Abstract 3849: HuPBL humanized models as a tool to evaluate the efficacy and immune regulation of immune checkpoint inhibitors
Authors: Tang Xuzhen , Zhai Xianzhi , Qi Hui , Hong Qin , Zhang Qiyao , Jin Lei , Yan Shaoyu , Wang Zhuozhi , Zheng Yong , Gu Qingyang , Zhang Norman , Li Jing , Ji Qunsheng 
Published: July 2017

After the success of PD-1, PD-L1 and CTLA-4 antibodies, a number of immune-checkpoint inhibitors are already in advanced stages. Meanwhile, tumor infiltrating lymphocytes (TIL) are well recognized as features of tumor progression and keys to effective cancer immunotherapy. Therefore, there is an urgent need to establish an effective pre-clinical platform for the evaluation of therapeutical outcomes in the human immune-system and the understanding of TILs. Either traditional syngeneic models or human target knockin models have their drawbacks: syngeneic models disable the development of antibodies that do not recognize mouse receptors; neither of them can achieve a good clinical prediction due to their inherent property as a murine system. To get a reconstitution of the human immune system in murine models, we have established several customized Human peripheral blood lymphocytes (hu-PBL) humanized models in NOG (NOD/Shi-scid/IL-2Rγnull) mice either systemically or focalized in tumors. Those models were validated by immune-checkpoint inhibitors for efficacy and by conducting TIL analysis with the support of sophisticated Flow Cytometry-Based Approach.

Here we report that the engrafted human cells can expand and infiltrate in tumors in response to xenogenic stimulation with functional Th and Tc detected. The cell lineages are mainly CD3+ T lymphocytes (90%) and to lesser extent NK/NKT cells; the redistribution in tumors is unique not only compared to splenic and peripheral blood T cells, but also varies among different cancer cell lines when the same donor was applied. In addition, cell surface expression of immune checkpoint targets showed unique redistributions. We further investigated the correlation between the efficacy and the immune-regulation in these models: Models with more dense infiltration at the early phase usually grew more slowly than its NON-PBMC control, which also are prone to be better responders to immunotherapy due to the higher Effector cell: Target cell ratio (E:T ratio). When compared the efficacy of 2 different hPD-1 test antibodies in A375 systemic humanized model, the one with better efficacy also achieved stronger inhibition on PD-1 expression in TILs. Treatment with the clinically used Opdivo showed not only different responses in HCC827, A375 and A431 xenograft models but also unique profiles in TILs subsets and related immune-checkpoint expression.

These models can be used for the purpose of pre-clinical immune-checkpoint inhibitor and bi-specific antibody screening under human background, as well as for further investigations regarding distinct functions of TILs subsets and target expression.

Citation Format: Xuzhen Tang, Xianzhi Zhai, Hui Qi, Qin Hong, Qiyao Zhang, Lei Jin, Shaoyu Yan, Zhuozhi Wang, Yong Zheng, Qingyang Gu, Norman Zhang, Jing Li, Qunsheng Ji. HuPBL humanized models as a tool to evaluate the efficacy and immune regulation of immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3849. doi:10.1158/1538-7445.AM2017-3849