Anti-carbonic anhydrase IX CAR T cell releasing anti-programmed cell death antibodies in the treatment of glioblastoma in vitro

• Grant number: 20/05296-9
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2020
• Effective date (End): June 30, 2021
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal researcher: Eloah Rabello Suarez
• Grantee: Gabriela Lagreca
• Home Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

Glioblastoma (GBM) is the most malignant and prevalent of all brain tumors, leading to the death of most patients within a year and a half after the initial diagnosis. Hypoxia is a frequent feature of GBM that leads to the overexpression of several proteins, including carbonic anhydrase IX (CAIX). CAIX is a transmembrane metalloenzyme responsible for the reversible hydration of carbon dioxide, overexpressed in more than 60% of GBM cases. Solid tumors, including GBM, have a microenvironment that promotes the progressive loss of effector functions of T cells, a process known as T cell exhaustion, which, in turn, favors tumor development and progression. In the context of GBM, a member of the molecule's group related to exhaustion induction stands out: the programmed cell death ligand-1 (PD-L1), also overexpressed in more than 60% of GBM cases. PD-L1 interacts with its respective programmed cell death receptor 1 (PD-1), located on T cells, favoring the exhaustion of these cells. Since GBM often overexpress both CAIX and PD-L1, they become excellent targets for combined therapies against this type of tumor. A new therapeutic strategy has been highlighted in the fight against cancer: the use of T cells containing chimeric antigen receptors (CAR T cells) designed against a tumor antigen. This project aims to evaluate the in vitro efficacy of second-generation anti-CAIX CAR T cell, capable of releasing anti-PD-L1 antibodies in the tumor microenvironment, in combating different GBM cell lines.