Abstract 1732: Investigation of the best therapeutic approach to target CCR8 expressed on tumor regulatory T cells to boost anti-tumor immune responses

Abstract The goal of this study was to investigate the therapeutic potential of targeting regulatory T cells (Treg) through CC motif chemokine receptor 8 (CCR8) and to determine the optimal mode of action for CCR8 targeting molecules to elicit anti-tumor immune response. Infiltration of high levels of Treg cells in tumors is associated with a poor survival prognosis suggesting that the latter cells restrain effector T cell and overall immune activity in the tumor microenvironment. Modulation and inhibition of Treg cells in the tumor is expected to lead to a reinvigorated immune response against the tumor cells. Since Treg cells are also essential for controlling autoimmunity, modulating regulatory T cell activity is preferably restricted to the tumor microenvironment. CCR8 has been identified as a chemokine receptor expressed specifically on tumor-infiltrating, but not on peripheral Treg cells. Surrogate molecules targeting mouse CCR8 having distinct modes of action were generated and were tested in different syngeneic tumor mouse models. In the CT26 and MC38 models, anti-CCR8 monotherapy showed a reduction in tumor growth, prolonged survival and tumor stasis in the majority of the mice. Tumor regression was observed in 20-40% of the mice. Combining anti-CCR8 with anti-PD-1 treatment resulted in both models in complete tumor regression in the majority of the mice. Immunophenotyping analysis showed that anti-CCR8 treatment resulted in strongly decreased Treg cell levels in the tumor. In addition, anti-CCR8 monotherapy and anti-PD1 combination therapy lead to an increase of intratumoral CD8 T cell levels resulting in a favorable CD8/Treg cell ratio. Molecules lacking Fc mediated effector function and only blocking the CCL1-CCR8 signaling showed limited or no efficacy in these tumor models, suggesting that the observed anti-tumor effect is due to ADCC/ADCP - mediated Treg cell depletion and not to blocking of CCR8. Moreover, re-challenge of the complete responders (in both MC38 and CT26) resulted in full tumor rejection in the majority of the mice, indicative of a strong immunological memory. Next to the surrogate molecules, a large set of molecules binding to human CCR8 were identified. Based on human CCR8 binding, CCL1 blocking and in vitro ADCC cell based assay data a final panel of molecules binding to a diverse set of epitopes on human CCR8 have been selected. Final leads are available and are progressing into preclinical development. Our results demonstrate that targeting CCR8 represents a very attractive and promising method to unleash anti-tumor immune responses in patients. Citation Format: Heleen Roose, Elizabeth Allen, Helena Van Damme, Bruno Dombrecht, Rosa Martín-Pérez, Damya Laoui, Jo A. Van Ginderachter, Pascal Merchiers. Investigation of the best therapeutic approach to target CCR8 expressed on tumor regulatory T cells to boost anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1732.