The Lewis-Y carbohydrate antigen is expressed by many human tumors and can serve as a target for genetically redirected T cells despite the presence of soluble antigen in serum.
In this study we aimed to determine the suitability of the Lewis-Y carbohydrate antigen as a target for immunotherapy using genetically redirected T cells. Using the 3S193 monoclonal antibody and immunohistochemistry, Lewis-Y was found to be expressed on a range of tumors including 42% squamous cell lung carcinoma, 80% lung adenocarcinoma, 25% ovarian carcinoma, and 25% colorectal adenocarcinoma. Expression levels varied from low to intense on between 1% and 90% of tumor cells. Lewis- was also found in soluble form in sera from both normal donors and cancer patients using a newly developed enzyme-linked immunosorbent assay. Serum levels in patients was often less than 1 ng/mL, similar to normal donors, but approximately 30% of patients had soluble Lewis-Y levels exceeding 1 ng/mL and up to 9 ng/mL. Lewis-Y-specific human T cells were generated by genetic modification with a chimeric receptor encoding a single-chain humanized antibody linked to the T-cell signaling molecules, T-cell receptor-zeta, and CD28. T cells responded against the Lewis-Y antigen by cytokine secretion and cytolysis in response to tumor cells. Importantly, the T-cell response was not inhibited by patient serum containing soluble Lewis-Y. This study demonstrates that Lewis-Y is expressed on a large number of tumors and Lewis-Y-specific T cells can retain antitumor function in the presence of patient serum, indicating that this antigen is a suitable target for this form of therapy.
Westwood
Jennifer A
JA
Cancer Immunology Research Program, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, Victoria 3002, Australia.
Murray
William K
WK
Trivett
Melanie
M
Haynes
Nicole M
NM
Solomon
Benjamin
B
Mileshkin
Linda
L
Ball
David
D
Michael
Michael
M
Burman
Angela
A
Mayura-Guru
Preethi
P
Trapani
Joseph A
JA
Peinert
Stefan
S
Hönemann
Dirk
D
Miles Prince
H
H
Scott
Andrew M
AM
Smyth
Mark J
MJ
Darcy
Phillip K
PK
Kershaw
Michael H
MH
D000951:Antigens, Neoplasm / Q000097:blood / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007983:Lewis Blood Group Antigens / Q000097:blood / Q000235:genetics / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014161:Transduction, Genetic
D000951:Antigens, Neoplasm; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma