Abstract 1286: Humanized avian xenograft models: advancing preclinical evaluation of immunotherapies and immune cell therapies with enhanced predictive accuracy

Abstract Despite the success of immunotherapies and immune-cell therapies, clinical attrition remains high due to the limited predictive power of current preclinical models. This underscores the urgent need for innovative tumor-based platforms to facilitate the rapid and reliable evaluation of therapeutic efficacy. To address this challenge, we have developed advanced humanized avian xenograft models, leveraging our proprietary AVI-PDX™ technology. These models involve implanting human cancer cells into avian embryos, enabling the evaluation of therapeutic responses in a matter of days. Our humanized models, IMMUNO-AVI-PDX™ and IMMUNO-AVI-CellDX™, utilize two distinct approaches: (i) co-implantation of human peripheral blood mononuclear cells (PBMCs) and cancer cells, or (ii) implantation of cancer cells followed by intravenous injection of human PBMCs. Using a combination of whole embryo light-sheet microscopy, molecular marker analysis via immunolabelling of cryosections, and flow cytometry on microdissected tumors, we demonstrated efficient PBMC intake, robust immune cell survival, and minimal allogenicity. This approach successfully establishes tumor-immune interactions, with enhanced infiltration and persistence of human T cells, B cells, monocytes, and NK cells within tumors. We validated the functionality of our models by testing the anti-PD1 immune checkpoint inhibitor, pembrolizumab. Intravenous administration of the anti-PD1 monoclonal antibody (mAb) efficiently targeted PD1 receptors on T cells, resulting in their activation and subsequent tumor response. Next, we evaluated anti-PD1 efficacy in a panel of humanized AVI-PDX™ and AVI-CellDX™ models, including colorectal cancer (CRC), breast cancer, and melanoma. Using whole embryo light-sheet imaging and tumor volume quantification, we observed that our models successfully replicated the known response to anti-PD1, showing efficacy in sensitive cell lines and resistance in resistant ones. Notably, our CRC models revealed patient-specific heterogeneity in tumor responses, correlating with molecular features currently used to predict clinical outcomes. Finally, in collaboration with ErVimmune, we extended the application of our models to immune cell therapy by demonstrating the efficacy of a co-implanted HERV-specific T cell clone in an ovarian cancer IMMUNO-AVI-CellDX™ model. Together, these findings highlight the potential of our humanized avian xenograft models to advance the study of immune-based therapies and to identify predictive biomarkers for therapeutic efficacy. Citation Format: Marjorie Lacourrège, Romain Teinturier, Paola Bonaventura, Clélia Costechareyre, Loraine Jarrosson, Camille Futelot, Mayrone Mongellaz, Stéphane Depil, Céline Delloye-Bourgeois, Valérie Castellani. Humanized avian xenograft models: advancing preclinical evaluation of immunotherapies and immune cell therapies with enhanced predictive accuracy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1286.