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Proteomic and phosphoproteomic analysis of molecular mechanisms and signaling for Anti CD-19 CAR-T cell therapy in Leukemia and Lymphoma

Grant number: 20/13463-2
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): October 01, 2021
Effective date (End): November 30, 2025
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal researcher:Vitor Marcel Faça
Grantee:John Oluwafemi Teibo
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID

Abstract

Hematological malignances, accounts for around 25 thousand every year in Brazil. Among few therapeutic options, Chimeric Antigen Receptor (CAR) T lymphocytes cell therapy has emerged as a novel and effective therapeutic practice for the treatment of B-cell Leukemia and Lymphoma. For this autologous cellular immunotherapy, T-cells derived from patient blood are bioengineered in vitro to express artificial receptors, such as anti-CD-19 to specifically target B-cells-derived malignant cells. The current therapeutic challenges with CAR-T therapy are related to the improvement of effectiveness and persistence of bioengineered cells, the eventual occurrence of relapse and adverse effects, which includes the severe Cytokine Release Syndrome (CRS). Understanding the molecular signaling mechanisms involved in the treatment and patient response is also a challenge. Here we propose to elucidate molecular mechanism of CAR-T cell therapy using proteome-wide strategies to analyze cellular changes induced by anti-CD19 transfection and expression. Alterations in the cellular proteome, secretome, and phosphoproteome profiles will be analyzed first in models of anti-CD19 CAR-T induction in healthy donor's cells. Additional experiments of co-culturing of CAR-T cells expressing CD19 isotopically labeled will reveal signaling events and cytokine profiles during cellular contact and communication in a engagement environment. Follow-up experiments based on the elucidated molecular signatures using targeted proteomics, flow cytometry and conventional immunoassays will provide new insights on the CAR-T mechanisms, directly contributing for the CAR-T therapy development, as well as potentially improving the clinical management of Leukemia and Lymphoma. (AU)

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