Abstract 2229: A panel of NSCLC patient derived xenografts displays a distinct sensitivity profile towards checkpoint inhibitor treatment in vitro and in vivo
Authors: Nunan Robert , Oswald Eva , Aylott Ilona , Feuerhake Friedrich , Jenkinson Rhiannon , Schüler Julia 
Published: September 2020

The field of cancer immunology is rapidly moving towards innovative therapeutic strategies. As a consequence there is a need for robust and predictive preclinical platforms for assessing therapies. The current project aims to establish a drug screening workflow bridging between innovative 3D in vitro assays and humanized mouse models based on the same PDX model panel. A total of six different lung cancer patient derived xenograft models (NSCLC PDX) were transduced to express nuclear RFP, cultivated as 3D spheroids and co-cultured with human peripheral blood monocytes (PBMC). Spheroid fluorescent intensity was monitored every 4 hours over a total of 120h. Efficacy of different checkpoint inhibitors was determined using a live cell imaging technology (IncuCyte S3, Sartorius). In vivo a total of 14 different NSCLC PDX were screened for their sensitivity towards α-CTLA-4, α-PD-1 or the combination thereof. With n=1 per treatment arm and model and the study design followed the screening approach of the single mouse trial (SMT). Human immune cell infiltrates of tumor (=TILs), peripheral blood, spleen and bone marrow (determined by flow cytometry, FC, and IHC) and secretion of human and mouse cytokines in murine serum (determined by cytokine array & Luminex based technology) were determined in all models.In the spheroid assay as well as in vivo all three treatment arms displayed a discrete activity pattern throughout the PDX panel. The activity pattern of the 14 PDX mirrored the clinical diversity of tumor responses to checkpoint inhibitor treatment ranging from complete remission to resistance. The sensitivity towards checkpoint inhibitors was stable in a distinct PDX model across the two drug development platforms. Tumor models with high tumor infiltrating lymphocyte (TIL) rates (&gt;5%) in the untreated control group were more susceptible towards checkpoint inhibitor treatment than models with low TIL rates. In either case, numbers of TILs were markedly increased in the treatment groups as compared to control vehicle. The analysis of human and mouse cytokines in the serum of tumor bearing mice led to the identification of a cytokine pattern specific for PDX models sensitive towards checkpoint inhibitor treatment. 11 human cytokines were upregulated in the sensitive tumor models (e.g. GM-CSF, IL-4 & CX3CL1). The use of PDX based innovative 3D in vitro models in combination with humanized mouse models enables screening campaigns in the immune-oncology field using clinically relevant tumor models. The predictivity of the 3D spheroid platform towards the in vivo humanized mouse assay is a critical feature as it allows the optimal selection of promising drug candidates to be profiled in more detail.

Citation Format: Robert Nunan, Eva Oswald, Ilona Aylott, Friedrich Feuerhake, Rhiannon Jenkinson, Julia Schüler. A panel of NSCLC patient derived xenografts displays a distinct sensitivity profile towards checkpoint inhibitor treatment in vitro and in vivo [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 2229.