Differential expression of CCR8 in tumors versus normal tissue allows specific depletion of tumor-infiltrating T regulatory cells by GS-1811, a novel Fc-optimized anti-CCR8 antibody. (31st December 2022)

• Record Type: Journal Article
• Authors: Weaver, Jessica D.; Stack, Edward C.; Buggé, Joshua A.; Hu, Changyun; McGrath, Lara; Mueller, Amy; Wong, Masie; Klebanov, Boris; Rahman, Tanzila; Kaufman, Rosemary; Fregeau, Christine; Spaulding, Vikki; Priess, Michelle; Legendre, Kristen; Jaffe, Sarah; Upadhyay, Dhruvkumar; Singh, Anirudh; Xu, Chang-Ai; Krukenberg, Kristin; Zhang, Yan; Ezzyat, Yassine; Saddier Axe, Dorothée; Kuhne, Michelle R.; Meehl, Michael A.; Shaffer, Donald R.; Weist, Brian M.; Wiederschain, Dmitri; Depis, Fabien; Gostissa, Monica
• Is Part Of: Oncoimmunology. Volume 11:Number 1(2022)
• Publication Date: 2022-12-31
• Subjects: CCR8 -- T regulatory cells -- cancer immunotherapy -- treg depletion -- PD-1 resistance; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2022.2141007
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: The presence of T regulatory (Treg) cells in the tumor microenvironment is associated with poor prognosis and resistance to therapies aimed at reactivating anti-tumor immune responses. Therefore, depletion of tumor-infiltrating Tregs is a potential approach to overcome resistance to immunotherapy. However, identifying Treg-specific targets to drive such selective depletion is challenging. CCR8 has recently emerged as one of these potential targets. Here, we describe GS-1811, a novel therapeutic monoclonal antibody that specifically binds to human CCR8 and is designed to selectively deplete tumor-infiltrating Tregs. We validate previous findings showing restricted expression of CCR8 on tumor Tregs, and precisely quantify CCR8 receptor densities on tumor and normal tissue T cell subsets, demonstrating a window for selective depletion of Tregs in the tumor. Importantly, we show that GS-1811 depleting activity is limited to cells expressing CCR8 at levels comparable to tumor-infiltrating Tregs. Targeting CCR8 in mouse tumor models results in robust anti-tumor efficacy, which is dependent on Treg depleting activity, and synergizes with PD-1 inhibition to promote anti-tumor responses in PD-1 resistant models. Our data support clinical development of GS-1811 to target CCR8 in cancer and drive tumor Treg depletion in order to promote anti-tumor immunity.