High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome.
We have investigated the therapeutic potential of a prototypic melanoma vaccine based on recombinant adenovirus expressing human dopachrome tautomerase in the B16F10 murine melanoma model. We found that in the presence of a tumor, the magnitude of T-cell immunity evoked by the vaccine was significantly reduced. This impairment was compounded by defects in cytokine production and degranulation within the tumor-infiltrating lymphocytes (TILs). We showed that the combination of vaccination with high-dose cyclophosphamide was able to skew the response toward the target antigen and enhanced both the quantity and quality of antigen-specific CD8+ and CD4+ T-cell responses in tumor-bearing mice, which resulted in the inhibition of tumor growth. Furthermore, when tumor-specific antigens were targeted by the vaccine, the combination therapy could actually produce tumor regression, which appeared to result from the high frequency of antigen-specific T cells. These data show that recombinant adenovirus vaccines are compatible with conventional high-dose chemotherapy and that the combined treatment results in improved therapeutic outcomes relative to either agent individually.
Grinshtein
N
N
Department of Pathology and Molecular Medicine, McMaster University, ON, Canada.
Ventresca
M
M
Margl
R
R
Bernard
D
D
Yang
T-C
TC
Millar
J B
JB
Hummel
J
J
Beermann
F
F
Wan
Y
Y
Bramson
J L
JL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000627:therapeutic use*
D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D019444:Vaccines, DNA; D003520:Cyclophosphamide; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase