A novel human cancer vaccine elicits cellular responses to the tumor-associated antigen, human chorionic gonadotropin beta.
OBJECTIVE
The oncofetal antigen, human chorionic gonadotropin beta subunit (hCGbeta), is expressed by a number of carcinomas and is a prognostic indicator in renal, colorectal, bladder, and pancreatic cancers. We describe the development of a novel antibody-based dendritic cell (DC)-targeted cancer vaccine capable of eliciting cellular immune responses directed against hCGbeta.


METHODS
The tumor-associated antigen hCGbeta was coupled genetically to a human anti-DC antibody (B11). The resulting fusion protein (B11-hCGbeta) was evaluated for its ability to promote tumor antigen-specific cellular immune responses in a human in vitro model. Monocyte-derived human DCs from normal donors were exposed to purified B11-hCGbeta, activated with CD40 ligand, mixed with autologous lymphocytes, and tested for their ability to promote hCGbeta-specific proliferative and cytotoxic T-lymphocyte responses.


RESULTS
B11-hCGbeta was found to be a soluble, well-defined, and readily purified product that specifically recognized the human mannose receptor via the B11 antibody portion of the fusion protein. B11-hCGbeta functionally promoted the uptake and processing of tumor antigen by DCs, which led to the generation of tumor-specific HLA class I and class II-restricted T-cell responses, including CTLs capable of killing human cancer cell lines expressing hCGbeta.


CONCLUSIONS
Although other hCG vaccines have been shown to be capable of eliciting antibody responses to hCGbeta, this is the first time that cellular immune responses to hCGbeta have been induced by a vaccine in a human system. This DC-targeted hCGbeta vaccine holds promise for the management of a number of cancers and merits additional clinical development.
He
Li-Zhen
LZ
Medarex, Inc., Bloomsbury, New Jersey, and Dartmouth Medical School, Lebanon, New Hampshire, USA.
Ramakrishna
Venky
V
Connolly
John E
JE
Wang
Xi-Tao
XT
Smith
Patricia A
PA
Jones
Charles L
CL
Valkova-Valchanova
Maria
M
Arunakumari
Alahari
A
Treml
John F
JF
Goldstein
Joel
J
Wallace
Paul K
PK
Keler
Tibor
T
Endres
Michael J
MJ
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000302:isolation & purification; D019496:Cancer Vaccines / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007074:Immunoglobulin G; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018997:Chorionic Gonadotropin, beta Subunit, Human; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins