Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma.

Abstract

PURPOSE:

Nineteen patients with high-risk resected stage III and IV melanoma were immunized with three tumor antigen epitope peptides from gp100, MART-1, and tyrosinase emulsified with adjuvant Montanide ISA 51 and received a fully human anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody MDX-010. Each of three cohorts received escalating doses of antibody with vaccine primarily to evaluate the toxicities and maximum-tolerated dose (MTD) of MDX-010 with vaccine. MDX-010 pharmacokinetics and immune responses were secondary end points.

PATIENTS AND METHODS:

Peptide immunizations with MDX-010 were administered every 4 weeks for 6 months and then every 12 weeks for 6 months. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was performed before treatment and after the sixth vaccination. Patients were observed until relapse.

RESULTS:

Grade 3 gastrointestinal (GI) toxicity (diarrhea or abdominal pain) was observed in three patients in the highest dose cohort and one in the middle dose cohort who seemed to be autoimmune. That defined the MTD with vaccine on this schedule at 1 mg/kg. Of eight patients with evidence of autoimmunity, three have experienced disease relapse. Of 11 patients without autoimmune symptoms, nine have experienced disease relapse. Significant immune responses were measured by tetramer and enzyme-linked immunospot assays against gp100 and MART-1.

CONCLUSION:

Dose-related autoimmune adverse events, predominantly skin and GI toxicities, were reversible. Patients mounted an antigen-specific immune response to a peptide vaccine when combined with a human anti-CTLA-4 antibody.

• Authors: Kristin Sanderson, Ronald Scotland, Peter Lee, Dongxin Liu, Susan Groshen, Jolie Snively, Shirley Sian, Geoffrey Nichol, Thomas Davis, Tibor Keler, Michael Yellin, Jeffrey Weber
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 4 Pg. 741-50 (Feb 01 2005) ISSN: 0732-183X [Print] United States
• PMID: 15613700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antigens, Differentiation
• Antigens, Neoplasm
• CC chemokine receptor 9
• CTLA-4 Antigen
• CTLA4 protein, human
• Cancer Vaccines
• MART-1 Antigen
• MLANA protein, human
• Membrane Glycoproteins
• Neoplasm Proteins
• Oleic Acids
• PMEL protein, human
• Peptide Fragments
• Receptors, CCR
• Receptors, Chemokine
• gp100 Melanoma Antigen
• montanide ISA 51
• Mannitol
• Monophenol Monooxygenase

Topics

• Antibodies, Monoclonal (adverse effects)
• Antigens, CD
• Antigens, Differentiation (immunology)
• Antigens, Neoplasm
• Autoimmunity
• CTLA-4 Antigen
• Cancer Vaccines (immunology)
• Female
• Flow Cytometry
• Humans
• MART-1 Antigen
• Male
• Mannitol (analogs & derivatives, therapeutic use)
• Melanoma (immunology, pathology, therapy)
• Membrane Glycoproteins (immunology)
• Middle Aged
• Monophenol Monooxygenase (immunology)
• Neoplasm Proteins (immunology)
• Neoplasm Staging
• Oleic Acids (therapeutic use)
• Peptide Fragments (immunology)
• Receptors, CCR
• Receptors, Chemokine (analysis)
• Vaccination
• gp100 Melanoma Antigen