title: Phase I study of the sequential combination of interleukin-12 and interferon alfa-2b in advanced cancer: evidence for modulation of interferon signaling pathways by interleukin-12.
abstract: OBJECTIVE
  To evaluate the safety of sequentially administered recombinant (r) human (h) interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) in patients with advanced cancer and to determine the effects of endogenously produced IFN-gamma on Janus kinase-signal transducer and activator of transcription (Jak-STAT) signal transduction in patient peripheral-blood mononuclear cells (PBMCs).
  
  
  METHODS
  Forty-nine patients with metastatic cancer received rhIL-12 on day 1 and IFN-alpha-2b on days 2 to 6 of either a 14-day (n = 43) or a 7-day treatment cycle (n = 6). rhIL-12 was initially administered subcutaneously at a dose of 100 ng/kg, whereas IFN-alpha-2b was escalated from 1 to 10 million units (MU) in cohorts of three patients (1, 3, 5, 7, or 10 MU). rhIL-12 was subsequently administered intravenously (IV) in escalating doses (100 to 500 ng/kg) to achieve greater IFN-gamma production. Peripheral blood was drawn for measurement of plasma IFN-gamma and the induction of Jak-STAT signal transduction in PBMCs.
  
  
  RESULTS
  No IL-12-or IFN-alpha-related dose-limiting toxicities were observed. There were no responses in 41 assessable patients. Five patients exhibited stable disease lasting 6 months or longer while on therapy. Optimal induction of IFN-gamma by IL-12 occurred after an IV dose of 250 ng/kg. Patient PBMCs exhibited increased levels of STAT1 after IL-12 administration. The peak level of IFN-gamma achieved with IL-12 therapy correlated with the peak level of intracellular STAT1 in patient PBMCs (r = 0.38, P = .021).
  
  
  CONCLUSIONS
  The combination of rhIL-12 and IFN-alpha-2b can be administered sequentially with minimal toxicity. IV administration of rhIL-12 modulates IFN-alpha-induced Jak-STAT signal transduction in patient PBMCs.
authors.affiliation: Division of Hematology, The Ohio State University, Columbus, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Eisenbeis
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.forename: Mirela
authors.initials: M
authors.lastname: Anghelina
authors.forename: Robin
authors.initials: R
authors.lastname: Parihar
authors.forename: Daniel
authors.initials: D
authors.lastname: Valentino
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Padma
authors.initials: P
authors.lastname: Nadella
authors.forename: Poongothai
authors.initials: P
authors.lastname: Sundaram
authors.forename: Donn C
authors.initials: DC
authors.lastname: Young
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Walker
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma