title: Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients.
abstract: Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG ≤ 1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28 months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto-antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials.
authors.affiliation: Department of Medical Biotechnologies, Siena University, Siena, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cusi
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Pastina
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rossetti
authors.forename: Elena
authors.initials: E
authors.lastname: Dreassi
authors.forename: Giacomo Maria
authors.initials: GM
authors.lastname: Guidelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Fioravanti
authors.forename: Elodia Claudia
authors.initials: EC
authors.lastname: Martino
authors.forename: Claudia
authors.initials: C
authors.lastname: Gandolfo
authors.forename: Marco
authors.initials: M
authors.lastname: Pagliuchi
authors.forename: Assunta
authors.initials: A
authors.lastname: Basile
authors.forename: Salvatore Francesco
authors.initials: SF
authors.lastname: Carbone
authors.forename: Veronica
authors.initials: V
authors.lastname: Ricci
authors.forename: Lucia
authors.initials: L
authors.lastname: Micheli
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: Luigi
authors.initials: L
authors.lastname: Pirtoli
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Correale
mesh_terms: D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013940:Thymidylate Synthase / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D022223:Vaccines, Subunit; D013940:Thymidylate Synthase