Engineering Cytolytic Effectors to Eliminate Virus-Infected and Cancer Cells

Project Summary The goal of this STTR grant application is to engineer powerful NK cell-based cytolytic effector cells for therapeutic applications. The cells will combine the selectivity and specificity of T cells and the ability of NK cells to mediate effective cytolytic activity against a wide spectrum of aberrant cells, including those with impaired adhesion properties. To achieve this goal we intend to endow NK92 cytolytic cells with either the entire T-cell receptor (TCR)-CD3 complex or a chimericantigen receptor (CAR) with the same specificity. In our previous work we developed in vitro evolution approaches to increase the affinities of native TCRs. Using this approach, we have developed high-affinity TCRs and CARs that are specific for different viral- or cancer- associated epitopes. While both of these receptors bind the antigen with high affinity, receptor-mediated signaling will differ due to differences in the receptor's intracellular signaling domain. The kinetics of signaling mediated by