Unexpected central-memory CD8+ T cell reduction hampers the antitumor efficacy of mogamulizumab (anti-CC chemokine receptor 4 mAb) treatment

Abstract Developing Treg cell-targeted therapies is an important aspect in cancer immunotherapy. Here, we investigate anti-CCR4 mAb (mogamulizumab) with solid cancer patients in phase 1b clinical trial based on the predominant detection of CCR4-expressing eTreg cells in tumors. While eTreg cells in peripheral blood were significantly decreased after mogamulizumab administration in all patients, clinical responses were hardly detected. Comprehensive immune-monitoring revealed that concomitant reduction of central-memory CD8+ T cells with CCR4 expression, that reportedly play an important role in antitumor activity. This reduction was subsided in long survivors in whom central-memory CD8+ T cells possessed lower CCR4 expression and/or NK cells exhibited an exhausted phenotype. Thus, excess doses of mogamulizumab harboring enhanced antibody-dependent cellular cytotoxicity could unexpectedly deplete central-memory CD8+ T cells with CCR4 expression. We therefore need to carefully determine the optimal dose of mogamulizumab for successful clinical application as cancer immunotherapy to avoid unexpected depletion of effector components.