Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon.
Twenty-two HLA A*0201 patients with stage IV melanoma were enrolled in a phase 1 safety and feasibility trial using a composite dendritic cell (DC) vaccine generated by culturing CD34 hematopoietic progenitors and activated with IFN-alpha. The DC vaccine was loaded with peptides derived from four melanoma tissue differentiation antigens (MART-1, tyrosinase, MAGE-3, and gp100) and influenza matrix peptide (Flu-MP). Twenty patients were evaluable, 14 of whom received vaccination with peptide-pulsed DCs without keyhole limpet hemocyanin (KLH) and 6 of whom received vaccination with KLH-loaded DCs. Patients were vaccinated until disease progression or until they had received eight vaccinations. None of the analyzed patients showed the expansion of melanoma-peptide-specific circulating effector memory T cells that secrete IFN-gamma in direct ELISPOT. Melanoma-peptide-specific recall memory CD8 T cells able to secrete IFN-gamma and to proliferate could be detected in six of the seven analyzed patients. There were no objective clinical responses. The estimated median overall survival was 12 months (range 2-38), and the median event-free survival was 4 months (range 1-12). There was no statistically significant survival advantage in patients who received KLH-loaded vaccines. As of March 2005, four patients remained alive, 26+, 28+, 28+, and 36+ months. Three of them had received KLH-loaded vaccines and all of them had had additional therapy. Overall, these results suggest that IFN-alpha-activated CD34-DCs are safe but elicit only limited immune responses, underscoring the need to test different DC maturation factors.
Banchereau
Jacques
J
Baylor Institute for Immunology Research, Dallas, TX, USA. jacquesb@baylorhealth.edu
Ueno
Hideki
H
Dhodapkar
Madhav
M
Connolly
John
J
Finholt
Jennifer P
JP
Klechevsky
Eynav
E
Blanck
Jean-Philippe
JP
Johnston
Dennis A
DA
Palucka
A Karolina
AK
Fay
Joseph
J
D000328:Adult; D018952:Antigens, CD34 / Q000096:biosynthesis*; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000737:chemistry; D019496:Cancer Vaccines; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology*; D018450:Disease Progression; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D015234:HLA-A Antigens / Q000096:biosynthesis; D015789:HLA-A2 Antigen; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D009980:Influenza A virus / Q000737:chemistry; D007370:Interferon Type I / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000627:therapeutic use; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D016896:Treatment Outcome; D014763:Viral Matrix Proteins / Q000737:chemistry; D058951:gp100 Melanoma Antigen
D018952:Antigens, CD34; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007370:Interferon Type I; D016898:Interferon-alpha; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; D014763:Viral Matrix Proteins; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma; D014442:Monophenol Monooxygenase