Peptide vaccination of patients with metastatic melanoma: improved clinical outcome in patients demonstrating effective immunization.
OBJECTIVE
Therapeutic peptide vaccines for melanoma continue to only demonstrate anecdotal success. We set out to evaluate the impact of low-dose GM-CSF emulsified in Montanide ISA-51 on the immunogenicity of HLA-A2 restricted melanoma differentiation antigen peptide vaccines (MART-1, gp100 and tyrosinase) administered in separate subcutaneous injections.


METHODS
We conducted a randomized phase II clinical trial of HLA-A2+ patients with metastatic melanoma that were immunized every 3 weeks with one of the following vaccine preparations: (A) peptides + Montanide ISA-51; (B) peptides + Montanide ISA-51 + GM-CSF (10 microg); (C) peptides + Montanide ISA-51 + GM-CSF (50 microg). Immunization efficacy was determined by quantification of vaccine specific tetramer positive cytotoxic T cells in peripheral blood. Global assessment of immune competence was ascertained using DTH testing to common recall antigens as well as peripheral blood immunophenotyping.


RESULTS
Twenty-five eligible patients were equally distributed across all 3 treatment groups. Only 9 patients demonstrated evidence of immunization. Most commonly, immune response was achieved to the gp100 peptide. The addition of low-dose GM-CSF did not impact immunization efficacy. DTH reactivity to Candida appeared predictive of successful immunization. Successful immunization with the peptide vaccines was associated with improved clinical outcomes.


CONCLUSIONS
The addition of low dose GM-CSF to peptide vaccines did not enhance immunogenicity. Higher doses of GM-CSF may be needed to achieve this effect and this is a testable hypothesis. Likewise, better patient selection based on immunologic status (DTH reactivity) may be helpful to better understand the clinical impact of therapeutic cancer vaccines.
Markovic
Svetomir N
SN
Melanoma Study Group of the Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55905, USA. markovic.svetomir@mayo.edu
Suman
Vera J
VJ
Ingle
James N
JN
Kaur
Judith S
JS
Pitot
Henry C
HC
Loprinzi
Charles L
CL
Rao
Ravi D
RD
Creagan
Edward T
ET
Pittelkow
Mark R
MR
Allred
Jakob B
JB
Nevala
Wendy K
WK
Celis
Esteban
E
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed; D016130:Immunophenotyping; D058965:MART-1 Antigen; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000031:analogs & derivatives; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology*; D009829:Oleic Acids / Q000008:administration & dosage; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use*; D058951:gp100 Melanoma Antigen
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009829:Oleic Acids; C548637:PMEL protein, human; D011994:Recombinant Proteins; D022223:Vaccines, Subunit; D058951:gp100 Melanoma Antigen; C477385:montanide ISA 51; D008353:Mannitol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D014442:Monophenol Monooxygenase