Pbmc Humanized Nsg-((Kdb)-D-B)(Null) (Ia)(Null) Mouse Model To Evaluate Immune-Oncology Drug Efficacy

Multiple types of humanized mouse models using immunodeficient NOD-scid IL2rgnull (NSG) mice have been developed by The Jackson Laboratory for preclinical studies of new cancer therapies. Humanized NSG mice engrafted with both human peripheral blood mononuclear cells (PBMC) and human cancers have been used for evaluating antibody-based therapeutics targeting T cells. Compared to CD34+ HSC-mediated humanization, NSG mice engrafted with PBMC are ready to use more quickly and are more cost-effective. The major limitation of PBMC engrafted NSG is the development of acute xenogeneic graft-versus-host disease (GVHD) due to human T cell activation through mouse MHC class I and class II molecules. The experimental window for drug efficacy evaluation is limited to three-four weeks post PBMC injection and strong xeno-GVHD may hinder drug-induced T cell activation. A new strain lacking murine MHC molecules, NSG-(KbDb)null (IA)null, was created to address this limitation. Here we engrafted non-irradiated adult NSG and MHC double knockout NSG-(KbDb)null (IA)null mice using the same human PBMC donors to compare their survival and engraftment level. We found that most of the MHC deficient mice can survive over 100 days and can support human T cell engraftment. We also evaluated drug efficacy response using checkpoint inhibitors anti-CTLA-4 (lpilimumab) and anti-PDL-1 (Avelumab) in human tumor xenograft models. Anti-CTLA-4 treatment resulted in reduced growth of mantle cell lymphoma Jeko-1. Anti-PDL-1 treatment reduced growth of a melanoma PDX. In consistent with their anti-tumor response, flow analysis showed increased T cell frequency in blood and tumor in the drug treated group when compared to the vehicle control. Additional cancer treatment evaluated in the PBMC engrafted NSG-(KbDb)null (IA)null mice will also be discussed. Citation Format: Li-Chin Yao, Mingshan Cheng, Leonard D. Shultz, James G. Keck. PBMC humanized NSG-(KbDb)null (IA)null mouse model to evaluate immune-oncology drug efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5619.