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Bioengineered of T- and NK-cells by CAR against invasive fungal infections

Grant number: 18/18538-0
Support Opportunities:Research Grants - Young Investigators Grants
Duration: December 01, 2019 - November 30, 2025
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Thiago Aparecido da Silva
Grantee:Thiago Aparecido da Silva
Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated researchers:Kamilla Swiech Antonietto ; Sandro Gomes Soares
Associated grant(s):22/14188-0 - Controlling infection using NK cells expressing a Chimeric Antigen Receptor (CAR) specific to Cryptococcus spp, AP.R SPRINT
Associated scholarship(s):22/14669-9 - Expression in macrophages of chimeric antigen receptor (CAR) specific for Cryptococcus spp to subvert its escape mechanisms, BP.PD
22/13035-6 - Construction of second and third generation of 2DA6-CAR constructs and their expression in NK-92 cells to control the Paracoccidioides brasiliensis infection, BP.MS
22/13543-1 - Generation of chimeric antigen receptor (CAR) to recognize Paracoccidioides brasiliensis, BP.IC
+ associated scholarships 21/02758-4 - Construction of CAR receptors to redirect T and NK cells to control invasive Candida albicans infection, BP.DR
21/07174-0 - Identification of CAR with high specificity to Cryptococcus gattii by Jurkat cell line, BP.IC
20/16738-2 - Redirection of T cells via CAR to fight against Candida albicans infection, BP.MS
20/11307-3 - Impact of different scFv in GXMR-CAR expressed by T lymphocytes during T-cell activation against Cryptococcus spp, BP.MS
20/09113-6 - Functional activity of T cells modified with GXMR-CAR expressing the intracellular domain of CD28 or CD137, to control of experimental cryptococcosis, BP.MS
19/26074-7 - Bioengineered of T- and NK-cells by CAR against invasive fungal infections, BP.JP - associated scholarships

