Abstract
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Here we report the utility of antigen-specific T lymphocytes as a regulatable peptide delivery platform for in vivo therapy. piggyBac transposon modification of murine cells with luciferase allows us to visualize T cells after adoptive transfer. Vaccination stimulates long-term T-cell engraftment, persistence, and transgene expression enabling detection of modified cells up to 300 days after adoptive transfer. We demonstrate adoptive transfer of antigen-specific T cells expressing erythropoietin (EPO) elevating the hematocrit in mice for more than 20 weeks. We extend our observations to human T cells demonstrating inducible EPO production from Epstein–Barr virus (EBV) antigen-specific T lymphocytes. Our results reveal antigen-specific T lymphocytes to be an effective delivery platform for therapeutic molecules such as EPO in vivo, with important implications for other diseases that require peptide therapy.
Highlights
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies
We demonstrate the feasibility of using antigen-specific CD8+ T lymphocytes to deliver EPO long term in an animal model, correct anemia in an anemic animal model of kidney disease, and provide data supporting the use of Epstein–Barr virus (EBV)-specific T lymphocytes for regulated EPO expression from human T cells
We used OT-1 T cells that express a transgenic T-cell receptor (TCR) for a peptide fragment derived from chicken ovalbumin (SIINFEKL) presented on H2-Kb major histocompatibility complex (MHC) class I16, and SIINFEKL as the vaccine antigen
Summary
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Several features of transposon systems make them attractive tools for generating cell therapy platforms, including potentially reduced immunogenicity compared to viral vectors and capacity for multi-gene insertion that is facilitated by the relatively large cargo capacity and ability to deliver multiple constructs to a single cell[14] Another transposon system, Sleeping Beauty, is currently approved for use in human clinical trials aimed at engineering T cells to target CD19-positive B-cell malignancies for immunotherapy[15]. In these studies, we demonstrate the feasibility of using antigen-specific CD8+ T lymphocytes to deliver EPO long term in an animal model, correct anemia in an anemic animal model of kidney disease, and provide data supporting the use of EBV-specific T lymphocytes for regulated EPO expression from human T cells
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