The use of chimeric human Fc(epsilon) receptor I to redirect cytotoxic T lymphocytes to tumors.
Chimeric receptors that redirect effector cell function to tumor cells or virus-infected cells have received much attention. Given the high affinity of Fc(epsilon)RI for immunoglobulin E (IgE) and low serum IgE levels, redirection of effector cells using Fc(epsilon) receptor may provide a novel, versatile, and effective anti-tumor strategy. We have used a mouse perforin 5'-promoter to express a single-chain human Fc(epsilon) receptor in the mouse cytotoxic T lymphocyte cell line, CTLL-R8. Upon ligation of the chimeric Fc(epsilon) receptors by IgE, a signal for effector function is transmitted via the intracellular domain of CD3zeta. Selection in G418-containing medium produced CTLLR8 transfectant clones that: (1) expressed chimeric Fc(epsilon) receptor as determined by flow cytometry; (2) bound human IgE antibodies with high affinity as determined by Scatchard analysis; (3) specifically rosetted IgE-coated SRBC; (4) lysed target cells in IgE-mediated ADCC and reverse ADCC assays; and (5) retarded tumor growth in a Winn assay. Therefore these chimeric Fc(epsilon) receptors can effectively redirect cytotoxicity to tumor cells. Future efforts will assess the versatility and efficacy of these IgE-binding chimeric receptors to redirect killer cell function in animal tumor models.
Kershaw
M H
MH
Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia.
Darcy
P K
PK
Trapani
J A
JA
Smyth
M J
MJ
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D017252:CD3 Complex / Q000737:chemistry; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007167:Immunotherapy; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017455:Receptors, IgE / Q000737:chemistry* / Q000276:immunology; D011993:Recombinant Fusion Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D017252:CD3 Complex; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D054353:Perforin; D007073:Immunoglobulin E