Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T‐cell malignancies

With the emerging success of treating CD19 expressing B cell malignancies with ex vivo modified, autologous T cells that express CD19‐directed chimeric antigen receptors (CAR), there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors. Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long term survival we generated a lentivirus‐based CAR gene transfer system to target the chemokine receptor CCR4 that is over‐expressed in a spectrum of T cell malignancies as well as in CD4+CD25+Foxp3+T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti‐tumor immunity. Ex vivo modified, donor‐derived T cells that expressed CCR4 directed CAR displayed antigen‐dependent potent cytotoxicity against patient‐derived cell lines representing ATL, CTCL, ALCL and a subset of HDL. Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T cell malignancies.