Artificial T-cell receptors.

ABSTRACT

Artificial T-cell receptors are generated by joining an Ag-recognizing domain (ectodomain) to the transmembrane and intracellular portion of a signaling molecule (endodomain). The ectodomain is most often derived from Ab variable chains, but may also be generated from T-cell receptor variable chains, as well as from other molecules. Various alternative ectodomain designs exist, with some comparative studies suggesting optimal forms. The endodomain most often used is the intracellular portion of CD-zeta. Although signaling by CD-zeta leads to IFN-n release and cell killing, it fails to transmit a full activation signal. Recently, unions of different signaling molecule segments have facilitated transmission of more potent signals, stimulating T-cell proliferation and overcoming this major limitation. Artificial T-cell receptors allow grafting of nearly any specificity to T cells. This allows generation of large numbers of specific T cells, without laborious selection and expansion procedures. Efficacy against tumors has been demonstrated in animal models. Phase I and II studies of T-cells transduced with artificial T-cell receptors as therapy for HIV infection have been performed. This rapidly advancing technology will make new strategies of adoptive immunotherapy possible.