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Development and validation of a scalable method for the production of “off-the-shelf” exosomes-based products derived from CAR-T cells

P Heredia(1) B Perucha(1) K Pavlovic(1,2) M Cortijo(1) V Ronco(1) N Maldonado(1) M Tristán(1) F Martín(1) I C Herrera(2,3) M D Carmona(2) J A Marchal(4,5,6) K Benabdellah(1)

1:Genomic Medicine Department, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Av. de la Illustration 114, Granada, 18016, Spain.; 2:GC14 Cell Therapy, IMIBIC. University of Cordoba, Reina Sofia University Hospital, Cordoba 14004, Spain.; 3:Department of Hematology, Reina Sofía University Hospital, Córdoba, Spain.Biomedical Research Institute (IBS. Granada), Granada, 18012, Spain.; 4:Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, 18016, Spain.; 5:Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18016, Spain.; 6:Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada - University of Granada, Granada, 18016, Spain

Adoptive cell therapies (ACTs) based on modified T cells with chimeric antigen receptors (CAR) have shown remissions in hematopoietic neoplasms but not in solid tumors. This is mainly due to the complexity of the tumor microenvironment in this kind of tumors. Unlike disseminated liquid tumors, solid tumors present an impenetrable physical barrier, which prevents the arrival of therapeutic cells to their targets, reducing the effectiveness of CAR-T cells in such type of tumors. Recently, the peculiar properties of nanomaterials have made possible to improve current cell therapies against cancer, particularly exosomes have emerged as a potential therapeutic agent in the field of immunotherapy. One innovative application is the production of exosomes from CAR-T cells (EXO-CAR-T), which present CAR on their surface, allowing a specific lysis of the tumor. Two major challenges in developing exosome-based therapies should be considered; 1. The need to produce sufficient amount of exosomes with appropriate and intact biophysical properties. 2. The existence of HLA surface molecules on the EXO-CAR-Ts that may induce some type of rejection. With this in mind, we set up a large-scale EXO-CAR-T production and we evaluated the feasibility, safety and efficacy of the exosome’s purification. Our preliminary data showed that CAR-T cell-derived exosomes purified from large-scale EXO-CAR-T production are functional, express exosomes markers and carry CARs on their surface.

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