IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients.

Abstract

BACKGROUND:

IRX-2 is a primary biologic which has been used for the therapy of head and neck squamous cell cancer (HNSCC) with promising clinical results. Since NK-cell function is compromised in HNSCC patients, we tested the effects of IRX-2 on the restoration of human NK-cell functions in vitro.

METHODS:

Peripheral blood mononuclear cells (PBMC) were isolated from 23 HNSCC patients and 10 normal controls (NC). The NK-cell phenotype and functions were compared before and after culture ± IRX-2 or ± 50 IU/ml rhIL-2. Flow cytometry was used to study the NK-cell phenotype, cytotoxic activity and cytokine expression.

RESULTS:

Impaired NK-cell cytotoxicity in HNSCC patients was related to lower expression of NKG2D, NKp30 and NKp46 receptors (P < 0.05) and not to a decreased frequency of NK cells. Incubation of patients' NK cells with IRX-2 up-regulated the percentage of receptor-positive NK cells (P < 0.05). It also up-regulated cytotoxicity of patients' NK cells (P < 0.01) more effectively than rhIL-2 (P < 0.01). IRX-2, but not rhIL-2, protected NK cells from suppression mediated by TGF-β, and it restored (P < 0.05) expression of activating NK-cell receptors and NK-cell cytotoxicity suppressed by TGF-β. Expression of pSMAD was decreased in NK cells treated with IRX-2 but not in those treated with rhIL-2.

CONCLUSIONS:

IRX-2 was more effective than IL-2 in enhancing NK-cell cytotoxicity and protecting NK-cell function of HNSCC patients in vitro, emphasizing the potential advantage of IRX-2 as a component of future therapies for HNSCC.

• Authors: B Schilling, E S Halstead, P Schuler, M Harasymczuk, J E Egan, T L Whiteside
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 61 Issue 9 Pg. 1395-405 (Sep 2012) ISSN: 1432-0851 [Electronic] Germany
• PMID: 22270713 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• IRX 2
• Interleukin-2
• KLRK1 protein, human
• NCR1 protein, human
• NCR3 protein, human
• NK Cell Lectin-Like Receptor Subfamily K
• Natural Cytotoxicity Triggering Receptor 1
• Natural Cytotoxicity Triggering Receptor 3
• Smad Proteins
• Transforming Growth Factor beta1

Topics

• Carcinoma, Squamous Cell (blood, immunology, therapy)
• Cytokines (immunology, pharmacology)
• Cytotoxicity, Immunologic (drug effects, immunology)
• Flow Cytometry
• Head and Neck Neoplasms (blood, immunology, therapy)
• Humans
• Immunotherapy
• Interleukin-2 (immunology, pharmacology)
• K562 Cells
• Killer Cells, Natural (drug effects, immunology)
• Leukocytes, Mononuclear (drug effects, immunology)
• NK Cell Lectin-Like Receptor Subfamily K (biosynthesis, immunology)
• Natural Cytotoxicity Triggering Receptor 1 (biosynthesis, immunology)
• Natural Cytotoxicity Triggering Receptor 3 (biosynthesis, immunology)
• Phosphorylation (drug effects)
• Smad Proteins (biosynthesis, immunology)
• Transforming Growth Factor beta1 (immunology, pharmacology)
• Up-Regulation (drug effects, immunology)