Selective expansion of genetically modified T cells using an antibody/interleukin-2 receptor chimera

Abstract

Although adoptive transfer of tumor-specific T cells is a plausible approach for cancer immunotherapy, the therapeutic application was hampered due to severe side effects caused by administration of high-dose interleukin (IL)-2, which was used for long-lasting maintenance of tumor-specific T cells in vivo. To solve this problem, here we propose to use an antibody/IL-2 receptor chimera, which can transduce a growth signal in response to a cognate antigen. As a model system, V(H) or V(L) region of anti-hen egg lysozyme (HEL) antibody HyHEL-10 was tethered to extracellular D2 domain of erythropoietin receptor and transmembrane/cytoplasmic domains of IL-2 receptor beta or gamma chain. When the pairs of chimeric receptors (V(H)-IL-2Rbeta and V(L)-IL-2Rgamma, or V(H)-IL-2Rgamma and V(L)-IL-2Rbeta) were expressed in IL-3-dependent pro-B cell line Ba/F3 and IL-2-dependent T cell line CTLL-2, the cognate antigen HEL induced selective expansion of gene-modified cells in the absence of IL-3 and IL-2, respectively. Growth assay revealed that the combination of V(H)-IL-2Rbeta and V(L)-IL-2Rgamma transduced a more stringent HEL-dependent growth signal, indicating some conformational effects of the chimeras. Furthermore, STAT3, STAT5 and ERK1/2, which are hallmarks for IL-2R signaling, were all activated by the antibody/IL-2R chimeras. These results clearly demonstrate that the antibody/IL-2R chimeras could substantially mimic the wild-type IL-2R signaling, suggesting the potential application in expansion of gene-modified T cells.