Phase; Self Tolerance; peripheral blood; CD8 Cell; CD8 T cells; CD8 lymphocyte; CD8+ T cell; CD8+ T-Lymphocyte; CD8-Positive Lymphocytes; T8 Cells; T8 Lymphocytes; CD8-Positive T-Lymphocytes; Disease Progression; Replacement Therapy; Solid Tumor; Solid Neoplasm; Immunological response; host response; immune system response; immunoresponse; Immune response; cell mediated therapies; cell-based therapeutic; cell-based therapy; cellular therapy; Cell Therapy; Therapeutic; Malignant Cell; cancer cell; Nature; adoptive cell therapy; adoptive cellular therapy; Adoptive Cell Transfers; Hematologic Cancer; Hematologic Malignancies; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; Malignant Hematologic Neoplasm; Hematologic Neoplasms; catalog; Catalogs; Immunes; Immune; interest; Remission; Disease remission; Toxicities; Toxic effect; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; Sampling; response; glucometer; glucose meter; glucose monitor; Genomics; diabetes mellitus therapy; diabetes therapy; Eragrostis; Teff; Insulin Cell; Insulin Secreting Cell; ß-cell; ß-cells; ßCell; Beta Cell; µfluidic; Microfluidics; preventing; prevent; Ph.D.; PhD; Doctor of Philosophy; Recombinants; in vivo; Cancer Patient; Expression Library; Newly Diagnosed; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; symptom management; manage symptom; safety study; pre-clinical; preclinical; preclinical study; pre-clinical study; autoreactive T cell; self-reactive T cell; chronic autoimmune disease; autoreactivity; design; designing; beta cell replacement; ß-Cell replacement; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; FDA approved; effective therapy; effective treatment; Biological Markers; bio-markers; biologic marker; biomarker; T cell therapy; T cell based therapeutics; T cell based therapy; T cell directed therapies; T cell targeted therapeutics; adoptive T cell transfer; adoptive T-cell therapy; therapeutic T-cell platform; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; efficacy study; Adaptive Immune System; acquired immune system; DNA sequencing; DNA seq; DNAseq; Insulin deficiency; Immunogenomics; infection risk; effector T cell; Teff cell; CAR T cell therapy; CAR T therapy; chimeric antigen receptor (CAR) T cell therapy; chimeric antigen receptor T cell therapy; diabetes pathogenesis; Immune mediated destruction; Immune destruction
