{
  "abstract": "Background Intratumoral regulatory T cells (itTregs) are associated with resistance to anticancer therapy, including PD-1 inhibitors. CCR8 is a G-protein coupled receptor (GPCR) predominantly upregulated on itTregs. Selective depletion of CCR8 +itTregs aims to improve anticancer therapy and avoid autoimmunity associated with broad Treg depletion. CHS-114 is a highly selective, cytolytic anti-CCR8 mAb designed to deplete immunosuppressive CCR8+ itTregs and remodel the tumor microenvironment (TME) to promote antitumor immunity. An ongoing Phase 1 (NCT05635643), single-agent and toripalimab (tori) combination dose escalation/expansion study is evaluating CHS-114 in advanced solid tumors and head and neck squamous cell carcinoma (HNSCC). CHS-114 has demonstrated an acceptable safety profile to date, and antitumor activity in HNSCC. We present interim clinical biomarker data characterizing itTregs and establishing CHS-114 proof of mechanism.Methods Phase 1 study that enrolled adults whose disease progressed on or after standard therapies into 3 arms: 1a: advanced solid tumors (dose escalation 5 to 1200 mg); 1b: HNSCC (2 dose levels [DL5/DL6 of pharmacologically active CHS-114); 2: HNSCC (CHS-114 DL5/DL6 + tori 240 mg). Serum and PBMC samples were collected longitudinally for proteomic and immune profiling analysis, respectively. Additionally, baseline (fresh and/or archival) and on-treatment tumor biopsies were collected to assess changes in Tregs, CD8 + T cells and other immune biomarkers.Results CHS-114 induced robust and sustained depletion of CCR8 + Tregs in peripheral blood while sparing effector T cells. Increases in serum and immune markers indicative of TH1 responses and CD8+ T cell activation were observed and sustained at DL5 or higher, confirming biologically active doses for expansion. In baseline tumor tissues from HNSCC participants, CCR8+ Tregs were significantly enriched. Additionally, notable differences in CCR8+ Treg density were observed between archival and screening (fresh) tumor tissues, indicating intervening-treatment induced changes on itTreg density. In on-treatment tumor biopsies, CHS-114 with and without tori mediated robust depletion of CCR8+ Tregs but not CCR8- (negative) Tregs, demonstrating selective targeting. A marked increase in CD8+ T cell infiltration and a higher CD8+ T cell/Treg ratio in the TME indicated favorable CHS-114 mediated anti-tumor remodeling.Conclusions CHS-114 administration to HNSCC patients demonstrates selective depletion of CCR8 + itTregs, an increase in CD8+ T cells in tumors, and anti-tumor responses in combination with toripalimab. Remarkably, the tumor biopsy data indicate that CHS-114 administration converts cold tumors to immunologically ‘hot’ thereby supporting evaluation with immune agents beyond PD-1 inhibitors such as T cell engagers and CAR-T cell therapy.Trial Registration NCT05635643Ethics Approval The protocol and informed consent forms were reviewed and approved by an institutional review board (IRB), and the study was conducted in accordance with Good Clinical Practice. All participants provided informed consent before initiation of any study procedures.",
  "authors": [
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Varun Kapoor"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Xiaoguang Wang"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Xiao Wang"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Daniel J Chin"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Federico Baruffaldi"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Hong Tang"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Koho Iizuka"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Rosh Dias"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Narendiran Rajasekaran"
    },
    {
      "affiliations": [
        "Coherus Oncology, Redwood City, CA, USA"
      ],
      "name": "Theresa LaVallee"
    }
  ],
  "title": "640 CHS-114, an anti-CCR8 cytolytic monoclonal antibody demonstrates selective intratumoral Treg depletion and favorable immune remodeling in participants with advanced solid tumors",
  "uid": "6778903e-0cfd-5566-a44c-b74667ca5155"
}