Preclinical qualification of a new multi-antigen candidate vaccine for metastatic melanoma.
New therapies are urgently required for the treatment of patients with melanoma. Here we describe the generation and preclinical evaluation of 3 new recombinant ALVAC(2) poxviruses vCP2264, vCP2291, and vCP2292 for their ability to induce the desired cellular immune responses against the encoded melanoma-associated antigens. This was done either in HLA-A2/K transgenic mice or using in vitro antigen-presentation studies. These studies demonstrated that the vaccine was able to induce HLA-A*0201-restricted T-cell responses against gp100 and NY-ESO-1, detectable directly ex vivo, in HLA-A2/K-transgenic mice. The in vitro antigen presentation studies, in the absence of appropriate animal models, demonstrated that target cells infected with the vaccine construct were lysed by MAGE-1, MAGE-3 or MART-1 peptide-specific T cells. These data indicate that ALVAC(2)-encoded melanoma-associated antigens can be properly processed and presented to induce antigen-specific cytotoxic T-cell responses. To enhance the immunogenicity of the melanoma antigens, a TRIad of COstimulatory Molecules (TRICOM) were also cloned into all 3 vectors. Increased in vitro proliferation and IFN-γ production was observed with all ALVAC(2) poxviruses encoding TRICOM, confirming the immune-enhancing effect of the ALVAC-encoded TRICOM. These studies demonstrated that all components of the vaccine were functionally active and provide a rationale for moving this candidate vaccine to the clinic.
Vogel
Thorsten U
TU
Sanofi Pasteur, Toronto, Ontario, Canada. thorsten.vogel@sanofipasteur.com
Visan
Lucian
L
Ljutic
Belma
B
Gajewska
Beata
B
Caterini
Judy
J
Salha
Danielle
D
Wen
Tao
T
He
Liwei
L
Parrington
Mark
M
Cao
Shi-Xian
SX
McNeil
Bryan
B
Sandhu
Devender
D
Scollard
Nancy
N
Zhang
Linong
L
Bradley
Bill
B
Tang
Mei
M
Lovitt
Corey
C
Oomen
Ray
R
Dunn
Pamela
P
Tartaglia
Jim
J
Berinstein
Neil L
NL
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D004353:Drug Evaluation, Preclinical; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011212:Poxviridae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D011213:Poxviridae Infections / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014765:Viral Vaccines
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D014765:Viral Vaccines