PT  - JOURNAL ARTICLE
AU  - Kvistborg, Pia
AU  - Philips, Daisy
AU  - Kelderman, Sander
AU  - Hageman, Lois
AU  - Ottensmeier, Christian
AU  - Joseph-Pietras, Deborah
AU  - Welters, Marij J. P.
AU  - van der Burg, Sjoerd
AU  - Kapiteijn, Ellen
AU  - Michielin, Olivier
AU  - Romano, Emanuela
AU  - Linnemann, Carsten
AU  - Speiser, Daniel
AU  - Blank, Christian
AU  - Haanen, John B.
AU  - Schumacher, Ton N.
TI  - Anti–CTLA-4 therapy broadens the melanoma-reactive CD8<sup>+</sup> T cell response
AID  - 10.1126/scitranslmed.3008918
DP  - 2014 Sep 17
TA  - Science Translational Medicine
PG  - 254ra128--254ra128
VI  - 6
IP  - 254
4099  - http://stm.sciencemag.org/content/6/254/254ra128.short
4100  - http://stm.sciencemag.org/content/6/254/254ra128.full
AB  - 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.