Bioprinting Plant Virus Nanoparticles for Immunotherapy and Relapse Prevention of Ovarian Cancer

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Summary Bioprinting plant virus nanoparticles for immunotherapy and relapse prevention of ovarian cancer High grade serous ovarian cancer (HGSOC) is the most common and severe form of ovarian cancer and women with HGSOC have a poor prognosis. Immunotherapy approaches that induce systemic antitumor immunity, in particular those that prevent relapse, are urgently needed for HGSOC. We propose to employ plant virus-like nanoparticles (VLPs) combined with slow release antigen depots as a cancer vaccine approach to launch sys- temic antitumor immunity during remission to block relapse. Our data indicate that intraperitoneal (IP) admin- istration of plant VLPs in a mouse model of ovarian cancer modulates the tumor microenvironment to relieve immunosuppression and generate adaptive anti-tumor immunity and memory against tumor antigens. The VLPs are non-infectious, non-cytotoxic, and non-cytolytic, but the highly repetitive nature of the proteinaceous VLPs triggers innate immune activation and associated adaptive immune response. Building on this, we will develop a VLP biopolymer formulation to enable effective immunotherapy following surgical debulking in HGSOC. We will incorporate irradiated tumor cells as source for patient specific tumor antigens; the cells will be delivered together with the VLPs which act as adjuvant to launch long-lasting anti-tumor immunity. The proposed immu- notherapy implant will be produced through an innovative 3D bioprinting technique; specifically, rapid, microscale continuous optical bioprinting (µCOB). This platform offers control over both the topographical complexity and the cellular and material composition of the scaffold at micron-level resolution. Our rapid 3D bioprinting process allows for photopolymerization of multiple biocompatible materials, and facilitates incorporation of VLPs and/or cells. The engineering design space and tunability of this approach is impeccable; in particular the implant will be designed so that therapeutic doses are released in programmed intervals (prime/boost) vs. continuous slow release. We will fulfill three specific aims: 1) Bioprint VLP biopolymer implants and test various configurations to optimize slow, continuous release vs. staged, e.g. weekly release of the therapeutic VLPs. The implants will undergo rigorous quality control and reproducibility testing and released VLPs will undergo structural analysis and biological testing. 2) Evaluate efficacy of the immunotherapy implants vs. soluble VLPs will be evaluated using mouse model of ovarian cancer (ID8vegf/defb29). Immunological investigation will provide insights into the mechanism of the immunotherapy. 3) To further explore vaccine parameters and model very low endogenous patient antigen loads during remission, we will bioprint biopolymer implants to deliver VLPs and antigen (from irradiated cells) prior to challenge with ID8vegf/defb29 cells. For future translational approaches, patient tumor from surgical debulking and/or patient neoantigen peptides would be used. The clinical significance is high: we envision a simple modification to the current treatment work-flow, where small degradable vaccine implants are left in the intraperitoneal (IP) cavity during surgery or administered subcutaneously (SC) post-surgery, or both.