THE USE OF CHIMERIC HUMAN FC-EPSILON-RECEPTOR-I TO REDIRECT CYTOTOXICT-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 Fe epsilon RI for immunoglobulin E (IgE) and low serum IgE levels, redirection of effector cells using Fc epsilon receptor may p rovide a novel, versatile, and effective anti-tumor strategy. We have used a mouse perforin 5'-promoter to express a single-chain human Fc e psilon receptor in the mouse cytotoxic T lymphocyte cell line, CTLL-R8 , Upon ligation of the chimeric Fee receptors by IgE, a signal for eff ector function is transmitted via the intracellular domain of CD3 zeta . Selection in G418-containing medium produced CTLL-R8 transfectant cl ones that: (1) expressed chimeric Fee receptor as determined by flow c ytometry; (2) bound human IgE antibodies with high affinity as determi ned by Scatchard analysis; (3) specifically rosetted IgE-coated SRBC; (4) lysed target cells in IgE-mediated ADCC and reverse ADCC assays; a nd (5) retarded tumor growth in a Winn assay, Therefore these chimeric Fc epsilon receptors can effectively redirect cytotoxicity to tumor c ells, Future efforts will assess the versatility and efficacy of these IgE-binding chimeric receptors to redirect killer cell function in an imal tumor models.