CBP/p300 as a target for boosting CAR-T cell response: implications in haematological malignancies and solid tumours

• Grant number: 24/01951-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): July 01, 2024
• Effective date (End): April 30, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Tiago da Silva Medina
• Grantee: Maria Letícia Rodrigues Carvalho
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated research grant: 18/14034-8 - Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets, AP.JP

Abstract

The use of T cells with chimeric antigen receptors (CAR-T) has revolutionized the treatment of hematologic malignancies. However, applying this approach to solid tumors faces technical challenges, such as the inefficient infiltration of these cells into the tumor microenvironment and the immunosuppressive environment encountered in these tumors. Molecular profiles of CAR-T cells associated with memory T cells and possessing characteristics of stem cells are linked to better responses. Such profiles can be induced during the manufacturing of CAR-T cells and involve epigenetic remodeling of these cells. Previously, we identified epigenetic inhibitors that enhance cytotoxic capacity and induce a memory and effector profile in CAR-T cells, improving tumor control in in vitro and in vivo models of B-cell neoplasms (manuscript attached). In this project, we will use similar approaches to enhance the function of anti-HER2 CAR-T cells, aiming to improve and expand the application of these cells in solid tumors. To this end, T lymphocytes will be collected from healthy donors, electroporated for CAR incorporation, and expanded in the presence of the CBP/p300 inhibitor or after genetic modifications to delete or overexpress the proteins involved in this process. The molecular profile of these cells will then be evaluated by RNA-Seq, as well as by flow cytometry assessment of protein expression of activation markers, tissue residence, effector response, immune checkpoints, and differentiation profile. The tumor control capacity of these cells will be assessed in in vitro and in vivo models of HER2+ ovarian cancer. As a result, this project will develop and consolidate knowledge and technologies for the manufacturing and enhancement of CAR-T cells, potentially extending the therapeutic potential of CAR-T approaches to solid tumors.