IL-27-engineered CAR.19-NK-92 cells exhibit enhanced therapeutic efficacy

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Biggi, Alison Felipe Bordini ; Silvestre, Renata Nacasaki ; Tirapelle, Mariane Cariati ; de Azevedo, Julia Teixeira Cottas ; Garcia, Henry David Mogollo ; dos Santos, Matheus Henrique ; de Lima, Sarah Caroline Gomes ; de Souza, Lucas Eduardo Botelho ; Covas, Dimas Tadeu ; Malmegrim, Kelen Cristina Ribeiro ; Figueiredo, Marxa L. ; Picanco-Castro, Virginia

• Document type: Journal article
• Source: CYTOTHERAPY; v. 26, n. 11, p. 11-pg., 2024-10-11.

Abstract

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells has shown promising results in early- phase clinical studies. However, advancing CAR-NK cell therapeutic efficacy is imperative. In this study, we investigated the impact of a fourth-generation CD19-targeted CAR (CAR.19) coexpressing IL-27 on NK-92 cells. We observed a significant improvement in NK-92 cell proliferation and cytotoxicity activity against B-cell cancer cell lines, both in vitro and in a xenograft mouse B-cell lymphoma model. Our systematic transcriptome analysis of the activated NK-92 CAR variants further supports the potential of IL-27 in fourth-generation CARs to overcome limitations of NK cell-based targeted tumor therapies by providing essential growth and activation signals. Integrating IL-27 into CAR-NK cells emerges as a promising strategy to enhance their therapeutic potential and elicit robust responses against cancer cells. These findings contribute substantially to the mounting evidence supporting the potential of fourth-generation CAR engineering in advancing NK cell-based immunotherapies. (c) 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) (AU)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/25309-0 - Off-the-shelf engineered NK cells for the treatment of Leukemia and Lymphoma treatment
• Grantee: Virginia Picanço e Castro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/08279-8 - Establishment of a platform for generating NK-CAR cells with greater therapeutic effectiveness in vitro and in vivo
• Grantee: Júlia Teixeira Cottas de Azevedo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/07055-9 - Nucleus of Cellular Therapy - NuTeC
• Grantee: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Support Opportunities: Research Grants - Problem-Oriented Research Centers in São Paulo