在HNSCC模型中，Rilvegostomig较临床批准的抗PD-1单药疗法引发更强的免疫激活和肿瘤抑制

Background: Rilvegostomig (AZD2936) is a monovalent, bispecific humanized IgG1 monoclonal antibody that targets human TIGIT and PD-1, engineered with a triple-mutation in its fragment crystallizable (Fc)-domain to prevent Fc-effector functionality. Rilvegostomig has shown promising anti-tumor activity in NSCLC patients in a Phase I/II clinical trial (NCT04995523) and is currently being investigated in multiple Phase III trials. Here, we report the enhanced anti-tumor activity of rilvegostomig compared to a clinically approved anti-PD-1 (alphaPD1) mAb in ex vivo and in vivo models of head and neck squamous cell carcinoma (HNSCC). Methods: Primary HNSCC explants, derived from freshly resected patient tumors, were cultured ex vivo in a 3D platform for therapeutic agent testing. Ex vivo immune activity was assessed via IFN-gamma quantification. Baseline tumor features-characterized by IHC, flow cytometry, scRNA-seq, and multiplex imaging-were used to stratify patient response and identify candidate biomarkers. A CD34+ humanized mouse model of HNSCC was developed to enable long-term engraftment of functional multi-lineage hematopoietic cells and used to investigate efficacy and effects of IO therapeutics on different components of the immune system. Results: We investigated a cohort of 42 newly diagnosed HNSCC patient resected tumor samples. These samples represent the incidence of HNSCC by anatomical sites and share similar cohort attributes as those enrolled in KEYNOTE-689. Patient-derived tumor explants maintain tumor architecture and intact tumor microenvironment (TME), including tumor cells, immune cells, stroma cells, and extracellular matrix. alphaPD1 monotherapy elicited immune activity in 9.5% of HNSCC samples tested in our ex vivo platform, consistent with clinical observation of major pathological response in KEYNOTE-689. In contrast, rilvegostomig induced a significantly higher rate of ex vivo immune activity (28.6%). Rilvegostomig's activity was observed in samples derived from multiple anatomical sites, showing the highest response rate in oral cavity samples. Moreover, our analyses identified key baseline correlates that distinguish rilvegostomig activity from alphaPD1. Lastly, using a CD34-engrafted humanized mouse model of oral cavity HNSCC, we compared the therapeutic efficacy of alphaPD-1 monotherapy with rilvegostomig. In contrast to alphaPD-1, which produced modest effects on tumor growth, rilvegostomig induced significant tumor growth inhibition. Conclusions : Rilvegostomig elicits greater immune cell activation and broader activity in samples derived from different anatomical sites of HNSCC compared to alphaPD1 monotherapy in a 3D ex vivo platform and a humanized mouse model of HNSCC. These results underscore rilvegostomig's potential as a promising treatment for newly diagnosed HNSCC and support its investigation in clinical trials.