Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.

Abstract

PURPOSE:

Previously, we reported our experience treating 14 patients with metastatic melanoma using a fully human antibody to cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) in conjunction with peptide vaccination. We have now treated 56 patients to evaluate two different dose schedules of anti-CTLA-4 and to explore the relationship between autoimmunity and tumor regression.

PATIENTS AND METHODS:

A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status > or = 60% with no prior history of autoimmunity. Twenty-nine patients received 3 mg/kg anti-CTLA-4 every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. In both cohorts patients received concomitant vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V).

RESULTS:

Two patients achieved a complete response (ongoing at 30 and 31 months, respectively) and five patients achieved a partial response (durations of 4, 6, 25+, 26+, and 34+ months, respectively), for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites. Of 14 patients with grade 3/4 autoimmune toxicity, five (36%) experienced a clinical response compared with only two responses in the 42 patients (5%) with no autoimmune toxicity (P = .008). There were no significant differences in response rate or toxicity between the two dose schedules.

CONCLUSION:

Administration of anti-CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma.

• Authors: Peter Attia, Giao Q Phan, Ajay V Maker, Michael R Robinson, Martha M Quezado, James C Yang, Richard M Sherry, Suzanne L Topalian, Udai S Kammula, Richard E Royal, Nicholas P Restifo, Leah R Haworth, Catherine Levy, Sharon A Mavroukakis, Geoff Nichol, Michael J Yellin, Steven A Rosenberg
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 25 Pg. 6043-53 (Sep 01 2005) ISSN: 0732-183X [Print] United States
• PMID: 16087944 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Antigens, CD
• Antigens, Differentiation
• CTLA-4 Antigen
• CTLA4 protein, human
• Cancer Vaccines
• Immunosuppressive Agents

Topics

• Adult
• Aged
• Antigens, CD
• Antigens, Differentiation (administration & dosage, immunology)
• Autoimmunity
• CTLA-4 Antigen
• Cancer Vaccines (immunology, therapeutic use)
• Drug Administration Schedule
• Female
• Humans
• Immunosuppressive Agents (administration & dosage, immunology)
• Injections, Intravenous
• Male
• Melanoma (drug therapy, immunology)
• Middle Aged
• Prognosis
• Skin Neoplasms (drug therapy, immunology)
• Treatment Outcome