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

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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.

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Abbreviations

NK cells:

Natural killer cells

HNSCC:

Head and neck squamous cell carcinoma

NC:

Normal controls

KIR:

Killer immunoglobulin-like receptor

TGF-β:

Transforming growth factor beta

rhIL-2:

Recombinant human interleukin 2

AJCC:

American joint committee on cancer

NCR:

Natural cytotoxicity receptor

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Acknowledgments

Supported in part by NIH grant PO-1 CA 109688 to TLW. BS was supported by a grant from IRX Therapeutics Inc.

Conflict of interest

Two of the authors (BS and JEE) received support from IRX Therapeutics Inc. The other authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    B. Schilling, P. Schuler, M. Harasymczuk & T. L. Whiteside

  2. University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Center Avenue, Suite 1.32d, Pittsburgh, PA, 15213-1863, USA

    B. Schilling, P. Schuler, M. Harasymczuk & T. L. Whiteside

  3. Penn State Hershey Children’s Hospital, Hershey, PA, USA

    E. S. Halstead

  4. IRX Therapeutics Inc., Farmingdale, NY, USA

    J. E. Egan

Authors
  1. B. Schilling
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  2. E. S. Halstead
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  3. P. Schuler
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  4. M. Harasymczuk
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  5. J. E. Egan
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  6. T. L. Whiteside
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Correspondence to T. L. Whiteside.

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Schilling, B., Halstead, E.S., Schuler, P. et al. IRX-2, a novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients. Cancer Immunol Immunother 61, 1395–1405 (2012). https://doi.org/10.1007/s00262-011-1197-x

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  • DOI: https://doi.org/10.1007/s00262-011-1197-x

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