title: Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised "proof-of-principle" phase II study.
abstract: BACKGROUND
  Vaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed.
  
  
  METHODS
  This is a phase II, "proof-of-principle", randomized, open-label trial of vaccination with autologous DC loaded with tumor lysate or homogenate in metastatic melanoma patients combined with immunomodulating RT and/or preleukapheresis IFN-α. All patients will receive four bi-weekly doses of the vaccine during the induction phase and monthly doses thereafter for up to a maximum of 14 vaccinations or until confirmed progression. Patients will be randomized to receive:(1.) three daily doses of 8 Gy up to 12 Gy radiotherapy delivered to one non-index metastatic field between vaccine doses 1 and 2 and, optionally, between doses 7 and 8, using IMRT-IMAT techniques;(2.) daily 3 MU subcutaneous IFN-α for 7 days before leukapheresis;(3.) both 1 and 2;(4.) neither 1 nor 2.At least six patients eligible for treatment will be enrolled per arm. Daily 3 MU IL-2 will be administered subcutaneously for 5 days starting from the second day after each vaccine dose. Serial DTH testing and blood sampling to evaluate treatment-induced immune response will be performed. Objective response will be evaluated according to immune-related response criteria (irRC).
  
  
  CONCLUSIONS
  Based upon the emerging role of radiotherapy as an immunologic modifier, we designed a randomized phase II trial adding radiotherapy and/or preleukapheresis IFN-α to our DC vaccine in metastatic melanoma patients. Our aim was to find the best combination of complementary interventions to enhance anti-tumor response induced by DC vaccination, which could ultimately lead to better survival and milder toxicity.
authors: Francesco
authors: F
authors: de Rosa
authors: Immunotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei, Tumori (IRST) IRCCS, Meldola, FC, Italy. laura.ridolfi@irst.emr.it.
authors: Laura
authors: L
authors: Ridolfi
authors: Ruggero
authors: R
authors: Ridolfi
authors: Giorgia
authors: G
authors: Gentili
authors: Linda
authors: L
authors: Valmorri
authors: Oriana
authors: O
authors: Nanni
authors: Massimiliano
authors: M
authors: Petrini
authors: Laura
authors: L
authors: Fiammenghi
authors: Anna Maria
authors: AM
authors: Granato
authors: Valentina
authors: V
authors: Ancarani
authors: Elena
authors: E
authors: Pancisi
authors: Valentina
authors: V
authors: Soldati
authors: Serena
authors: S
authors: Cassan
authors: Angela
authors: A
authors: Riccobon
authors: Elisabetta
authors: E
authors: Parisi
authors: Antonino
authors: A
authors: Romeo
authors: Livia
authors: L
authors: Turci
authors: Massimo
authors: M
authors: Guidoboni
mesh_terms: D019496:Cancer Vaccines / Q000276:immunology; D002457:Cell Extracts / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007109:Immunity; D056747:Immunomodulation; D016898:Interferon-alpha / Q000627:therapeutic use*; D007937:Leukapheresis; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D008840:Microfilament Proteins; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018401:Sample Size; D014611:Vaccination
chemical_list: C473287:ANTXR1 protein, human; D019496:Cancer Vaccines; D002457:Cell Extracts; D016898:Interferon-alpha; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface