Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice.
In this study, human T cells were provided with a reactivity against the Lewis-Y (Le(Y)) carbohydrate antigen, which is overexpressed on 70% of epithelial-derived tumors, but not normally recognized by T cells. Antitumor reactivity was achieved by transduction of T cells with a gene encoding a cell-surface chimeric receptor composed of single-chain anti-Le(Y) antibody linked to an enhanced cytoplasmic signaling domain made up of CD28 and CD3-zeta. Importantly, the single-chain antibody was humanized to try to reduce potential problems of human anti-mouse antibody responses in patients receiving chimeric receptor-modified T cells in future clinical trials. T cells expressing the chimeric receptor were demonstrated to secrete cytokines and proliferate in response to receptor ligation and lysed Le(Y+) tumors in vitro. Another aspect of this study was the finding that no activity was observed against normal tissue, as represented by autologous neutrophils that express low levels of Le(Y). Significantly, systemic delivery of anti-Le(Y) T cells dramatically inhibited established s.c. human ovarian OVCAR-3 tumors (a recognized difficult model to treat) in mice. Finally, we demonstrated that anti-Le(Y) T cells preferentially expanded or accumulated in the tumor compared with control empty vector T cells, thereby providing mechanistic insight into the specific antitumor response. This study supports the use of humanized gene-modified T cells as a potential therapy for Le(Y+) malignancies.
Westwood
Jennifer A
JA
Cancer Immunology Program and Department of Hematology and Medical Oncology, Peter MacCallum Cancer Centre, St. Andrew's Place, Melbourne, Victoria 3002, Australia.
Smyth
Mark J
MJ
Teng
Michele W L
MW
Moeller
Maria
M
Trapani
Joseph A
JA
Scott
Andrew M
AM
Smyth
Fiona E
FE
Cartwright
Glenn A
GA
Power
Barbara E
BE
Hönemann
Dirk
D
Prince
H Miles
HM
Darcy
Phillip K
PK
Kershaw
Michael H
MH
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D015551:Autoimmunity; D018106:CD28 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D007983:Lewis Blood Group Antigens / Q000737:chemistry*; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D063268:Sialic Acid Binding Ig-like Lectin 3; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018106:CD28 Antigens; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D016207:Cytokines; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3