Abstract

Invasive fungal infections (IFIs) show mortality at similar and higher levels compared to tuberculosis and malaria. Regarding neglected diseases, IFIs have a low financial support while tuberculosis and malaria are better supported. Since IFIs, candidiasis, aspergilosis, criptococosis and histoplasmosis have more effect on the global public health. The risk factors of IFIs are related to immunocompromised host over many situations, but previous data showed growth rate of immunocompetent host affected by IFIs. In this case, the virulence factors of Cryptococcus spp, C. albicans and H. capsulatum are responsible to promote the escape from host immune response. The CD4+ T cells can differentiate in T helper (Th) 1 (Th1) and 17 (Th17), Tc1 and Tc17 profiles originated from CD8+ T cells and the cytotoxic effects of natural killer (NK) cells, which can be impair to reach the infection site. Then, the current project aims to redirect T and NK cells by chimeric antigen receptor (CAR) promoting the direct effect of these immune cells in the infection site affected by IFIs. This new strategy of cell therapy against IFIs was started by Laurence J.N. Cooper's and Kumaresan's lab, which added into CAR the carbohydrate recognition domain of Dectin-1 (DectinCAR). Basically, CAR has four regions: (I) binding domain, (II) hinge or stalk region, (III) transmembrane region, (IV) cytoplasmic signaling domain. Cooper's and Kumar's lab created T cells modified expressing DectinCAR that showed a therapeutic effect against Aspergillus fumigatus. This strategy therapeutic was realized for the responsible the current project that trained in these leader's groups of CAR, between 2017 and 2018 supported by FAPESP/BEPE, and I developed a CAR T cells to target Cryptococcus spp. These factors together support the aim of this current project, and three steps are essentials: (I) Phage Display technique to generate scFv (single chain variable fragment) specific to target C. gattii, C. neoformans, C. albicans or H. capsulatum; (II) construction of lentiviral vector to express a CAR specific for each fungi, and to do the transduction of the Jurkat cells to evaluate the recognition and activation triggered by CAR in the presence of the target; (III) redirection of CAR T cells and CAR NK cells for each fungi, and to analyze the effector activity of these modified cells against in vitro and in vivo infection by C. gattii, C. neoformans, C. albicans ou H. capsulatum. The current proposal has strong evidence that redirected T and NK cells by CAR to target fungi into the infection site can mediate a protective immune response against IFIs. Thus, this project opens perspectives for clinical application with high impact in the scientific field, and some steps from this project can produce a patent process due the relevance of CAR T cells in the cell therapy. Keywords: T cells; NK cells; Invasive fungal infections; CAR; Cell therapy. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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Scientific publications (7)
(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)
DOS SANTOS, MATHEUS HENRIQUE; MACHADO, MICHELE PROCOPIO; KUMARESAN, PAPPANAICKEN R.; DA SILVA, THIAGO APARECIDO. Titan Cells and Yeast Forms of Cryptococcus neoformans and Cryptococcus gattii Are Recognized by GXMR-CAR. MICROORGANISMS, v. 9, n. 9, . (18/18538-0, 20/09113-6, 19/26074-7, 20/11307-3)
DE CAMPOS, GABRIELA YAMAZAKI; OLIVEIRA, RAQUEL AMORIM; MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. Pro-inflammatory response ensured by LPS and Pam3CSK4 in RAW 264.7 cells did not improve a fungistatic effect on Cryptococcus gattii infection. PeerJ, v. 8, . (16/17037-2, 18/21708-5, 18/18538-0, 18/19949-4)
DOS SANTOS, MATHEUS HENRIQUE; MACHADO, MICHELE PROCOPIO; KUMARESAN, PAPPANAICKEN R.; DA SILVA, THIAGO APARECIDO. Modification of Hinge/Transmembrane and Signal Transduction Domains Improves the Expression and Signaling Threshold of GXMR-CAR Specific to Cryptococcus spp.. CELLS, v. 11, n. 21, p. 20-pg., . (18/18538-0, 20/09113-6, 20/11307-3, 19/26074-7)
MARTINS OLIVEIRA-BRITO, PATRICIA KELLEN; DE CAMPOS, GABRIELA YAMAZAKI; GUIMARAES, JULIA GARCIA; DA COSTA, LETICIA SERAFIM; DE MOURA, EDANIELLE SILVA; LAZO-CHICA, JAVIER EMILIO; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. Adjuvant Curdlan Contributes to Immunization against Cryptococcus gattii Infection in a Mouse Strain-Specific Manner. VACCINES, v. 10, n. 4, p. 26-pg., . (19/13979-1, 19/09261-8, 18/18538-0, 19/09260-1, 18/19949-4, 16/04877-2, 18/21708-5, 19/26074-7)
DA SILVA, THIAGO APARECIDO. CAR T cell-therapy for infectious diseases with emphasis on invasive fungal infections. THERAPEUTIC DELIVERY, v. 12, n. 9, p. 4-pg., . (18/18538-0)
BARBOZA, BRUNO RAFAEL; THOMAZ, SANDRA MARIA DE OLIVEIRA; DE CARVALHO, AIRTON; ESPREAFICO, ENILZA MARIA; MIYAMOTO, JACKSON GABRIEL; TASHIMA, ALEXANDRE KEIJI; CAMACHO, MAURICIO FROTA; ZELANIS, ANDRE; ROQUE-BARREIRA, MARIA CRISTINA; DA SILVA, THIAGO APARECIDO. ArtinM Cytotoxicity in B Cells Derived from Non-Hodgkin's Lymphoma Depends on Syk and Src Family Kinases. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 2, p. 24-pg., . (16/04877-2, 18/18538-0, 18/21708-5, 19/05867-9, 17/20106-9)
SILVA, THIAGO APARECIDO DA; HAUSER, PAUL J.; BANDEY, IRFAN; LASKOWSKI, TAMARA; WANG, QI; NAJJAR, AMER M.; KUMARESAN, PAPPANAICKEN R.. Glucuronoxylomannan in the Cryptococcus species capsule as a target for Chimeric Antigen Receptor T-cell therapy. CYTOTHERAPY, v. 23, n. 2, p. 119-130, . (16/04877-2, 18/18538-0, 16/23044-1)

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