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


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.


CONCLUSIONS
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.
Attia
Peter
P
Surgery Branch, National Cancer Institute, National Institutes of Health, CRC, Room 3W-3940, 10 Center Dr, Bethesda, MD 20892-1201, USA.
Phan
Giao Q
GQ
Maker
Ajay V
AV
Robinson
Michael R
MR
Quezado
Martha M
MM
Yang
James C
JC
Sherry
Richard M
RM
Topalian
Suzanne L
SL
Kammula
Udai S
US
Royal
Richard E
RE
Restifo
Nicholas P
NP
Haworth
Leah R
LR
Levy
Catherine
C
Mavroukakis
Sharon A
SA
Nichol
Geoff
G
Yellin
Michael J
MJ
Rosenberg
Steven A
SA
D000328:Adult; D000368:Aged; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000276:immunology*; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology*; D007275:Injections, Intravenous; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology*; D008875:Middle Aged; D011379:Prognosis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D016896:Treatment Outcome
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D007166:Immunosuppressive Agents