BACKGROUND: Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. METHODS: Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored. RESULTS: Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. CONCLUSIONS: DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.
BACKGROUND: Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. METHODS: Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored. RESULTS: Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. CONCLUSIONS: DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.
Authors: Stephen R Walsh; Michael S Seaman; Lauren E Grandpre; Cherie Charbonneau; Katherine E Yanosick; Barbara Metch; Michael C Keefer; Raphael Dolin; Lindsey R Baden Journal: Vaccine Date: 2012-11-07 Impact factor: 3.641
Authors: David A Garber; Leigh A O'Mara; Sailaja Gangadhara; Monica McQuoid; Xiugen Zhang; Rui Zheng; Kiran Gill; Meena Verma; Tianwei Yu; Brent Johnson; Bing Li; Cynthia A Derdeyn; Chris Ibegbu; John D Altman; Eric Hunter; Mark B Feinberg Journal: J Virol Date: 2012-09-12 Impact factor: 5.103
Authors: Lisa H Butterfield; A Karolina Palucka; Cedrik M Britten; Madhav V Dhodapkar; Leif Håkansson; Sylvia Janetzki; Yutaka Kawakami; Thomas-Oliver Kleen; Peter P Lee; Cristina Maccalli; Holden T Maecker; Vernon C Maino; Michele Maio; Anatoli Malyguine; Giuseppe Masucci; Graham Pawelec; Douglas M Potter; Licia Rivoltini; Lupe G Salazar; Dolores J Schendel; Craig L Slingluff; Wenru Song; David F Stroncek; Hideaki Tahara; Magdalena Thurin; Giorgio Trinchieri; Sjoerd H van Der Burg; Theresa L Whiteside; Jon M Wigginton; Francesco Marincola; Samir Khleif; Bernard A Fox; Mary L Disis Journal: Clin Cancer Res Date: 2011-05-10 Impact factor: 12.531
Authors: Edwin P Hui; Graham S Taylor; Hui Jia; Brigette B Y Ma; Stephen L Chan; Rosalie Ho; Wai-Lap Wong; Steven Wilson; Benjamin F Johnson; Ceri Edwards; Deborah D Stocken; Alan B Rickinson; Neil M Steven; Anthony T C Chan Journal: Cancer Res Date: 2013-01-24 Impact factor: 12.701