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Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab
- Yuan, Jianda, Adamow, Matthew, Ginsberg, Brian A., Rasalan, Teresa S., Ritter, Erika, Gallardo, Humilidad F., Xu, Yinyan, Pogoriler, Evelina, Terzulli, Stephanie L., Kuk, Deborah, Panageas, Katherine S., Ritter, Gerd, Sznol, Mario, Halaban, Ruth, Jungbluth, Achim A., Allison, James P., Old, Lloyd J., Wolchok, Jedd D., Gnjatic, Sacha
- Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.40 pp. 16723-16728
- antigens, cytotoxic T-lymphocytes, dissociation, enzyme-linked immunosorbent assay, immune response, melanoma, metastasis, models, patients, prospective studies, relative risk, seroprevalence, testes, vaccines
- Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1âseropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1âseronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1âspecific CD4+ and CD8+ T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1âseropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1âseropositive patients with associated CD8+ T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8+ T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.