Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes.
The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-gamma and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-gamma mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels.
van Herpen
Carla M
CM
Department of Medical Oncology, UMC Nijmegen, Nijmegen, The Netherlands. C.vanherpen@onco.umcn.nl
Looman
Maaike
M
Zonneveld
Marijke
M
Scharenborg
Nicole
N
de Wilde
Peter C
PC
van de Locht
Louis
L
Merkx
Matthias A W
MA
Adema
Gosse J
GJ
de Mulder
Pieter H
PH
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D005260:Female; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology*; D016131:Lymphocyte Subsets / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000166:cytology*; D013997:Time Factors; D016896:Treatment Outcome
D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma