Development of a new immunotherapy approach for solid tumors using T cells genetically modified to express a novel anti-NY-ESO-1 engineered TCR

• Grant number: 20/11413-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2021
• End date: July 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Dimas Tadeu Covas
• Grantee: Rafaela Rossetti
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID

Abstract

The adoptive transfer of T cells expressing anti-CD19 Chimeric Antigen Receptors (CAR) has shown impressive clinical results in some B cell hematological neoplasms. However, the application in solid tumors is strongly limited by the absence of tumor antigens located on the cell surface. Unlike CAR, T Cell Receptors (TCR) can recognize intracellular antigens conjugated to the Major Histocompatibility Complex (MHC or HLA). Therefore, T cells expressing engineered TCR can recognize a wider range of antigens than T-CAR cells and, therefore, are considered promising in the immunotherapy of solid tumors. Among the target antigen options for the treatment of solid tumors with T-TCR cells, Cancer-Testicular Antigens (CTA) are highlighted for their immunogenicity and restricted expression in tumors and immunoprivileged organs. Among CTA, NY-ESO-1 is the most explored in clinical studies on immunotherapy and presents strong and homogeneous expression in several types of solid tumors. Our research group has developed a platform for the generation and use of T-CAR cells for the treatment of hematological diseases. In order to expand this research platform to include solid tumors, an international partnership was established that provided our research center with access to a new genetic construction of engineered TCR against NY-ESO-1: HLA-A * 02. Thus, this proposal aims to generate and characterize T cells modified with this engineered construction of TCR, seeking to evaluate their antitumor potential through in vitro tests and in a murine model of Synovial Sarcoma. In addition, we will evaluate the antitumor efficiency of T-TCR cells cultured with different interleukins and the silencing of endogenous TCR in order to obtain an optimized protocol for T-TCR cells generation. We hope that the results of this project will contribute to the generation of a new cell immunotherapy product for solid tumors, in addition to allowing for the nucleation and training of human resources in the area of advanced cell therapies. (AU)