Generation of human macrophages expressing Chimeric Antigen Receptor (CAR) from cord blood CD34+ cells to treat tumors

• Grant number: 22/11481-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2023
• End date: July 31, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Rodrigo Nalio Ramos
• Grantee: Ian Costa Ovider
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

For many years the therapy of neoplastic diseases has been the focus of several research groups around the world. Among these, adoptive cell therapies, where the cells of the own immune system, and their own mechanisms of effects, are used in the possible tumor remission, has been shown to be effective for some tumor types. In recent years, the functionalization of T lymphocytes with Chimeric Antigen Receptors (CAR) to combat tumors has been highlighted, due to their satisfactory results in the treatment of hematological malignancies, such as leukemias. However, the clinical success of CAR-T cells could not achieve solid tumors, due to the great complexity of the microenvironment, involving: heterogeneity of tumor antigen expression, difficulty in maintaining and persisting immune response, the immunosuppressive tumor microenvironment and a dense extracellular matrix, which prevents the migration of the infused T cells for efficient contact with the tumor. In this way, macrophages emerge as an option for use in cell therapy, given its functional capabilities to enter the tumor environment, phagocytosis of malignant cells, presenting antigens and secreting cytokines, thus exceptionally orchestrating an immune response. In this scenario, the objective of this work is the ex vivo generation of macrophages expressing CAR (CAR-Mac), differentiated from cryopreserved Umbilical and Placental Cord Blood (SCUP) CD34+ cells. The different cells transformation methods will be tested, as well as the CAR role in phagocytosis capacity, cytokine release and T cell activation against modified glioblastoma cell expressing CD19+. We believe in being able to provide a CAR-Mac cell platform for pre-clinical and clinical trials for the treatment of patients via SUS.