title: Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study.
abstract: Clinical activity was observed in metastatic melanoma (MM) patients treated with ipilimumab (IPI) combined with fotemustine (FTM) in the phase II NIBIT-M1 study. Peripheral blood mononuclear cells (PBMCs) and serum were collected from MM patients at pre- and at weeks 12 and 24 post-treatment. A comprehensive phenotypic and functional immunomonitoring of circulating T cells, and the detection of soluble immunoregulatory molecules was carried out and correlated with clinical outcome. The frequency at baseline and along the treatment of circulating T central memory cells expressing activation/differentiation markers, such as CD3+CD4+CD45RO+BTLA+, CD3+CD4+4-1BB or Th17 lymphocytes correlated with the clinical outcome of MM patients. Moreover, either the absence or the presence of soluble NKG2D ligands (ULBP-1 or -2) at baseline in the serum of MM patients enabled to discriminate subjects with long-term survival (median overall survival, (OS) = 33.6 mo for ULBP-1 and -2) from poor survivors (OS = 9.8 or 6.6 mo, respectively). Conversely, no significant association between the levels of soluble MICA, MICB and ULBP-3 and the clinical outcome of patients was observed. An inverse correlation between circulating levels of these molecules at baseline and frequency of either CD3+CD4+CD45RO+BTLA+or Th17 or CD3+CD4+4-1BB+T cells occurred in patients with a favorable clinical outcome. The simultaneous monitoring of different immune parameters, though validation in a large cohort of patients is needed, allowed to identify an association between phenotypic and soluble markers representing a possible predictive immunological signature for the clinical activity of IPI plus FTM.
authors.affiliation: Italian Network for Biotherapy of Tumors-(NIBIT)-Laboratory, Siena, Italy; Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Unit of Immuno-biotherapy of Melanoma and Solid Tumors, San Raffaele Foundation Center, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccalli
authors.affiliation: Unit of Statistics, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Unit of Immuno-biotherapy of Melanoma and Solid Tumors, San Raffaele Foundation Center , Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Capocefalo
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Unit of Immuno-biotherapy of Melanoma and Solid Tumors, San Raffaele Foundation Center, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pilla
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori , Siena, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Fonsatti
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori , Siena, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giacomo
authors.affiliation: Italian Network for Biotherapy of Tumors-(NIBIT)-Laboratory, Siena, Italy; Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Unit of Immuno-biotherapy of Melanoma and Solid Tumors, San Raffaele Foundation Center, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.affiliation: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori , Siena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
keywords: Cytotoxic T-lymphocyte Antigen-4 (CTLA-4); Melanoma; NKG2D ligands; T cell subsets 