title: A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice.
abstract: BACKGROUND
  The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.
  
  
  METHODS
  In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious.
  
  
  RESULTS
  Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA.
  
  
  CONCLUSIONS
  The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.
authors.affiliation: Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. m.tagliamonte@istitutotumori.na.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Tagliamonte
authors.affiliation: Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. a.petrizzo@istitutotumori.na.it.
authors.forename: Annacarmen
authors.initials: A
authors.lastname: Petrizzo
authors.affiliation: Laboratory of Clinical Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. m.napolitano@istitutotumori.na.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. a.luciano@istitutotumori.na.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Luciano
authors.affiliation: Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. d.rea@istitutotumori.na.it.
authors.forename: Domenica
authors.initials: D
authors.lastname: Rea
authors.affiliation: Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. a.barbieri@istitutotumori.na.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Barbieri
authors.affiliation: Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. c.arra@istitutotumori.na.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.affiliation: Pharmacy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. p.maiolino@istitutotumori.na.it.
authors.forename: Piera
authors.initials: P
authors.lastname: Maiolino
authors.affiliation: Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. m.tornesello@istitutotumori.na.it.
authors.forename: Marialina
authors.initials: M
authors.lastname: Tornesello
authors.affiliation: Scientific Direction, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. g.ciliberto@istitutotumori.na.it.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.affiliation: Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. f.buonaguro@istitutotumori.na.it.
authors.forename: Franco M
authors.initials: FM
authors.lastname: Buonaguro
authors.affiliation: Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy. l.buonaguro@istitutotumori.na.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Buonaguro
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D037282:Calreticulin / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D037282:Calreticulin; D007371:Interferon-gamma