Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by FcgR IIIa (CD16)– expressing effector cells in vivo via antibody-dependent cell-mediated cytotoxicity (ADCC), as observed for naturalkiller(NK)cells.Inpractice,chemotherapy-inducedleukopeniaandexhaustionofNKcellsresultingfrom ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene-modified to express a newly generated affinity-matured (158V/V) chimeric CD16CD3z receptor (cCD16z-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16z-T cells werereadilyexpandableinexvivocultureusinganti-CD2/CD3/CD28beadsandrecombinanthumaninterleukin2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonizedcancercellstotheintroducedcCD16z-Tcellsstimulatedtheeffectorcellstoproduceproinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3z chain. In parallel, these stimulated cCD16z-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16z-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20 þ lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2–treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16z-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs. Cancer Immunol Res; 2(3); 249–62. � 2014 AACR.