A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vß Families.

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) ß chain in human α/ß TCRs are grouped into Vß families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vß families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vß families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vß family in vitro and in vivo. These findings provide proof of concept that TCR Vß-family-specific T cell lysis can be achieved using this novel combination cell-antibody platform and illuminates a path toward high precision targeting of T cell malignancies without substantial immune compromise.