title: Pharmacokinetics and immunological aspects of a phase Ib study with intratumoral administration of recombinant human interleukin-12 in patients with head and neck squamous cell carcinoma: a decrease of T-bet in peripheral blood mononuclear cells.
abstract: The aim of this study was to evaluate the tolerability of intratumoral administered recombinant human interleukin-12 (rhIL-12) in patients with head and neck squamous cell carcinoma. Six patients were treated once a week at two dose levels of 100 or 300 ng/kg, respectively, up to 24 weeks. The primary end point was to assess the toxicity and safety of intratumoral injected rhIL-12 in head and neck squamous cell carcinoma patients; the pharmacokinetics and pharmacodynamics of rhIL-12 and any evidence of antitumor effect were also determined. Toxicity was mild, with prolonged grade 4 lymphopenia observed in only one patient. No dose-limiting toxicities occurred. In all six patients, the rhIL-12 was detectable in plasma within 30 min. Significant reductions in absolute number of peripheral blood lymphocytes and all lymphocyte subsets, especially cytotoxic T cells and natural killer cells, were observed that were maximal between 12 and 24 h. Maximal plasma concentrations of IFN-gamma and IL-10 were detected after 12 h. A real-time semiquantitative PCR analysis in peripheral blood mononuclear cells showed a mean increase of mRNA encoding IFN-gamma of 2.2 times relative to the pretreatment sample. An unexpected, significant decrease of 80% in T-bet mRNA, a T-helper 1 transcription factor, was detected after 12 h, with normalization after 48-72 h. No complete or partial responses were observed. In one patient, a 40% regression of a tumor lesion was noted. In conclusion, rhIL-12 at these dose levels and schedule was well tolerated and resulted in measurable immunological responses.
authors.affiliation: Department of Medical Oncology, UMC Nijmegen, 6500 HB Nijmegen, the Netherlands. vanherpen@onco.umcn,nl
authors.forename: Carla M
authors.initials: CM
authors.lastname: Van Herpen
authors.forename: Richard
authors.initials: R
authors.lastname: Huijbens
authors.forename: Maaike
authors.initials: M
authors.lastname: Looman
authors.forename: Jolanda
authors.initials: J
authors.lastname: De Vries
authors.forename: Henri
authors.initials: H
authors.lastname: Marres
authors.forename: Johanna
authors.initials: J
authors.lastname: Van De Ven
authors.forename: Rob
authors.initials: R
authors.lastname: Hermsen
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Pieter H
authors.initials: PH
authors.lastname: De Mulder
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma