Highly Selective Anti-Ccr8 Antibody-Mediated Depletion Of Regulatory T Cells Leads To Potent Antitumor Activity Alone And In Combination With Anti-Pd-1 In Preclinical Models

Background: Tumor-infiltrating CD4+ FOXP3+ regulatory T cells (Tregs) are a major driver of the immunosuppressive tumor microenvironment. CC chemokine receptor 8 (CCR8) expression is selectively upregulated in tumor-resident Tregs in multiple cancers, including breast, colon, and lung. These CCR8+ Tregs represents a highly activated and suppressive subset. High abundance of CCR8+ Tregs in these tumor types is associated with poor prognosis. Therefore, depletion of CCR8+ Tregs may be a promising approach to specifically address whether removal of Tregs will lead to augmentation of antitumor immunity. We evaluate the effect of CCR8-mediated Treg depletion alone and in combination with PD-1 blockade on antitumor immune responses in preclinical mouse tumor models and in a human tumor explant system. Methods: Human CCR8 and FOXP3 gene-gene correlations in The Cancer Genome Atlas (TCGA) were analyzed. Treg-specific protein expression of CCR8 was evaluated on tumor and peripheral tissues for both human and mice via flow cytometry and IHC. Single-cell RNA seq was performed on human tumors for differential gene expression analysis of CCR8+ Tregs. A variety of syngeneic mouse tumor models were used to determine antitumor activity of anti-CCR8 mouse surrogate antibody alone and in combination with anti–PD-1. Phenotyping of immune cell subsets was also conducted for proximal and distal pharmacodynamic changes. BMS-986340 (anti-CCR8 hIgG1-nonfucosylated [NF] antibody) was developed and used for CCR8+ Treg depletion in human tumor explants. Results: CCR8 gene expression had the highest correlation with FOXP3 in most cancer types in TCGA. CCR8 was specifically expressed on FOXP3hi Tregs while not on FOXP3mid and FOXP3neg effector T cells in patient tumors. Limited expression in peripheral blood, thymus, and skin resident T cells was seen. A similar expression profile was observed in mouse tumor models. CCR8 antibody–mediated Treg depletion and subsequent pro-inflammatory responses (↑CD8/CD4/IFNγ/GranzymeB/Ki67) induced robust tumor growth inhibition as a single agent in immunogenic tumor models and in combination with anti–PD-1 in I-O–resistant models. In these models, a dose-dependent pharmacokinetic/pharmacodynamic/efficacy relationship was observed. We also found tumor Treg–specific depletion in human tumor explant models upon treatment with BMS-986340. Conclusions: BMS-986340, a novel anti-CCR8 NF monoclonal antibody in development, led to measurable CCR8+ Treg depletion in human tumor explants. CCR8+ Treg depletion led to robust antitumor activity alone and in combination with anti–PD-1 in mouse tumor models. These results support further clinical evaluation of CCR8 depletion in combination with immune checkpoint blockade as a novel immunotherapy for cancer. Citation Format: Ruth Lan, Amy Jhatakia, Joseph Campbell, Nathan Siemers, Kai Lu, Mohammed Nasser, Tetiana Grigoriev, Priti Singh, Logan Vlach, Tim Sproul, Chengyue Zhang, Xi-Tao Wang, Olufemi Adelakun, Felix Findeisen, Pavel Strop, Arvind Rajpal, Natalie Bezman, Michael Quigley, Renu Jain. Highly selective anti-CCR8 antibody-mediated depletion of regulatory T cells leads to potent antitumor activity alone and in combination with anti-PD-1 in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6694.