Targeting Immunosuppression with FPA157: A Novel Anti-CCR8 Approach to Deplete Tumor-Infiltrating Regulatory T Cells

The abstract discusses the significance of immunosuppression in limiting anti-tumor responses and the need for novel therapeutics targeting immune-suppressive mechanisms beyond PD-1 and CTLA-4 inhibitors. It highlights the role of regulatory T cells (Tregs) in inhibiting immune responses within the tumor microenvironment and the challenges with existing Treg-targeting agents due to their lack of specificity. The focus then shifts to CCR8, a receptor selectively expressed on highly activated intratumoral Tregs, which is associated with poor prognosis in various cancers. The correlation between CCR8 expression and poor outcomes and the potent anti-tumor activity observed upon depletion of CCR8+ Tregs in preclinical models is discussed.

The methods section describes the analysis of human FOXP3 and CCR8 expression across different tumor types using TCGA datasets, flow cytometry evaluation of CCR8 expression in tumor explants and peripheral blood mononuclear cells (PBMCs), and the assessment of the efficacy of an anti-CCR8 antibody in murine tumor models. The antibody's specificity and its ability to enhance antibody-dependent cell-mediated cytotoxicity (eADCC) are also detailed.

The results reveal a strong correlation between CCR8 and FoxP3 expression across cancer subtypes, with low or absent expression on effector T cells and no detection on peripheral human leukocytes. The anti-CCR8 antibody treatment is shown to reduce tumor growth in a dose-dependent manner, leading to complete tumor regressions and the development of memory. This treatment is associated with a decrease in intratumoral Tregs and an increase in CD8 T cells within the tumor.

FPA157 is identified as a highly specific CCR8 antibody that does not bind to closely related chemokine receptors and has been engineered to enhance eADCC, resulting in potent NK cell-mediated killing of CCR8-expressing target cells.

In conclusion, FPA157 is a CCR8-specific monoclonal antibody with eADCC activity being developed for cancer treatment. The depletion of CCR8+ Tregs has shown significant anti-tumor activity in preclinical models, suggesting the potential of FPA157 as a novel therapeutic approach to counter immune suppression in human solid tumors.