title: CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.
abstract: Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable clinical responses in patients with metastatic melanoma. The functional impact of anti-CTLA-4 therapy on human immune responses is still unclear. To explore this, we analyzed immune-related adverse events and immune responses in metastatic melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal antibody. Fifteen patients were selected on the basis of availability of suitable specimens for immunologic monitoring, and eight of these showed evidence of clinical benefit. Five of the eight patients with evidence of clinical benefit had NY-ESO-1 antibody, whereas none of seven clinical non-responders was seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1 CD4(+) and CD8(+) T cell response, possibly related to prior vaccination with NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1 CD4(+) T cell response and this patient did not have detectable anti-NY-ESO-1 antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-gamma, MIP-1beta and TNF-alpha. We therefore suggest that CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Powel
authors.forename: Humilidad F
authors.initials: HF
authors.lastname: Gallardo
authors.forename: Erika
authors.initials: E
authors.lastname: Ritter
authors.forename: Geoffrey Y
authors.initials: GY
authors.lastname: Ku
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Neil H
authors.initials: NH
authors.lastname: Segal
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Rasalan
authors.forename: Gregor
authors.initials: G
authors.lastname: Manukian
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Xu
authors.forename: Ruth-Ann
authors.initials: RA
authors.lastname: Roman
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Terzulli
authors.forename: Melanie
authors.initials: M
authors.lastname: Heywood
authors.forename: Evelina
authors.initials: E
authors.lastname: Pogoriler
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008565:Membrane Proteins / Q000276:immunology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D000074324:Ipilimumab; D008565:Membrane Proteins