Autoimmunity Correlates With Tumor Regression in Patients With Metastatic Melanoma Treated With Anti–Cytotoxic T-Lymphocyte Antigen-4

• Published in: Journal of clinical oncology Vol. 23; no. 25; pp. 6043 - 6053
• Main Authors: ATTIA, Peter, PHAN, Giao Q, RESTIFO, Nicholas P, HAWORTH, Leah R, LEVY, Catherine, MAVROUKAKIS, Sharon A, NICHOL, Geoff, YELLIN, Michael J, ROSENBERG, Steven A, MAKER, Ajay V, ROBINSON, Michael R, QUEZADO, Martha M, YANG, James C, SHERRY, Richard M, TOPALIAN, Suzanne L, KAMMULA, Udai S, ROYAL, Richard E
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.09.2005; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Antigens, CD; Antigens, Differentiation - administration & dosage; Antigens, Differentiation - immunology; Autoimmunity; Biological and medical sciences; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; CTLA-4 Antigen; Dermatology; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - immunology; Injections, Intravenous; Male; Medical sciences; Melanoma - drug therapy; Melanoma - immunology; Middle Aged; Prognosis; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Treatment Outcome; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Autoimmunity; Human; Cancerology; Treatment; Malignant melanoma; Regression; Advanced stage; Malignant tumor; Metastasis; Cytotoxic T lymphocyte antigen 4
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2005.06.205

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. 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). 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. 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.