Abstract SAIL

Improvement in drug technology is driving a revolution in drug delivery systems and generated a wide spectrum of novel nanotechnology-based therapeutics. One of these novel nanostructures consists in nanoparticles (NP) that can be loaded with drugs or factors, such as nucleic acids or proteins. We propose a most innovative approach to prevent both, cancer progression and chronic transplanted organ injury, which exploits nanoparticles as vehicles of immunomodulating factors. In cancer, there is an increased interest in the epigenetic reprogramming of tumor-resident myeloid components, responsible for blunting anti-tumor lymphocyte infiltration, through delivery of microRNAs (miR) able to interfere at transcriptional level. The Consortium developed an efficient miR delivery system based on poly(lactic-co- glycolic acid) (PGLA) NP to transfect myeloid cells. Preliminary in vitro experiments show that antago-miR146a/155 delivery to cancer patients’ peripheral blood mononuclear cells (PBMC) relieves immunosuppressive activity of myeloid-derived suppressor cells (MDSC). In the setting of organ transplantation, the Consortium showed that miR146a is upregulated in peripheral blood of lung transplant recipients by extracorporeal photochemotherapy, an immunoregulatory therapy that is adopted in the context of chronic lung allograft dysfunction (CLAD). Preliminary in vitro data indicate that agonist-miR146a/155 delivery to PBMC from healthy subjects and CLAD patients is effective in enhancing their immunosuppressive activity. This project aims to optimize the miR candidate set for targeted regulation of myeloid and/or other cell subsets and to transfer it to tumor and transplant models, to facilitate GMP process development. Through in vitro and in vivo experiments, we shall select the best-performing immune-modulating miR for each clinical setting, and optimize NP formulations to improve targeting and optimal GMP production, to launch phase I clinical studies.