Generation and evaluation of antitumor efficiency of CAR-T cells harboring a T helper 17 phenotype

• Grant number: 19/18702-8
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): December 01, 2019
• Effective date (End): April 30, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Lucas Eduardo Botelho de Souza
• Grantee: Heloisa Brand
• 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

Adoptive transfer of T lymphocytes expressing chimeric antigen receptors (CARs) against CD19 glycoprotein has already shown long-lasting clinical remission in patients with some types of B-cell lymphomas and leukemias. However, in patients with chronic lymphoid leukemia, treatment response is restricted to about 20% of patients and there is no evidence of therapeutic efficacy in solid tumors so far. One of the main factors responsible for treatment failure is the low persistence of CAR-T cells after transplantation. To circumvent this limitation, a promising approach would be the transplantation of CAR-T cells harboring a T helper 17 (Th17) phenotype, whose differentiation is coordinated by the transcription factor ROR³t. Th17 cells exhibit memory effector cell phenotype and induce long-lasting antitumor responses after transplantation. Thus, the hypothesis of this project is that the combined expression of ROR³t and CAR in human T lymphocytes will induce the reprogramming in Th17 CAR lymphocytes, which will present higher in vivo persistence and higher antitumor activity compared to conventional CAR-T cells. To test this hypothesis, we will use a novel approach in which human T lymphocytes will be transduced with a lentiviral vector encoding an anti-CD19 CAR and the ROR³t transcription factor. The therapeutic efficiency and persistence of Th17 CAR lymphocytes will be evaluated in co-cultivation assays and in a human Burkitt lymphoma murine model. This project addresses one of the goals of the Cell Therapy Center (project CEPID 013/08135-2), which aims to develop innovative therapies against neoplasms using genetically engineered immune cells. We are confident that the potential findings of this project will contribute to expand the use of CAR-T cells against hitherto refractory neoplasms and thus help to consolidate this therapeutic approach as truly disruptive in the treatment of cancer. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BOTELHO DE SOUZA, LUCAS EDUARDO; FERREIRA, FERNANDA URSOLI; THOME, CAROLINA HASSIBE; BRAND, HELOISA; ORELLANA, MARISTELA DELGADO; FACA, VITOR MARCEL; FONTES, APARECIDA MARIA; COVAS, DIMAS TADEU. Human and mouse melanoma cells recapitulate an EMT-like program in response to mesenchymal stromal cells secretome. Cancer Letters, v. 501, p. 114-123, MAR 31 2021. (19/18702-8, 08/08944-0, 13/08135-2)

BATISTA, L. C.; BRAND, H.; FANTACINI, D. M. C.; COVAS, D. T.; SOUZA, L. E. B.. EVALUATION OF ANTI-CD19 CAR-T CELL PERSISTENCE AND EFFICACY USING A DEVELOPED MULTIPARAMETRIC FLOW CYTOMETRY AND QPCR TRACKING PLATFORM FOR PRECLINICAL AND CLINICAL STUDIES. CYTOTHERAPY, v. 23, n. 4, p. 2-pg., 2021-04-01. (13/08135-2, 19/18672-1, 19/18702-8)

LIMA, S. C. G.; BRAND, H.; BATISTA, L. C.; FANTACINI, D. M. C.; COELHO, M. G. B.; CASTRO, F. A.; COVAS, D. T.; SOUZA, L. E. B.. DEVELOPMENT OF CRISPR/CAS9-BASED GENOME EDITING PLATFORM FOR THE GENERATION OF ALLOGENEIC CAR-T CELLS. CYTOTHERAPY, v. 23, n. 4, p. 1-pg., 2021-04-01. (13/08135-2, 19/18672-1, 19/18702-8, 20/02043-2)

GOMES DE LIMA, SARAH CAROLINE; CARVALHO FANTACINI, DAIANNE MACIELY; BATISTA, LAIS DE CASTRO; SILVEIRA, ROBERTA MARANINCHI; FURTADO, IZADORA PETER; ROSSETTI, RAFAELA; BRAND, HELOISA; COVAS, DIMAS TADEU; BOTELHO DE SOUZA, LUCAS EDUARDO. Strategies to Enhance the Therapeutic Efficacy, Applicability, and Safety of Genetically Engineered Immune Cells. CRITICAL REVIEWS IN IMMUNOLOGY, v. 41, n. 1, p. 27-pg., 2021-01-01. (13/08135-2, 20/02043-2, 19/18702-8, 19/18672-1)

GOMES DE LIMA, SARAH CAROLINE; CARVALHO FANTACINI, DAIANNE MACIELY; BATISTA, LAIS DE CASTRO; SILVEIRA, ROBERTA MARANINCHI; FURTADO, IZADORA PETER; ROSSETTI, RAFAELA; BRAND, HELOISA; COVAS, DIMAS TADEU; BOTELHO DE SOUZA, LUCAS EDUARDO. Strategies to Enhance the Therapeutic Efficacy, Applicability, and Safety of Genetically Engineered Immune Cells. CRITICAL REVIEWS IN IMMUNOLOGY, v. 41, n. 1, SI, p. 41-67, 2021. (20/02043-2, 19/18702-8, 13/08135-2, 19/18672-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

BRAND, Heloisa. Functional characterization of anti-CD19 CAR-T lymphocytes polarized for the Th17 phenotype through RORγt overexpression. 2022. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.