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Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma—safety and efficacy in a phase II study

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Abstract

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

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Abbreviations

AEC:

Absolute eosinophil counts

AJCC:

American Joint Committee on Cancer

CR:

Complete response

irDCR:

Immune-related disease control rate

irRC:

Immune-related response criteria

MIU:

Million international units

mWHO:

Modified World Health Organization

PR:

Partial responses

RLC:

Relative lymphocyte counts

SD:

Stable disease

Tregs:

Regulatory T cells

T-VEC:

Talimogene laherparepvec

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Acknowledgements

This study was funded by Bristol–Myers–Squibb (Munich, Germany) to B. Weide.

Author information

Authors and Affiliations

  1. Department of Dermatology, University Hospital Tübingen, Tübingen, Germany

    Benjamin Weide, Alexander Martens, Kilian Wistuba-Hamprecht, Daniel Soffel, Thomas K. Eigentler & Claus Garbe

  2. Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany

    Alexander Martens & Kilian Wistuba-Hamprecht

  3. Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tübingen, Tübingen, Germany

    Henning Zelba

  4. University Hospital Ulm Pharmacy, University Hospital Ulm, Ulm, Germany

    Ludwig Maier

  5. Department of Hospital Pharmacy, University Hospital Tübingen, Tübingen, Germany

    Hans-Peter Lipp

  6. Department for Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany

    Bernhard D. Klumpp

Authors
  1. Benjamin Weide
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  5. Ludwig Maier
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  8. Daniel Soffel
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Corresponding author

Correspondence to Benjamin Weide.

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Conflict of interest

B Weide reports receiving commercial research grants from Bristol–Myers Squibb (BMS) and MSD Sharp and Dohme (MSD) and reports receiving travel/accommodations/expenses from BMS, MSD, Roche, Amgen, Philogen, Curevac and compensated advisory services for MSD, BMS, Philogen and Curevac. C. Garbe reports receiving honoraria from BMS, MSD, Amgen, Novartis, Roche, GlaxoSmithKline (GSK) and reports receiving commercial research grants from MSD, BMS, Roche, GSK. T.K Eigentler reports receiving honoraria from BMS, MSD, Roche and Novartis, travel/accommodations/expenses from BMS and is a consultant/advisory board member for BMS. No potential conflicts of interest were disclosed by the other authors.

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Weide, B., Martens, A., Wistuba-Hamprecht, K. et al. Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma—safety and efficacy in a phase II study. Cancer Immunol Immunother 66, 441–449 (2017). https://doi.org/10.1007/s00262-016-1944-0

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  • DOI: https://doi.org/10.1007/s00262-016-1944-0

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