The recent introduction of Advanced Therapy Medicinal Products (ATMPs) into the clinical management of cancer patients still represents special challenges for their selective targeting. While a number of RNA-based therapies are emerging for the treatment of distinct hematological disorders, their translation to wide clinical use is still hindered by the major hurdle of their in vivo delivery. Most existing delivery systems have limitations linked to stability and packaging efficiency. Interest has shifted to naturally occurring nanovesicles, and especially exosomes, considered as the next generation of smart carriers thanks to their high biocompatibility, bioavailability, specificity and low immunogenicity. However, a standardized methodology for engineering and producing them is yet to be defined. The main underlying issues are a) a lack of a proper and scalable source of exosomes, b) non-standardized purification methodologies, and c) low efficiency of therapeutic cargo loading.

In collaboration with the Vesiprod-UB research team, our group has recently developed a set of genetic devices that enable customizable production of therapeutic exosomes, with the perspective to unleash the potential of ATMPs (shRNA) needs in blood cancers. exoLYMPH is designed in alignment with the latest advances in synthetic biology, RNA interference technology, and fundamental exosome biology, combining multiple state-of-the-art discoveries to produce a novel, fast and cost-effective therapeutic platform. We will create a set of devices modifiable ad libitum to virtually target any specific gene and determined tissue/cell type, facilitating the scalability. Finally, we will also introduce cell tropism and a purification system based on affinity chromatography. As a disease model, we will focus on Burkitt lymphoma (BL), an aggressive B-cell neoplasm of germinal center origin which genetic hallmark is the t(8;14) translocation associated with the overexpression of MYC, an oncogene still considered as “undruggable” and associated with refractoriness to standard dose-intensive chemotherapy and dismal prognosis.

After a first step dedicated to optimize the scalable production, the purification and the characterization of tumor B cell-targeting exosomes loaded with a MYC-specific shRNA, we will carry out a proof of concept evaluation of the loaded exosomes using 2D/3D multicellular cultures of BL cell lines and primary samples. Optimal exosome dosing schedule for in vivo applications (concentrations, periodicity) will be determined by high-throughput screening in BL cell-line derived xenografts developed in zebrafish, in collaboration with our private partner. Biodistribution, stability and in vivo safety/efficacy of the therapeutic exosomes will be established in a set of immunocompetent (chicken embryo chorioallantoic membrane, CAM) patient-derived xenograft models of lymphoma recently developed by our group.

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