Abstract NTX1088, a first-in-class anti-PVR (CD155) monoclonal antibody, is currently being evaluated in a Phase 1, open-label, multi-center study (NCT05378425) as monotherapy and in combination with pembrolizumab in patients with advanced solid malignancies. Preliminary clinical data, for the first time, demonstrate restoration of DNAM1 (CD226) expression and function on peripheral T and NK cells following PVR blockade by NTX1088. This mechanistic breakthrough is robustly observed across multiple dose levels and distinguishes NTX1088 as a unique immunotherapeutic agent, unlike all anti-TIGIT strategies, which have not achieved DNAM1 restoration in clinical settings. Clinical biomarker analyses confirm significant upregulation of DNAM1 across NK cells, CD4+, and CD8+ T cells, effectively reversing PVR-mediated DNAM1 downmodulation, a recognized mechanism of immune escape and resistance to checkpoint inhibition. In contrast to TIGIT blockade, which fails to restore DNAM1, NTX1088 drives a favorable shift in the TIGIT/DNAM1 ratio and expands potent effector subsets, directly enhancing antitumor immune activity. To further dissect the translational impact and molecular mechanisms, extensive in vitro work was performed, using PBMCs from healthy volunteers and Jurkat cell line. In these in-vitro assays, simultaneous engagement of DNAM1 with CD3 signaling resulted in increased induction of activation markers, unique changes in exhaustion profiles, and robust cytokine secretion, functional signatures which showed DNAM1 co-signaling is distinct from conventional CD28-mediated costimulation. Concordant findings in humanized mouse models reveal that much of NTX1088’s tumor growth inhibition and immune effector activation are DNAM1-dependent, and DNAM1 positive cells are significantly more activated and primed for anti-tumor activity compared to cells that did not upregulate DNAM1. Collectively, these data establish NTX1088 as the first immunotherapy to achieve clinical restoration of DNAM1, validating both DNAM1 induction and TIGIT/DNAM1 ratio remodeling as actionable biomarkers for drug effect, patient selection, and future immune-oncology combinations. The concurrent restoration of DNAM1, alongside blockade of other PVR inhibitory receptors like TIGIT, CD96, and KIR2DL5A, positions NTX1088 as an attractive therapeutic agent for synergistic IO/IO combinations, charting a transformative course for next-generation anticancer immunity Citation Format: Anas Atieh, Alon Vitenshtein, Akram Obiedat, Simona Chechik, Rivki Cashman, Guy Cinamon, Keren Paz, Paola Kučan Brlić, Tihana Lenac Roviš, Lea Hiršl, marija mazor, ema bellulovich, Stipan Jonjic, Ofer Mandelboim, Pini Tsukerman. NTX1088 demonstrates the first-ever clinical restoration of DNAM1, defining a novel immune-oncology axis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6543.
Atieh et al. (Fri,) studied this question.