Antigen-specific tumor vaccines. Development and characterization of recombinant adenoviruses encoding MART1 or gp100 for cancer therapy.
The human melanoma tumor Ags, MART1 and gp100, are specifically recognized by HLA-A2-restricted CD8+ CTLs derived from melanoma patients and appear to be involved in tumor regression. In order to develop immunizing vectors for the treatment of patients with metastatic melanoma, replication-defective recombinant adenoviruses, Ad2CMV-MART1 and Ad2CMV-gp100, which encode these tumor Ags, have been generated. Infection of non-Ag expressing HLA-A2+ cell lines A375 and MDA-231 with the vectors resulted in recognition by Ag-specific CTLs as demonstrated by specific target cell lysis and release of cytokines, including IFN-gamma, TNF-alpha, and granulocyte-macrophage-CSF. Sodium butyrate and TNF-alpha can further augment adenovirus-mediated transgene expression and increase recognition by specific CTLs. Although adenovirus-infected cells expressed the E3/19K protein at detectable levels, significant reduction of surface MHC class I expression was observed in only 3 of 10 tumor cell lines infected with either Ad2CMV-MART1 or Ad2CMV-gp100. Because of the suspected homology between the human MART1 and gp100 genes and their murine counterparts, we immunized C57BL/6 mice with these recombinant adenoviruses and demonstrated that immunization with Ad2CMV-gp100 could protect mice from murine melanoma B16 challenge administered intradermally. Depletion of CD8+ but not CD4+ T cells in vivo from Ad2CMV-gp100-vaccinated mice eliminated the protective effect. The anti-gp100 T cells induced by Ad2CMV-gp100 vaccinated appeared to be responsible for the protection. Thus, these recombinant adenoviruses encoding tumor Ags may be useful as vaccines to induce specific T cell immunity for cancer therapy.
Surgery Branch, National Cancer Institute, National Institute of Health Bethsda, MD 20892, USA.
Y
Y
Zhai
J C
JC
Yang
Y
Y
Kawakami
P
P
Spiess
S C
SC
Wadsworth
L M
LM
Cardoza
L A
LA
Couture
A E
AE
Smith
S A
SA
Rosenberg
D000256:Adenoviridae / Q000235:genetics*; D017503:Adenovirus E3 Proteins / Q000502:physiology; D000818:Animals; D000951:Antigens, Neoplasm; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002460:Cell Line; D004274:DNA, Recombinant; D003673:Defective Viruses / Q000235:genetics*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D016233:Immunotherapy, Active; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014611:Vaccination / Q000379:methods; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D058951:gp100 Melanoma Antigen
D017503:Adenovirus E3 Proteins; D000951:Antigens, Neoplasm; D002087:Butyrates; D004274:DNA, Recombinant; C084390:E3 glycoprotein 19k, Adenovirus type 7; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; D058951:gp100 Melanoma Antigen; D020148:Butyric Acid