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Programmable Off-the-Shelf Dendritic Cells as an Immunotherapy Discovery Platform

可编程现成树突状细胞作为免疫治疗发现平台

基本信息

批准号：
10449196
负责人：
David Minh Truong
金额：
$ 39.17万
依托单位：
NEW YORK UNIVERSITY
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：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10449196
关键词：
Address Adoptive Immunotherapy Alleles Allogenic Antigen-Presenting Cells Antigens Autologous Award Base Pairing Basic Science Binding Cell Line Cell physiology Cells Clinic Communicable Diseases Complex Consumption Custom Cytotoxic T-Lymphocytes DNA Dendritic Cell Vaccine Dendritic Cells Endogenous Retroviruses Engineering Genes Genetic Genome Goals HLA Antigens Haplotypes Harvest Human Human Genome Immune Immune system Immunotherapy In Vitro Industrialization Investments Libraries Malignant Neoplasms Marshal Mature T-Lymphocyte Methods Modification National Institute of Allergy and Infectious Disease Patients Peptides Persons Population Positioning Attribute Procedures Proliferating Reporter Research Research Personnel Role Safety Solid Neoplasm Source Stress Stretching Surface System T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Training Transgenes Tumor Antigens Tumor-Infiltrating Lymphocytes Untranslated RNA Vaccines Validation Vision Work Writing cancer immunotherapy career chemotherapy chimeric antigen receptor combinatorial directed differentiation efficacy testing engineered T cells epigenetic silencing genome-wide high reward high risk induced pluripotent stem cell induced pluripotent stem cell technology innovation investigator training monocyte neoplastic cell new technology next generation sequencing novel therapeutics peripheral blood programs receptor refractory cancer synthetic biology technology development tumor

项目摘要

Project Summary Adoptive Cell Immunotherapy using patient harvested T cells engineered against tumor-specific targets has ushered in a new therapeutic era. However, the lack of tumor-specific targets and T cell receptors limits the addressable cancers. A promising approach for solid tumors uses T cell receptors (TCRs) directed against tumor- specific antigens (TSAs) displayed on HLA receptors found on the surface of nearly every cell. Unfortunately, HLAs are highly polymorphic genes between people. This restricts both the TCRs and TSAs to a small number of patients. A platform that expands the number of HLA-restricted TSAs and TCRs will transform the entire immunotherapy pipeline. Here, I propose to address this unmet need by generating programmable Dendritic cells (DCs) – professional antigen presenting cells that function to mature and activate naive T cells. Programmable DCs would permit the discovery of new TCRs, validation of TSAs, and perhaps be used as "living" vaccines to marshal a patient’s own immune system against infectious disease and cancer. Thus far, efforts to leverage the potential of DCs have been limited principally by: (1) an inability to produce cells with HLAs matched to patients;; (2) an inability to robustly test and validate new TSAs against TCRs;; and (3) an inability to produce "off-the-shelf" DCs at industrial scale. As a new innovator, my vision is to produce off-the-shelf Dendritic Cells pre-engineered to match any HLA haplotype (even rare ones) and pre-encoded with any combination of TSAs. Using this new platform, my group will search for and validate "universal" TSAs/TCRs that can be used broadly in TCR-Therapy for any patient. Specifically, we will focus on peptides expressed from regions of the genome normally epigenetically silenced, but re-activated in tumor cells (such as endogenous retroviruses). To reach this goal, we will continue development of technology enabling the "writing" of millions of base-pairs of DNA in human induced pluripotent stem cells (iPSCs). This technology allows direct customization of the large HLA locus of iPSCs in a single step;; introduction of libraries of potential TSAs;; and integration of synthetic reporter constructs (which are excisable for safety) for enhancing the in vitro directed differentiation of iPSCs to DCs. Thus, allogeneic programmed DCs will catalyze a wide variety of immunotherapy applications and expand access of these advanced treatments for a greater number of patients.

项目总结