EAGER: Biomanufacturing: Creating a multifunctional nanoreagent that stimulates, genetically manipulates, and selectively expands therapeutic T cells for adoptive cell therapy

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1644363 - StephanAdoptive immunotherapy is a new disease treatment option based on patient-derived immune ("T") cells that are genetically modified to target cancer or infections. This approach has already established its potential in several medical arenas. But despite the obvious advantages afforded by these targeted therapies compared to chemotherapy, radiotherapy, and surgery, the complexity and costs of producing genetically-programmed lymphocytes pose major obstacles to their use as standard-of-care. This project addresses the problem by developing microscopic "nanoparticles" that can stimulate, genetically modify, and selectively expand therapeutic lymphocytes simply by adding them to the cells in culture. Nanoparticles can be repeatedly added to the cell culture until the required numbers of engineered lymphocytes are achieved. Implementing the large-scale manufacture of targeted T cells afforded by this approach could translate into treating patients with an immunotherapy that is practical, low-cost, and broadly-applicable. Furthermore, the project will help develop the scientists of tomorrow through its participation in ongoing teaching and outreach programs designed to generate enthusiasm in students learning how new developments in biomaterials impact medicine. Current lymphocyte manufacturing practices require an assortment of elaborate protocols to isolate, genetically modify, and selectively expand the redirected cells before infusing them back into the patient. Because these difficult procedures entail dedicated equipment and considerable technical expertise, providing this kind of personalized T cell therapy to every cancer patient in the United States is not practical. This project addresses the problem by developing microscopic "nanoparticles" that can stimulate, genetically modify, and selectively expand therapeutic lymphocytes simply by adding them to the cells in culture. The project tests the hypothesis that appropriately engineered DNA-carrying nanoparticles can efficiently shuttle tumor-specific chimeric antigen receptor (CAR) genes into cultured T cells (CAR-T cells), and at the same time induce the selective outgrowth of the genetically-modified lymphocyte population by presenting the cells with the same surface-anchored antigens that are targeted by the encoded CAR. The hypothesis is tested via two specific aims: 1) designing the proposed DNA nanocarriers and 2) comparing the functionality and therapeutic efficacy of CAR-T cells manufactured using the proposed DNA nanocarriers versus those created by the conventional approach using viral methods and magnetic bead expansion. The nanoparticle-based methods will be able to activate, engineer, and propagate T cells without special instruments, equipment, or training and could be manufactured using automated protocols that are compatible with any clinical setting, and at a fraction of the costs involved in multistep/multi-reagent methods. Nanoparticles can be repeatedly added to the culture until the required percentage of programmed T cells is achieved. They are biodegradable and biocompatible and the expanded T cells can easily be separated from free nanoparticles by centrifugation. The platform could easily be adapted to enable economical commercial-scale manufacturing of other therapeutic cell types, such as natural killer cells, hematopoietic stem cells, mesenchymal stem cells, or B lymphocytes, which substantially broadens the applicability of the approach for the treatment of disease.