Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer

Michael J. Robertson, Christine Cameron, Michael B. Atkins, Michael S. Gordon, Michael T. Lotze, Matthew L. Sherman, Jerome Ritz

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

The immunological effects of recombinant human interleukin 12 (rhIL-12) administration were examined during the conduct of a Phase I clinical trial. Forty patients with advanced cancer received bolus i.v. injections of rhIL- 12 in doses ranging between 3 and 1000 ng/kg. Dose-dependent increases in serum IFN-γ levels were seen during rhIL-12 therapy. Significant lymphopenia was observed 24 h after single i.v. injections of rhIL-12 at each dose level. The degree of lymphopenia was dose dependent, and a plateau effect was seen with rhIL-12 doses of 100 ng/kg and higher. Lymphocyte counts reached nadir levels at approximately 10 h after rhIL-12 injection and returned to baseline within 14 days postinjection. Rebound lymphocytosis, as seen after interleukin 2 therapy, was not observed after recovery from rhIL-12-induced lymphopenia, rhIL-12-induced lymphopenia involved all major lymphocyte subsets, although natural killer (NK) cell numbers were the most profoundly affected, and CD4 T-cell numbers were the least affected. CD2, LFA-1, and CD56 were transiently up-regulated on the surface of NK cells exposed to rhIL-12 in vivo. Peripheral blood mononuclear cells obtained from cancer patients before rhIL-12 therapy exhibited defective NK cell cytotoxicity and T-cell-proliferative responses. Peripheral blood mononuclear cells obtained after lymphocyte recovery following the administration of a single 500 ng/kg dose of rhIL-12 displayed augmented NK cell cytolytic activity in four of four patients tested and enhanced T-cell proliferation in three of four patients tested. These studies confirm that doses of rhIL-12 resulting in significant immunological activity can be administered with acceptable toxicity to cancer patients. Furthermore, rhIL-12 therapy can reverse defects in NK cell and T-cell function that are associated with advanced cancer in humans.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalClinical Cancer Research
Volume5
Issue number1
StatePublished - 1999

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Robertson, M. J., Cameron, C., Atkins, M. B., Gordon, M. S., Lotze, M. T., Sherman, M. L., & Ritz, J. (1999). Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer. Clinical Cancer Research, 5(1), 9-16.