LAUSR

Novel immunotherapeutic strategies targeting human Natural Killer (huNK) cells using monoclonal or multi-specific antibodies and immune modulator molecules are under development and there is a pressing need to have suitable mouse models for the evaluation of these therapeutics. Existing humanized mouse models have limitations and do not show an optimal development of innate immune cells such as NK, dendritic or other myeloid cells. We previously described the development of robust mouse models that allow the engraftment and maintenance of fully functional huNK cells using several strains of immunodeficient transgenic mice for human cytokines (IL-15). The optimal parameters (source of immune cells, pre-conditioning regimen, route of administration) were identified, and the models were validated by flow cytometry and in vivo efficacy studies using an anti-CD20 Ab. Here, we report further development and characterization of these models and highlight their value to evaluate a variety of NK based therapeutics. We show that huNK cells can infiltrate a subcutaneous B-cell lymphoma model after treatment with an anti-CD20 Ab. We show that SAR444245 (non-alpha IL2) can activate huNK cells in vivo in all developed huIL-15 transgenic models and confirmed the minimal effective dose by flow-cytometry PD studies. We show the efficacy of both reference and internal ADCC-enhanced antibodies in disseminated tumor models in our humanized huIL-15 transgenic mice. In addition, we performed a deep characterization of huNK cells in huIL-15 transgenic models, using a 28-color flow cytometry panel centered on NK cell biology and profiled them transcriptionally by single cell RNA Seq in a disseminated B-cell lymphoma model. Overall, we have developed robust models sustaining fully functional huNK cells that can be proficiently recruited in vivo by various NK-based therapeutics and can be used to evaluate the efficacy of combination therapies. Citation Format: Pauline Rettman, Laure-Marie Meyer, Ravi Rangara, Anna Ponchet-Lac, Nicolas Moindrot, Angélique Biancotto, Céline Lefranc, Fabien Delahaye, Emilia Rabia, Matteo Cesaroni, Sukhvinder Sidhu, Céline Nicolazzi. Use of NK humanized mouse models for the in vivo evaluation of anti-tumor NK-cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2940.