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Off-the-shelf engineered NK cells for the treatment of Leukemia and Lymphoma treatment

Abstract

In recent years, enormous advances have been made in genetic engineering of effector immune cells for cancer therapy. Although chimeric antigen receptors (CARs) have been widely used to redirect autologous T cell specificity against haematological malignancies, yielding impressive clinical results, studies with CAR-modified natural killer (NK) cells are still restricted to preclinical studies. NKs are highly cytotoxic cells and have a fundamental physiological role in tumor immunity. In the context of adoptive cell therapies, NK cells do not have the potential to cause graft versus host disease, so they can be used to generate an allogeneic cell product available for immediate clinical use. In addition, NK-CAR cells retain their native receptors and have the potential to exert anti-tumor activity through their physiological mechanisms. Studies indicate that the use of NK-CAR cells produces fewer side effects and are more effective in treating solid tumors than T-CAR cells. Thus, several inherent characteristics of NK cells make them promising candidates for genetic modification and use in immunotherapies. The ability to more powerfully target cytotoxicity against refractory tumors through CAR expression is likely to contribute to a paradigm shift in cancer treatment. However, NK cell expansion as well as gene modification of these cells is still a challenging task, particularly with non-viral vectors. We hypothesize that the use of non-viral vectors containing more NK cell-specific intracellular signaling domains will provide safer NK-CAR generation for clinical use as well as greater therapeutic efficacy (due to increased cell activation and cytolytic function) . In this context this project aims to: 1) Establish a robust, stable, reproducible and low cost anti-CD19 NK-CAR cell production bioprocess in the Institution; 2) Development of new CAR constructs with NK cell-specific signaling molecules to increase their proliferation, activation, cytokine secretion and cytolytic activity and 3) Development of a non-viral episomal vector for genetic modification of NK cells, that will provide more safety to this immunotherapy (NK-CAR virus-free). Therefore, this research project will allow the implementation of NK-CAR generation and production in Brazil and future application of these cells to treat patients with hematological neoplasms or solid tumors. The results of this project will offer an off the shelf platform suitable for the safe and effective use of NK-CAR cells in cancer immunotherapy. (AU)

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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)
PICANCO-CASTRO, VIRGINIA; BONAMINO, MARTIN HERNAN; RAMOS, RODRIGO NALIO; GUERINO-CUNHA, RENATO L.; OLIVEIRA, THEO GREMEN M.; REGO, EDUARDO M.. Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. VIII: CAR-T cells: preclinical development - Safety and efficacy evaluation. Hematology, Transfusion and Cell Therapy, v. 43, n. 2, p. S54-S63, . (19/25309-0, 20/07055-9, 13/08135-2)
RAMOS, RODRIGO NALIO; PICANCO-CASTRO, VIRGINIA; OLIVEIRA, THEO GREMEN M.; MENDRONE, ALFREDO; DE SANTIS, GIL CUNHA; BONAMINO, MARTIN HERNAN; ROCHA, VANDERSON. Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. VII. Present and future of technologies for production of CAR cell therapies. Hematology, Transfusion and Cell Therapy, v. 43, n. 2, p. S46-S53, . (19/25309-0, 13/08135-2)
SILVESTRE, R. N.; EITLER, J.; DE AZEVEDO, J. T. TEIXEIRA COTTAS; TONN, T.; PICANCO-CASTRO, V.. CD19-CAR NK CELLS CO-EXPRESSING IL15/IL15R alpha SHOW ENHANCED CYTOTOXICITY AGAINST B-CELL LEUKEMIA. CYTOTHERAPY, v. 24, n. 5, p. 2-pg., . (19/25309-0, 20/08279-8, 13/08135-2, 20/07055-9)
TEIXEIRA COTTAS DE AZEVEDO, J. T.; SILVESTRE, R. N.; COVAS, D.; PICANCO-CASTRO, V.. CD3Z-2B4 INTRACELLULAR DOMAIN IMPROVES CYTOTOXICITY FUNCTION OF CAR-NK CELLS AGAINST CD19+CELL LINES. CYTOTHERAPY, v. 24, n. 5, p. 1-pg., . (19/25309-0, 20/08279-8, 13/08135-2, 20/07055-9)
SILVESTRE, RENATA NACASAKI; EITLER, JIRI; DE AZEVEDO, JULIA TEIXEIRA COTTAS; TIRAPELLE, MARIANE CARIATI; FANTACINI, DAIANNE MACIELY CARVALHO; DE SOUZA, LUCAS EDUARDO BOTELHO; SWIECH, KAMILLA; COVAS, DIMAS TADEU; CALADO, RODRIGO T.; MONTERO, PAOLA ORTIZ; et al. Engineering NK-CAR.19 cells with the IL-15/IL-15Rα complex improved proliferation and anti-tumor effect in vivo. FRONTIERS IN IMMUNOLOGY, v. 14, p. 15-pg., . (13/08135-2, 19/25309-0, 20/08279-8, 20/07055-9)

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