title: Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.
abstract: 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-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative 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-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive 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.
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Matthew
authors.initials: M
authors.lastname: Adamow
authors.forename: Brian A
authors.initials: BA
authors.lastname: Ginsberg
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Rasalan
authors.forename: Erika
authors.initials: E
authors.lastname: Ritter
authors.forename: Humilidad F
authors.initials: HF
authors.lastname: Gallardo
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Xu
authors.forename: Evelina
authors.initials: E
authors.lastname: Pogoriler
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Terzulli
authors.forename: Deborah
authors.initials: D
authors.lastname: Kuk
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D000074324:Ipilimumab; D008545:Melanoma / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D016016:Proportional Hazards Models; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D008565:Membrane Proteins