Peptide vaccination of patients with metastatic melanoma: improved clinical outcome in patients demonstrating effective immunization.

Abstract

OBJECTIVES:

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.

• Authors: Svetomir N Markovic, Vera J Suman, James N Ingle, Judith S Kaur, Henry C Pitot, Charles L Loprinzi, Ravi D Rao, Edward T Creagan, Mark R Pittelkow, Jakob B Allred, Wendy K Nevala, Esteban Celis
• Journal: American journal of clinical oncology (Am J Clin Oncol) Vol. 29 Issue 4 Pg. 352-60 (Aug 2006) ISSN: 1537-453X [Electronic] United States
• PMID: 16891861 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Antigens, Neoplasm
• Cancer Vaccines
• HLA-A2 Antigen
• MART-1 Antigen
• MLANA protein, human
• Membrane Glycoproteins
• Neoplasm Proteins
• Oleic Acids
• PMEL protein, human
• Recombinant Proteins
• Vaccines, Subunit
• gp100 Melanoma Antigen
• montanide ISA 51
• Mannitol
• Granulocyte-Macrophage Colony-Stimulating Factor
• Monophenol Monooxygenase

Topics

• Adjuvants, Immunologic (administration & dosage)
• Adult
• Aged
• Aged, 80 and over
• Antigens, Neoplasm
• Cancer Vaccines (immunology, therapeutic use)
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor (administration & dosage)
• HLA-A2 Antigen (immunology)
• Humans
• Hypersensitivity, Delayed
• Immunophenotyping
• MART-1 Antigen
• Male
• Mannitol (administration & dosage, analogs & derivatives)
• Melanoma (immunology, secondary, therapy)
• Membrane Glycoproteins (immunology)
• Middle Aged
• Monophenol Monooxygenase (immunology)
• Neoplasm Proteins (immunology)
• Oleic Acids (administration & dosage)
• Recombinant Proteins
• Skin Neoplasms (drug therapy, immunology, pathology)
• Survival Analysis
• Vaccines, Subunit (immunology, therapeutic use)
• gp100 Melanoma Antigen