Tuesday, November 29, 2022
11/29/2022
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.
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