A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients.
OBJECTIVE
On the basis of preclinical studies, we hypothesized that interleukin (IL)12 would potentiate the antitumor actions of an antihuman epidermal growth factor receptor-2 (HER2) monoclonal antibody (trastuzumab). We conducted a Phase I trial to determine the safety and optimal biological dose of IL-12 when given in combination with trastuzumab.


METHODS
Patients with metastatic HER2-positive malignancies received trastuzumab on day 1 of each weekly cycle. Beginning in week 3, patients also received intravenous injections of IL-12 on days 2 and 5. The IL-12 component was dose-escalated within cohorts of 3 patients (30, 100, 300, or 500 ng/kg). Correlative assays were conducted using serum samples and peripheral blood cells obtained during the course of therapy.


RESULTS
Fifteen patients were treated, including 12 with HER2 2+ or 3+ breast cancer. The regimen was well tolerated with IL-12-induced grade 1 nausea and grade 2 fatigue predominating. Evaluation of dose-limiting toxicity and biological end points suggested that the 300 ng/kg dose was both the maximally tolerated dose and the optimal biological dose of IL-12 for use in combination with trastuzumab. Two patients with HER2 3+ breast cancer within the 500 ng/kg dose level experienced grade 1 asymptomatic decreases in left ventricular ejection fraction of 12% and 19% after 3 and 10 months of therapy, respectively. There was one complete response in a patient with HER2 3+ breast cancer metastatic to the axillary, mediastinal, and supraclavicular nodes, and 2 patients with stabilization of bone disease lasting 10 months and >12 months, respectively. Correlative assays showed sustained production of interferon (IFN)gamma by natural killer cells only in those patients experiencing a clinical response or stabilization of disease. Elevated serum levels of macrophage inflammatory protein-1alpha, tumor necrosis factor-alpha, and the antiangiogenic factors IFN-gamma inducible protein-10 and monokine induced by gamma were also observed in these patients. Patient genotyping suggested that a specific IFN-gamma gene polymorphism might have been associated with increased IFN-gamma production. The ability of patient peripheral blood cells to conduct antibody-dependent cellular cytotoxicity against tumor targets in vitro did not correlate with clinical response or dose of IL-12.


CONCLUSIONS
The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment. Sustained production of IFN-gamma and other cytokines were observed in three patients: One who exhibited a complete response and two others who had stabilization of disease lasting over 6 months. Given the small sample size and heterogeneity of the patient population, the effects of IL-12 on the innate immune response to trastuzumab therapy should be further explored in the context of a larger clinical trial.
Parihar
Robin
R
Department of Molecular Virology, Immunology, and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.
Nadella
Padma
P
Lewis
Adrian
A
Jensen
Rhonda
R
De Hoff
Carrie
C
Dierksheide
Julie E
JE
VanBuskirk
Anne M
AM
Magro
Cynthia M
CM
Young
Donn C
DC
Shapiro
Charles L
CL
Carson
William E
WE
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D054407:Chemokine CCL4; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000628:therapy*; D011110:Polymorphism, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054407:Chemokine CCL4; D016207:Cytokines; D066246:ErbB Receptors; D007371:Interferon-gamma; D018664:Interleukin-12; D019402:Macrophage Inflammatory Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014409:Tumor Necrosis Factor-alpha