Dual-Targeting Antibody Revives Antitumor Immunity in Animals

A novel antibody therapy empowers the immune system's tumor-fighting capabilities in mice by targeting immune-suppressing T cells with greater precision than previous approaches, according to new work. The antibody combated various tumor types both alone and in combination with checkpoint blockade antibodies, and was also safe and well-tolerated in nonhuman primates. Cancer immunotherapy has made great strides, but many barriers still impede its efficacy and undermine patient responses. The main obstacle is the tumor microenvironment, which is rife with molecular pathways and cells (including regulatory T cells) that suppress the immune system. Researchers are creating antibodies to target proteins such as CCR8 that are present on the surface of regulatory T cells, with the goal to deplete these turncoat cells and unleash the rest of the immune system. However, most existing approaches only target a single protein on regulatory T cells. Here, Baomei Wang and colleagues instead generated a more broadly potent bispecific antibody that engages two T cell receptors. In addition to targeting CCR8 on regulatory T cells, the antibody also activates CD3, which is found on a broad range of other T cell types. This approach suppresses regulatory T cells while also potentiating other T cell classes. The antibody depleted CCR8-bearing regulatory T cells in human tumor samples; restrained the growth of breast, lung, and colon tumors in mice; and augmented the efficacy of anti-PD-L1 antibodies. It was also well-tolerated in macaques and depleted circulating CCR8-bearing regulatory T cells in the blood. "Collectively, these findings establish CCR8×CD3 TCB as a promising therapeutic strategy to remodel the [tumor microenvironment] and enhance antitumor immunity," Wang et al. write.