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TGF-²RII Knock-out iPSC-derived anti-MAGE-A4 CAR-NK cells for the treatment of melanoma.

Grant number: 23/12325-3
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 01, 2024
Effective date (End): January 31, 2025
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Virginia Picanço e Castro
Grantee:Sima Ebrahimabadi
Supervisor: Dan Kaufman
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
Research place: University of California, San Diego (UC San Diego), United States  
Associated to the scholarship:21/06359-7 - Anti-MAGE-A4 CAR-NK cell therapy for the treatment of Melanoma, BP.DR

Abstract

Chimeric antigen receptor (CAR)-cell based therapies has emerged as a promising strategy in the field of cancer treatment. Natural killer (NK) cells are innate immune cells with the ability to exert rapid cytotoxicity against transformed and virus-infected cells without prior sensitization and in an HLA-unrestricted manner, which makes it a suitable candidate for "off-the-shelf" cancer immunotherapy and might circumvent some of the limitations of CAR-T cell therapy. CAR-NK cells are safer for clinical use as they have a shorter lifespan after infusion, reducing on-target/off-tumor toxicity. Also, in case of the allogeneic CAR-NK cell setting, they show lower risk for graft versus host disease (GVHD), Cytokine release syndrome (CRS) and neurotoxicity. Moreover, NK cells can be obtained from different sources, such as peripheral blood cells (PB), umbilical cord blood cells (UCB), human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) and NK cell lines like NK-92, thus bringing "off-the-shelf" products availability closer to the clinic. iPSC-derived NK cells are a potential source of NK cells as they are uniform, reproducible, and unlimited source of NK cells with the benefit of eliminating the donor-to-donor variability. Also, the ability to routinely genetically modify iPSCs, opens opportunities to improve the anti-tumor activity and in vivo persistence of iPSC-derived NK cells.While CAR-based therapies have been most successful for the treatment of hematological malignancies, treatment of solid tumors has been more challenging. In part, this is due to the immunosuppressive tumor microenvironment of solid tumors. TGF-² is one of the immunosuppressive factors secreted by tumor-associated cells in tumor microenvironment that can lead to tumor growth, tumor angiogenesis, and inhibition of T and NK cell proliferation, cytokine production and cytotoxicity. One of the gene modifications in NK cells to overcome the immunosuppressive role of TGF-² is to knock-out TGF-² receptor 2 (TGF-²RII) gene using CRISPR/Cas9 technology. Studies show that TGF-²RII gene knock-out improves NK cells cytotoxicity and persistence in the tumor microenvironment. The ongoing doctoral project (FAPESP, Process No. 2021/06359-7) aims to evaluate the cytotoxic efficacy of the anti-MAGE-A4-CAR-NK cells targeting the complex of the MAGE-A4/HLA-A2 presented on the surface of melanoma cell line. In this regard, to exchange knowledge in the field of cancer immunotherapy, our group intends to evaluate the present anti-MAGE-A4-CAR in TGF-²RII Knock-out iPSC-derived NK cells platform developed by Dr. Kaufman and his team.

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