Engineering NK-CAR.19 cells with the IL-15/IL-15Rα complex improved proliferation and anti-tumor effect in vivo

Frontiers in Immunology

Immunology

Renata Nacasaki Silvestre¹  Lucas Eduardo Botelho de Souza¹  Rodrigo T. Calado¹  Dimas Tadeu Covas¹  Mariane Cariati Tirapelle¹  Julia Teixeira Cottas de Azevedo¹  Kamilla Swiech¹  Virginia Picanço-Castro¹  Daianne Maciely Carvalho Fantacini¹  Kelen Cristina Ribeiro Malmegrim²  Marxa L. Figueiredo³  Jiri Eitler⁴  Paola Ortiz Montero⁴  Torsten Tonn⁵ 

[1] Center for Cell-based Therapy CTC, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil;Center for Cell-based Therapy CTC, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil;Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil;Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, United States;Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany;Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden, Germany;German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany;

关键词: CAR-NK cells;    NK-92;    adoptive cell therapy;    IL-15;    IL-15 receptor;    B-cell malignances;    allogeneic therapy;   

DOI  :  10.3389/fimmu.2023.1226518

 received in 2023-05-21, accepted in 2023-09-01,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionNatural killer 92 (NK-92) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers, different from T cells, once they can be used in the allogeneic setting. The modest in vivo outcomes observed with NK-92 cells continue to present hurdles in successfully translating NK-92 cell therapies into clinical applications. Adoptive transfer of CAR-NK-92 cells holds out the promise of therapeutic benefit at a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, it has not achieved breakthrough clinical results yet, and further improvement of CAR-NK-92 cells is necessary. MethodsIn this study, we conducted a comparative analysis between CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) with IL-15/IL-15Rα (CAR.19-IL15/IL15Rα) to promote NK cell proliferation, activation, and cytotoxic activity against B-cell leukemia. CAR constructs were cloned into lentiviral vector and transduced into NK-92 cell line. Potency of CAR-NK cells were assessed against CD19-expressing cell lines NALM-6 or Raji in vitro and in vivo in a murine model. Tumor burden was measured by bioluminescence. ResultsWe demonstrated that a fourth- generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15Rα (CAR.19-IL-15/IL-15Rα) significantly enhanced NK-92 cell proliferation, proinflammatory cytokine secretion, and cytotoxic activity against B-cell cancer cell lines in vitro and in a xenograft mouse model. ConclusionTogether with the results of the systematic analysis of the transcriptome of activated NK-92 CAR variants, this supports the notion that IL-15/IL-15Rα comprising fourth-generation CARs may overcome the limitations of NK-92 cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals.

【 授权许可】

Unknown   
Copyright © 2023 Silvestre, Eitler, de Azevedo, Tirapelle, Fantacini, de Souza, Swiech, Covas, Calado, Montero, Malmegrim, Figueiredo, Tonn and Picanço-Castro