A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-hodgkin Lymphoma

Michael J. Robertson, Justin Kline, Herbert Struemper, Kevin M. Koch, John W. Bauman, Olivia S. Gardner, Sharon C. Murray, Fiona Germaschewski, Jill Weisenbach, Zdenka Jonak, John F. Toso

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15 Scopus citations

Abstract

Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20 lymphoma. Cohorts of 3-4 patients were given infusions of rituximab (375 mg/m) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20 B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 μg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.

Original languageEnglish (US)
Pages (from-to)331-341
Number of pages11
JournalJournal of Immunotherapy
Volume36
Issue number6
DOIs
StatePublished - Jul 1 2013

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Keywords

  • IFN-γ
  • IL-18
  • Lymphoma
  • Rituximab

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

Robertson, M. J., Kline, J., Struemper, H., Koch, K. M., Bauman, J. W., Gardner, O. S., Murray, S. C., Germaschewski, F., Weisenbach, J., Jonak, Z., & Toso, J. F. (2013). A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-hodgkin Lymphoma. Journal of Immunotherapy, 36(6), 331-341. https://doi.org/10.1097/CJI.0b013e31829d7e2e