SELECTIVE EXPANSION OF HIGH-AVIDITY OR LOW-AVIDITY CYTOTOXIC T-LYMPHOCYTE AND EFFICACY FOR ADOPTIVE IMMUNOTHERAPY

The conventional approach to cytotoxic T-lymphocyte (CTL) induction us es maximal antigen concentration with the intent of eliciting more CTL . However, the efficacy of this approach has not been systematically e xplored with regard to the quality of the CTLs elicited or their in vi vo functionality. Here, we show that a diametrically opposite approach elicits CTLs that are much more effective at clearing virus. CTLs spe cific for a defined peptide epitope were selectively expanded with var ious concentrations of peptide antigen. CTLs generated with exceedingl y low-dose peptide lysed targets sensitized with >100-fold less peptid e than CTLs generated with high-dose peptide. Differences in expressio n of T-cell antigen receptors or a number of other accessory molecules did not account for the functional differences. Further, high-avidity CTLs adoptively transferred into severe combined immunodeficient mire were 100- to 1000-fold more effective at viral clearance than the low -avidity CTLs, despite the fact that all CTL lines lysed virus-infecte d targets ill vitro. Thus, the quality of CTLs is as important as the quantity of CTLs for adoptive immunotherapy, and the ability to kill v irally infected targets in vitro is not predictive of in vivo efficacy , whereas the determinant density requirement described here is predic tive. Application of these principles may be critical in developing ef fective adoptive cellular immunotherapy for viral infections and cance r.