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A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab

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Abstract

Trastuzumab mediates the lysis of HER2-expressing breast cancer cell lines by interleukin-2 (IL-2) primed natural killer (NK) cells. We hypothesized that IL-2 would augment the anti-tumor effects of trastuzumab in MBC in patients who had progressed on or within 12 months of receiving a trastuzumab-containing regimen. Secondary objectives were to measure antibody-directed cellular cytotoxicity (ADCC) against HER2 over-expressing target cells, and to measure serum cytokines. Patients received trastuzumab (4 mg/kg intravenously (IV)) every 2 weeks in combination with daily low-dose IL-2 (1 million IU/m2 subcutaneously (SC)) and pulsed intermediate-dose IL-2 (12 million IU/m2 SC). Samples were analyzed for NK cell expansion and ADCC against a HER2-positive breast cancer cell line. In addition, interferon-gamma (IFN-γ), mRNA expression in peripheral blood mononuclear cells (PBMC) and the following serum cytokines were measured: IFN-γ, monokine-induced by IFN-γ (MIG), and interferon-inducible protein ten (IP-10). The median number of treatment cycles was four (range 1–23) and the treatment was well tolerated. There were no objective responses. NK cells were not expanded and ADCC was not enhanced. Eight (62%) patients had a twofold or higher increase in mRNA transcript for IFN-γ, two (15%) patients had elevated serum levels of IFN-γ and 12 (92%) had increases angiogenic MIG and IP-10. In trastuzumab-refractory patients adding IL-2 did not produce responses and did not result in NK cell expansion. However, these patients had the ability to respond to IL-2 as evidenced by increases in IFN-γ transcripts and chemokines. The lack of NK cell expansion may explain the absence of clinical benefit.

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Acknowledgments

The authors wish to thank Amy Stark MS for biostatistical support, and all the patients and their families who participated in this trial. This work was supported by an unrestricted grant from Genentech and the NIH/NCI grants P30 (CA16058-29), K24 (CA93670-02), P01 CA95426, U01 (CA76576-07) and N01 (CM-62201). AM is a NRSA T32 fellow (5T32CA009338-28).

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Ohio State University Medical Center, Starling Loving Hall Rm B405, 320 W. 10th Avenue, Columbus, OH, 43210, USA

    Aruna Mani, Michael A. Caligiuri & Charles L. Shapiro

  2. Integrated Biomedical Sciences Graduate Program, Department of Molecular Virology, Ohio State University, Columbus, OH, USA

    Julie Roda

  3. Department of Biostatistics, Ohio State University, Columbus, OH, USA

    Donn Young

  4. University of Chicago, Chicago, IL, USA

    Gini F. Fleming

  5. Dartmouth University, Hanover, NH, USA

    Peter Kaufman

  6. University of Pittsburgh, Pittsburgh, PA, USA

    Adam Brufsky

  7. Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Susan Ottman

  8. Division of Surgical Oncology, Department of Surgery, Ohio State University, Columbus, OH, 43210, USA

    William E. Carson III

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  1. Aruna Mani
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  2. Julie Roda
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  3. Donn Young
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  9. William E. Carson III
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  10. Charles L. Shapiro
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Correspondence to Charles L. Shapiro.

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Mani, A., Roda, J., Young, D. et al. A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab. Breast Cancer Res Treat 117, 83–89 (2009). https://doi.org/10.1007/s10549-008-0251-7

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  • DOI: https://doi.org/10.1007/s10549-008-0251-7

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