Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma.
Previous studies have suggested that immunotherapy with dendritic cell (DC) vaccines may be effective in treatment of patients with AJCC stage IV melanoma. We examined this treatment in phase I/II studies in 33 patients with good performance status and low volume disease. Nineteen patients received DCs plus autologous lysates and 14 patients DCs plus peptides from the melanoma antigens MAGE-3.A2, tyrosinase, gp100, and MART-1. Keyhole limpet hemocyanin (KLH) was used as a helper protein and influenza peptide was given as a positive control. DCs were produced from adherent cells in blood lymphocytes (monocytic DCs), grown in IL-4 and GM-CSF without a maturation step. The DCs were injected into inguinal lymph nodes at weekly intervals (x4), 2 weeks (x1), and 4-weekly intervals (x2). There were 3 responses (3 partial responses) and 1 mixed response in the 19 patients treated with DCs plus autologous lysates. No responses were seen in the group treated with DCs plus peptides. Stable disease (defined as no progression over a period of 3 months) was seen in 4 patients in group 1 and 5 patients in group 2. Treatment was not associated with significant side effects. We examined whether DTH skin tests or assays of IFN-gamma cytokine production may be useful predictors of clinical responses. Twenty-two of 30 patients had DTH responses to KLH and 12 of 13 patients had DTH responses to the influenza peptide. Five of 15 DTH responses were seen against autologous lysates. This was strongly correlated with clinical responses. Approximately half the patients had responses to MART-1 peptide and a third to the other melanoma peptides. Similarly, cytokine production assays showed responses to influenza in 7 of 13 patients, and approximately one third of patients had responses to the other peptides. No IFN-gamma responses were seen in 5 patients against their autologous lysates. There was no correlation between assays of IFN-gamma production and clinical responses. The present studies suggest that autologous lysates may be more effective than the melanoma peptides used in the study as the source of antigen for DC vaccines. DTH responses to autologous lysates appear useful predictors of clinical responses, but further work is needed to identify other measures associated with clinical responses.
Oncology and Immunology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, 2300, Newcastle, NSW, Australia. peter.hersey@newcastle.edu.au
Peter
P
Hersey
Scott W
SW
Menzies
Gary M
GM
Halliday
Tam
T
Nguyen
Margaret L
ML
Farrelly
Chitra
C
DeSilva
Margaret
M
Lett
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology / Q000627:therapeutic use; D006433:Hemocyanins / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D006968:Hypersensitivity, Delayed; D007371:Interferon-gamma / Q000378:metabolism; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000276:immunology / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000276:immunology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D007371:Interferon-gamma; D006433:Hemocyanins; D014442:Monophenol Monooxygenase; C032808:keyhole-limpet hemocyanin