Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma: evidence of systemic immune dysfunction.
BACKGROUND
MPS160 (GRAMLGTHTMEVTV) is a glycoprotein 100-derived melanoma peptide that contains overlapping human leukemic antigen A2-, DR53-, and DQw6-restricted T-cell epitopes. In preclinical testing, MPS160 demonstrated superior immunization and antitumor activity. In this report, the authors present the results from a clinical trial that evaluated the safety and immunologic efficacy of the MPS160 vaccine in patients with metastatic melanoma.


METHODS
Patients with stage IV melanoma were randomized to 1 of 3 treatment arms: 1) MPS160 in incomplete Freund adjuvant (Montanide ISA-51); 2) MPS160 in Montanide ISA-51 with 75 microg of granulocyte-macrophage-stimulating factor (GM-CSF); or 3) MPS160 in Montanide ISA-51 with 100 microg of GM-CSF. Vaccines were administered every 3 weeks until patients developed disease progression or severe toxicity. Patients were aged >or=18 years with metastatic melanoma and a good performance status. Exclusion criteria included pregnancy/nursing, brain metastases, and ongoing chemotherapy. Immunologic efficacy was ascertained by using tetramer and functional analysis of peripheral blood lymphocytes.


RESULTS
None of the 28 patients exhibited objective tumor responses or severe toxicities. Four patients remained progression free for >or=100 days. Immunologic analysis was available for 21 patients. Laboratory data demonstrated 1) increased frequency of vaccine-specific, nonfunctional cytotoxic T lymphocytes in 10 patients; 2) no differences in immunization efficacy among the treatment arms; and 3) evidence of systemic cytokine/immune dysfunction.


CONCLUSIONS
Clinically, the MPS160 vaccine was ineffective. Phenotypic (tetramer) evidence of immunization was ineffective functionally and most likely was caused by global immune dysfunction, as illustrated by abnormal cytokine profiles in peripheral blood. In this report, the authors discuss possible implications of the current results on future cancer vaccine studies.
Mayo Clinic Cancer Center, Rochester, Minnesota 55905, USA. markovic.svetomir@mayo.edu
Celis
Esteban
E
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000737:chemistry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008353:Mannitol / Q000031:analogs & derivatives / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D009367:Neoplasm Staging; D009829:Oleic Acids / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D019496:Cancer Vaccines; D000939:Epitopes; C522195:GRAMLGTHTMEVTV; D006680:HLA Antigens; D009829:Oleic Acids; D009842:Oligopeptides; C477385:montanide ISA 51; D008353:Mannitol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005620:Freund's Adjuvant