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

Research output: Contribution to journalArticle

15 Scopus citations


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
Issue number6
StatePublished - Jul 1 2013



  • 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