Abstract 5340: NK-humanized mouse models for the in vivo evaluation of NK cell-based therapies in solid tumors

Abstract Novel immunotherapeutic strategies targeting Natural Killer (NK) cells using monoclonal or multi-specific antibodies and immune modulator molecules are under development and suitable mouse models are needed to evaluate these therapeutics. We developed and characterized robust in vivo models that allow the engraftment and long-term maintenance of fully functional human NK (huNK) cells in immunodeficient transgenic mice for human cytokines (IL15). In efficacy studies, we confirmed that huNK cells are recruitable by NK cell-based therapies including therapeutic antibodies or multi-specific biologics and able to control tumor growth in these models. To establish a more relevant model for better clinical translatability for Fc-competent therapeutics evaluation, we optimized the model by validating a mouse strain with a functional knock-out of murine Fcγ receptors (FcgR-KO) to minimize the confounding impact of mouse immune cells. We characterized huNK cells kinetics and profile by flow cytometry compared to NOG-huIL15 mice. In efficacy studies with the FcgR-KO strain, therapeutic antibodies are inactive in non-NK-humanized mice, whereas in NK-humanized mice huNK cells can be recruited by the therapeutic antibody to control tumor growth by ADCC, in B cell lymphoma or multiple myeloma bearing mice. We also report the development of NK-humanized models for the evaluation of NK-based therapies in solid tumors. We characterized huNK intratumoral infiltration in several subcutaneous tumor xenograft models and evaluated the impact of tumor environment on the expression of functional NK markers (NKp46, NKG2D, Tim3, CD69) by flow cytometry and IHC studies. In summary, we have developed and optimized robust murine models sustaining fully functional huNK cells that can be proficiently recruited in vivo by various NK-based therapeutics. These models can also be used to evaluate the efficacy of combination therapies. Citation Format: Pauline Rettman, Samira Benhamouche-Trouillet, Michel Pelat, Katarzyna Franciszkiewicz, Georges Azar, Lydia Blot, Loreley Calvet, Sukhvinder Sidhu, Céline Nicolazzi. NK-humanized mouse models for the in vivo evaluation of NK cell-based therapies in solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5340.