2B4 (CD244) Signaling by Recombinant Antigen-specific Chimeric Receptors Costimulates Natural Killer Cell Activation to Leukemia and Neuroblastoma Cells
- 29 July 2009
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 15 (15), 4857-4866
- https://doi.org/10.1158/1078-0432.ccr-08-2810
Abstract
Purpose: Novel natural killer (NK) cell–directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. The signaling lymphocyte activation molecule–related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell–resistant and autologous leukemia and tumor targets. Experimental Design: In vitro–stimulated NK cells from healthy donors and pediatric leukemia patients were gene modified with CD19 or GD2-specific chimeric receptors containing either the T-cell receptor ζ or 2B4 endodomain alone or combined. Results: Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into T-cell receptor ζ chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-γ and tumor necrosis factor-α, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity. Conclusion: These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4ζ-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.Keywords
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This publication has 46 references indexed in Scilit:
- Engineering antigen-specific primary human NK cells against HER-2 positive carcinomasProceedings of the National Academy of Sciences of the United States of America, 2008
- Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cellsPublished by American Society of Hematology ,2008
- Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia XenograftsClinical Cancer Research, 2007
- Adoptive Transfer of Chimeric Antigen Receptor Re-directed Cytolytic T Lymphocyte Clones in Patients with NeuroblastomaMolecular Therapy, 2007
- Modulation of 2B4 (CD244) activity and regulated SAP expression in human NK cellsEuropean Journal of Immunology, 2007
- A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian CancerClinical Cancer Research, 2006
- Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cellsBlood, 2005
- Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancerBlood, 2005
- Analysis of the receptor-ligand interactions in the natural killer–mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112)Blood, 2005
- Effectiveness of Donor Natural Killer Cell Alloreactivity in Mismatched Hematopoietic TransplantsScience, 2002