Abstract Introduction: CC-motif chemokine receptor 8 (CCR8) is selectively expressed on the surface of intratumoral regulatory T cells (itTregs). In mouse models, depletion of CCR8+ itTregs can induce antitumor activity and overcome resistance to checkpoint inhibitors, either as monotherapy or in combination with programmed cell death protein 1 (PD-1) blockade. We present interim data from an ongoing first-in-human dose-escalation phase 1 study of denikitug (DEN), an afucosylated anti-CCR8 monoclonal antibody (NCT05007782). Methods: Adults with advanced solid tumors whose disease had progressed on/after standard therapies were enrolled. We report results from 2 DEN monotherapy groups: Part A, dose escalation across 5 levels (range, 1-100 mg every 3 weeks Q3W), and Part B, paired biopsy cohort in select tumor types (range, 10-100 mg Q3W). Results: As of October 28, 2025, 57 participants (pts) were treated (Part A: 16; Part B: 41). There were no dose-limiting toxicities. The most common treatment-related adverse events (TRAEs) were pruritus and maculopapular rash (37% each), diarrhea (25%), fatigue (23%), and decreased appetite (13%) ; among these, 0%, 4%, 4%, 2%, and 0%, respectively, were grade ≥ 3 events. There were no grade 4 or 5 TRAEs. In the efficacy evaluable population (n = 52), objective response rate was 8% (n = 4; median of 6 prior lines of therapy, range 2-7) and disease control rate was 46% (n = 24; median of 2 prior lines of therapy, range 1-8) ; among the pts with disease control, 71% had prior exposure to PD-1/programmed cell death ligand 1 (PD-L1) inhibitors. The 4 confirmed partial responses were in pts across a variety of tumor types (non-small cell lung cancer, triple-negative breast cancer, vaginal squamous cell carcinoma, gastroesophageal junction adenocarcinoma). Based on the 23 evaluable paired biopsies, robust CCR8+ itTreg depletion (median 95%) and enhanced effector T cell (Teff) expansion (median 2. 3-fold) was observed at doses ≥ 10 mg. Rapid and sustained peripheral blood Treg depletion was also seen at all dose levels, with consistent CD8+ Teff (Ki67+) proliferation at doses ≥ 10 mg, along with changes in IFNG and PDL1 gene expression. Conclusions: DEN is pharmacologically active at doses ≥ 10 mg as shown by CCR8+ itTreg depletion with concurrent increase in Teff infiltration in tumor tissue. Gene expression changes of key biomarkers indicate biologic activity within the tumor microenvironment. DEN demonstrates a manageable safety profile and TRAEs were consistent with a Treg depleting mechanism of action. Single-agent antitumor activity was observed in heavily pretreated pts, including those with prior PD-1/PD-L1 inhibitor exposure and tumor types generally not responsive to immunotherapy. This supports further evaluation of DEN as monotherapy and in combination with other therapies. Citation Format: Bruno Bockorny, Christopher Chen, Jaffer Ajani, David Sommerhalder, Minal Barve, Meredith McKean, Sandip Patel, Renu Jain, Brian Weist, Julika Huber, Vaishnavi Ganti, Ling Han, Anna Seto, Lars Mueller, Nataliya V. Uboha. Preliminary results of a phase 1, first-in-human, dose-escalation study of the anti-CCR8 antibody denikitug in participants with advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT232.
Bockorny et al. (2026) studied this question.