title: Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response.
abstract: Anti-CTLA-4 treatment improves the survival of patients with advanced-stage melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an approved treatment for patients with metastatic disease, it remains unknown by which mechanism it boosts tumor-specific T cell activity. In particular, it is unclear whether treatment amplifies previously induced T cell responses or whether it induces new tumor-specific T cell reactivities. Using a combination ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility complex (pMHC) combinatorial coding, we monitored immune reactivity against a panel of 145 melanoma-associated epitopes in a cohort of patients receiving anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated that anti-CTLA-4 treatment induces a significant increase in the number of detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking contrast, the magnitude of both virus-specific and melanoma-specific T cell responses that were already detected before start of therapy remained unaltered by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. p.kvistborg@nki.nl t.schumacher@nki.nl.
authors.forename: Pia
authors.initials: P
authors.lastname: Kvistborg
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: Daisy
authors.initials: D
authors.lastname: Philips
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kelderman
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: Lois
authors.initials: L
authors.lastname: Hageman
authors.affiliation: National Institute for Health Research Southampton Experimental Cancer Medicine Centre and Southampton University Hospitals, Tremona Road, Southampton, Hampshire SO16 6YD, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottensmeier
authors.affiliation: National Institute for Health Research Southampton Experimental Cancer Medicine Centre and Southampton University Hospitals, Tremona Road, Southampton, Hampshire SO16 6YD, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Joseph-Pietras
authors.affiliation: Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van der Burg
authors.affiliation: Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Kapiteijn
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Rue Pierre-Decker 4, 1011 Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Rue Pierre-Decker 4, 1011 Lausanne, Switzerland.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Romano
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: Carsten
authors.initials: C
authors.lastname: Linnemann
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Rue Pierre-Decker 4, 1011 Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Speiser
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
authors.forename: John B
authors.initials: JB
authors.lastname: Haanen
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. p.kvistborg@nki.nl t.schumacher@nki.nl.
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008545:Melanoma / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D000074324:Ipilimumab