title: Safety and efficacy of a genetic vaccine targeting telomerase plus chemotherapy for the therapy of canine B-cell lymphoma.
abstract: Client-owned pet dogs represent exceptional translational models for advancement of cancer research because they reflect the complex heterogeneity observed in human cancer. We have recently shown that a genetic vaccine targeting dog telomerase reverse transcriptase (dTERT) and based on adenovirus DNA electro-gene-transfer (Ad/DNA-EGT) technology can induce strong cell-mediated immune responses against this tumor antigen and increase overall survival of dogs affected by B-cell lymphosarcoma (LSA) in comparison with historical controls when combined with a cyclophosphamide, vincristine, and prednisone (COP) chemotherapy regimen. Here, we have conducted a double-arm clinical trial with an extended number of LSA patients, measured the antigen-specific immune response, and evaluated potential toxic effects of the immunotherapy along with a follow-up of patients survival for 3.5 years. The immune response was measured by enzyme-linked immunospot assay. The expression of dTERT was quantified by quantitative polymerase chain reaction. Changes in hematological parameters, local/systemic toxicity or organic dysfunction and fever were monitored over time during the treatment. dTERT-specific cell-mediated immune responses were induced in almost all treated animals. No adverse effects were observed in any dog patient that underwent treatment. The overall survival time of vaccine/COP-treated dogs was significantly increased over the COP-only cohort (>76.1 vs. 29.3 weeks, respectively, p<0.0001). There was a significant association between dTERT expression levels in LSA cells and overall survival among vaccinated patients. In conclusion, Ad/DNA-EGT-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of LSA canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and support the evaluation of this approach for other cancer types as well as the translation of this approach to human clinical trials.
authors.affiliation: University of Pisa, Department of Veterinary Sciences, San Piero a Grado 56122, Pisa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gavazza
authors.forename: George
authors.initials: G
authors.lastname: Lubas
authors.forename: Arthur
authors.initials: A
authors.lastname: Fridman
authors.forename: Daniela
authors.initials: D
authors.lastname: Peruzzi
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Impellizeri
authors.forename: Laura
authors.initials: L
authors.lastname: Luberto
authors.forename: Emanuele
authors.initials: E
authors.lastname: Marra
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Roscilli
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurisicchio
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000592:standards*; D019496:Cancer Vaccines / Q000235:genetics* / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D018390:Gene Targeting; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000401:mortality / Q000628:therapy*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019496:Cancer Vaccines; D019098:Telomerase
references.citation: J Comp Pathol. 1997 Jul;117(1):35-59
references.pmid: 9263843
references.citation: Mol Ther. 2009 Oct;17(10):1804-13
references.pmid: 19623161
references.citation: Neoplasia. 2001 Jul-Aug;3(4):351-9
references.pmid: 11571635
references.citation: J Vet Intern Med. 2009 Sep-Oct;23(5):1064-70
references.pmid: 19627472
references.citation: Crit Rev Oncol Hematol. 2013 Oct;88(1):187-97
references.pmid: 23561333
references.citation: J Vet Med Sci. 1999 Oct;61(10):1125-9
references.pmid: 10563290
references.citation: Cancer Res. 2006 Jan 15;66(2):601-4
references.pmid: 16423984
references.citation: J Vet Intern Med. 2011 Jul-Aug;25(4):920-6
references.pmid: 21736624
references.citation: Science. 1997 Aug 15;277(5328):955-9
references.pmid: 9252327
references.citation: Vet Pathol. 2003 Jan;40(1):32-41
references.pmid: 12627711
references.citation: Vet Immunol Immunopathol. 2012 Feb 15;145(3-4):597-603
references.pmid: 22293625
references.citation: J Immunol. 2009 Jan 15;182(2):980-7
references.pmid: 19124741
references.citation: PLoS One. 2011;6(8):e24167
references.pmid: 21904611
references.citation: Vet Clin North Am Small Anim Pract. 2007 Nov;37(6):1111-9; vi-ii
references.pmid: 17950885
references.citation: Science. 2002 Oct 25;298(5594):850-4
references.pmid: 12242449
references.citation: J Immunother. 2007 Jan;30(1):1-15
references.pmid: 17198079
references.citation: Vet Immunol Immunopathol. 2009 Apr 15;128(4):359-65
references.pmid: 19100628
references.citation: J Vet Intern Med. 2012 Mar-Apr;26(2):355-62
references.pmid: 22303814
references.citation: Hum Gene Ther. 2009 Mar;20(3):253-65
references.pmid: 19257854
references.citation: Cancers (Basel). 2011 Sep 22;3(3):3687-713
references.pmid: 24212974
references.citation: Blood. 2010 Feb 18;115(7):1374-84
references.pmid: 19903903
references.citation: Nat Rev Cancer. 2008 Feb;8(2):147-56
references.pmid: 18202698
references.citation: Sci Rep. 2012;2:249
references.pmid: 22355761
references.citation: Vaccine. 2010 Feb 3;28(5):1201-8
references.pmid: 19944791
references.citation: Clin Cancer Res. 2011 Feb 15;17(4):907-17
references.pmid: 21106727
references.citation: Expert Opin Biol Ther. 2012 Aug;12(8):1043-58
references.pmid: 22577875
references.citation: Cell. 1997 Aug 22;90(4):785-95
references.pmid: 9288757
references.citation: Int J Cancer. 2007 Jun 1;120(11):2290-300
references.pmid: 17304509
references.citation: Top Companion Anim Med. 2009 Aug;24(3):157-62
references.pmid: 19732735
references.citation: Vet Pathol. 2003 Jan;40(1):1-7
references.pmid: 12627707
references.citation: J Vet Intern Med. 2001 May-Jun;15(3):190-5
references.pmid: 11380026
references.citation: Vet J. 2008 Feb;175(2):155-63
references.pmid: 17398127
references.citation: J Natl Cancer Inst. 1991 Sep 4;83(17):1226-31
references.pmid: 1870148
references.citation: Vet J. 2011 Apr;188(1):34-8
references.pmid: 20627636
references.citation: PLoS One. 2012;7(3):e33274
references.pmid: 22428007
references.citation: Int J Cancer. 2009 Jan 1;124(1):130-9
references.pmid: 18839429
references.citation: Vet Pathol. 2006 May;43(3):241-56
references.pmid: 16672571
references.citation: Curr Opin HIV AIDS. 2010 Sep;5(5):377-85
references.pmid: 20978377
references.citation: Hematol Oncol. 2013 Mar;31(1):1-9
references.pmid: 22674797
references.citation: Mol Ther. 2010 Aug;18(8):1559-67
references.pmid: 20531395
references.citation: J Am Vet Med Assoc. 2008 Mar 15;232(6):879-85
references.pmid: 18341445
references.citation: Cancer Immunol Immunother. 2007 May;56(5):641-8
references.pmid: 16960692
references.citation: Antioxid Redox Signal. 2011 Jan 15;14(2):261-73
references.pmid: 20524846
references.citation: Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):644-53
references.pmid: 17255288