Progress in Clinical Use of CC Chemokine Receptor 4 Antibody for Regulatory T Cell Suppression

Abstract

Recent clinical research advances in tumor immunity provide hope for the development of a novel tumor immunotherapy. Many clinical studies of cancer vaccines over the past 10 years have shown the augmentation of tumor immunity in some patients, although the clinical effects have been low. In addition, it was reported that blocking regulatory molecules involved in the immune checkpoint is important for immune activation in both in vitro and in vivo studies. In particular, studies using blocking antibodies to cytotoxic T lymphocyte-associated antigen (CTLA)-4, programmed cell death protein (PD)-1, or PD-1 ligand 1 (PD-L1) observed significant clinical effects including complete remission, suggesting that regulation of regulatory signals in the immune checkpoint is a new direction for the development of new drugs based on tumor immunity. As regulatory T cells (Tregs) also plays a key role in immune regulation, just as the regulatory molecules in the immune checkpoint become targets for the development of novel tumor immunotherapy, they may also become a target for development. Several reports have suggested that Tregs that infiltrate tumor sites as well as regulatory signals for immune checkpoints can inhibit tumor immunity, which is one explanation why treatment by cancer vaccine is limited. CC chemokine receptor 4 (CCR4) is selectively expressed on effector Tregs, and humanized monoclonal antibodies to CCR4 have been developed as a drug, ‘mogamulizumab’, to treat adult T cell leukemia/lymphoma (ATLL). Mogamulizumab depletes both ATLL cells and normal Tregs, resulting in the recovery of immune function in ATLL patients. Mogamulizumab is now expected to be accepted for use as a novel immuno-activator for tumor therapy by depletion of Tregs and is undergoing phase Ia/Ib studies for treatment of solid tumors in the lung, esophagus, intestine, ovary, and melanoma.