Based on TCGA data for expression of surface targets on regulatory T cells, which identified CCR8 as a preferentially expressed target in tumor Tregs, Weaver and Stack et al. demonstrated that treatment of multiple murine tumors with anti-CCR8 antibodies enhanced tumor control and synergized with anti-PD-1. Activity depended on an ADCC-active Ig-Fc for Treg depletion. Gene expression and IHC analyses of treated tumors demonstrated hallmarks of a remodeled antitumor TME. A humanized anti-CCR8 mAb was active in killing Treg cells in human in vitro assays and is being tested in an ongoing clinical trial.
Contributed by Ed Fritsch
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.
Author Info: (1) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (2) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (3) Jounce Therapeutics, I
Author Info: (1) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (2) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (3) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (4) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (5) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (6) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (7) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (8) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (9) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (10) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (11) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (12) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (13) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (14) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (15) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (16) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (17) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (18) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (19) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (20) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (21) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (22) Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. (23) Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. (24) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (25) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (26) Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. (27) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (28) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA. (29) Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA.
