Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma.
Preclinical studies have shown that low dose IL-12 can potentiate cytotoxic lymphocyte responses. Since previous trials have demonstrated significant toxicity from high dose recombinant human IL-12 (rhIL-12), we sought to determine an optimal biological dose for rhIL-12 at lower doses when combined with peptide antigens. Two studies were undertaken. The rhIL-12 was administered at doses of 0 (placebo), 10, 30 and 100 ng/kg, subcutaneously in one study and intravenously in the other. Apart from IL-12 dosing, the studies were identical. Subjects had evaluable stage III or IV melanoma which expressed Melan-A by RT-PCR or immunohistochemistry. Melan-A (26-35) (EAAGIGILTV) and influenza matrix (58-66) (GILGFVFTL) peptides were administered intradermally on weeks 1, 2, 3, 4 and 9. Twenty-eight subjects were enrolled, of whom 24 were evaluable for clinical and immunological responses. Therapy was well tolerated, the main adverse event being influenza-like symptoms. Immunological monitoring included the evaluation of cutaneous reactions and assays for antigen-specific T-cells. Clinical responses included a complete response in a subject with small volume subcutaneous disease, a partial response in a subject with hepatic metastases, and mixed responses in pulmonary, pleural and nodal disease. Biopsies of accessible tumors showed infiltration with CD4+ and CD8+ lymphocytes capable of lysing Melan-A peptide-pulsed targets in vitro. No clear dose-dependent effect of rhIL-12 could be determined. The rhIL-12 given either s.c. or i.v. was well tolerated at doses of 10-100 ng/kg. Clinical and immunological activity has been observed in this study where peptides were administered either with or without low dose rhIL-12.
Cebon
Jonathan
J
Ludwig Institute for Cancer Research, Melbourne, Australia. jonathan.cebon@ludwig.edu.au
Jäger
Elke
E
Shackleton
Mark J
MJ
Gibbs
Peter
P
Davis
Ian D
ID
Hopkins
Wendie
W
Gibbs
Sharen
S
Chen
Qiyuan
Q
Karbach
Julia
J
Jackson
Heather
H
MacGregor
Duncan P
DP
Sturrock
Sue
S
Vaughan
Hilary
H
Maraskovsky
Eugene
E
Neumann
Antje
A
Hoffman
Eric
E
Sherman
Mathew L
ML
Knuth
Alexander
A
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000009:adverse effects / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D009980:Influenza A virus / Q000737:chemistry; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014763:Viral Matrix Proteins / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; C098952:influenza virus membrane protein (58-66); D018664:Interleukin-12