Cancer Therapy: Clinical Phase Ia Study of FoxP3þ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients

Purpose: FoxP3þ Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-humanCCR4monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3þ CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, includingTregs,andinductionofimmuneresponseswereanalyzed. Results: The results showed that KW-0761 infusion in a dose rangebetween0.1mg/kgand1.0mg/kgwas safeandwell tolerated. Nodose-limiting toxicitywasobserved. Fourof 10patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3þ Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3þ Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses. Clin Cancer Res; 21(19); 4327–36. 2015 AACR.