Abstract 117: Improved PBMC humanized mouse models for immuno-oncology drugs evaluation

Abstract

Abstract It has been demonstrated that anti-PD(L)1 therapy could significantly improve survival outcomes for patients with metastatic solid cancers, such as melanoma, non-small cell lung cancer and MSI-H colorectal cancer. However, more than half of these patients (NCT02563002, NCT02142738, NCT02563002) do not respond to immune checkpoint blockade (ICB) therapy, and 90% of colorectal cancer patients have MSS/pMMR characteristics and almost no response at all, which drives scientists to design novel drug candidates urgently and integrate tumor and tumor microenvironment (TME) signals systemically to rejuvenate exhausted immune system and overcome ICB resistance. LIDE has developed both traditional PBMC humanized mice model, and human immune cells and cancer co-inoculated model for IO drugs functional evaluation in the last 5-years by using unique PBMC donor selection and standard cancer biobank (PDX patient-derived xenografts, CDX cell derived xenograft) establishment. Cancer biopsies with MDM2 amplification or DNMT3A alternation have been shown resistant to PD1-Ab therapy but sensitive to chemical combo-therapy, and pMMR cancer PDX models seem responsible well to EGFR targeted, CD39-CD73-Adenosine targeted therapy. Human IL15 transgenic mice are used as one useful tool to investigate in vivo function of NK cells, NK engagers/modulators as well as drugs with ADCC (Antibody dependent cell-mediated cytotoxicity) effect. The activated immune cells and cancer co-transfer model, can significantly delay the graft-versus-host-reaction for another month compared with traditional PBMC humanized model, and archives maximal therapeutic effect of the testing drugs by pre-activating T cells with specific tumor antigens. Dendritic cells or macrophages could be successfully introduced into this co-inoculated system to work together with T cells, mimic human tumor tissue complexity, to help determine the overall effect induced by integrated signals. It seems CD40 agonist or CD47 antagonist could well synergies with anti-PD(L)1 to control melanoma and triple negative breast cancer development, respectively. This optimized PBMC humanized cancer-bearing mice models have been tested for various cancer targets, e.g. PD(L)1, Tim3, Lag3, Tigit, PVRIG, TGFβ1, CD73/CD39, CD47/Sirpa, DLL3/CD3, Claudin18.2/4-1BB, B7-H3, GITR, to better understand the interaction between cancer cells and immune cells. Citation Format: Bin Xie, Xin Hou, Pengfei Yang, Yanbing Zhou, Danyi Wen. Improved PBMC humanized mouse models for immuno-oncology drugs evaluation [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(6_Suppl):Abstract nr 117.