title: Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.
abstract: Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.
authors.affiliation: Division of Molecular Oncology, Unit of Cancer Gene Therapy, Program in Immunology and Bio Immunotherapy and Gene Therapy of Cancer, San Raffaele Scientific Institute, Milan, Italy. v.russo@hsr.it
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Russo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pilla
authors.forename: Francesca
authors.initials: F
authors.lastname: Lunghi
authors.forename: Roberto
authors.initials: R
authors.lastname: Crocchiolo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Greco
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.forename: Daniela
authors.initials: D
authors.lastname: Maggioni
authors.forename: Raffaella
authors.initials: R
authors.lastname: Fontana
authors.forename: Sylvain
authors.initials: S
authors.lastname: Mukenge
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Rigamonti
authors.forename: Santo Raffaele
authors.initials: SR
authors.lastname: Mercuri
authors.forename: Roberto
authors.initials: R
authors.lastname: Nicoletti
authors.forename: Alessandro Del
authors.initials: AD
authors.lastname: Maschio
authors.forename: Luigi
authors.initials: L
authors.lastname: Gianolli
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Fazio
authors.forename: Alfonso
authors.initials: A
authors.lastname: Marchianò
authors.forename: Annabella Di
authors.initials: AD
authors.lastname: Florio
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Monica
authors.initials: M
authors.lastname: Salomoni
authors.forename: Corrado
authors.initials: C
authors.lastname: Gallo-Stampino
authors.forename: Matteo Del
authors.initials: MD
authors.lastname: Fiacco
authors.forename: Antonio
authors.initials: A
authors.lastname: Lambiase
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.forename: Roberto
authors.initials: R
authors.lastname: Patuzzo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Mario
authors.initials: M
authors.lastname: Santinami
authors.forename: Marco
authors.initials: M
authors.lastname: Bregni
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology*; D001859:Bone Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy; D019496:Cancer Vaccines / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy; D006801:Humans; D006968:Hypersensitivity, Delayed; D008113:Liver Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology*; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013937:Thymidine Kinase / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D013937:Thymidine Kinase