Abstract 2711: Modeling pancreatic and non-small cell lung cancer using a humanized mouse platform
Authors: Barnes Sheri , Draper David , Roys Stacey , Lapinski Philip , Franklin Maryland Rosenfeld 
Published: July 2021

The development of immuno-oncology agents against human targets is actively pursued in the preclinical space using immune deficient mice with reconstituted human immune systems. We utilized a human peripheral blood mononuclear cell (hPBMC) based humanized mouse model to investigate treatment response in human pancreatic and non-small cell lung cancers. Three human PBMC donors were identified that exhibited consistent T cell engraftment, allowing for a four-week treatment window, and robust growth of two human xenograft models in NSG mice, MiaPaCa-2 (pancreatic) and A549 (non-small cell lung). Anti-tumor efficacy of pembrolizumab (Keytruda®) targeting human PD-1 was also assessed in these humanized models. All animal work was performed in an AAALAC accredited facility, in alignment with applicable animal welfare regulations and with predetermined humane euthanasia criteria on all studies. Control growth of MiaPaCa-2 and A549 tumors were similar with and without hPBMC engraftment. Both tumor models progressed uniformly to a mean tumor volume of 1000 mm3 without apparent hPBMC impact.

Engraftment was assessed at 28 and 38 days (MiaPaCa-2) or 42 days (A549) after hPBMC administration by immunophenotypic analysis using flow cytometry in peripheral blood. At all timepoints, hCD45+ cells were detected. While intragroup variability occurred, engraftment remained constant or increased over time. hPBMC engraftment was reproducibly higher for animals harboring A549 compared to MiaPaCa-2 tumors, with hCD45+ cells in blood ranging from 31-52% and 19-33% of total live cells, respectively. It is unknown if this was a result of normal variability or whether this finding is model dependent. Pembrolizumab treatment in the hPBMC-engrafted mice did not inhibit A549 or MiaPaCa-2 tumor growth under the conditions tested (median ΔT/ΔC of 76-118% (Day 41) and 60-106% (Day 22), respectively). However, in vitro, CD8+ T cells from all donors responded to CD3/CD28 stimulation, demonstrating at least 36-fold upregulation of the Ki67 proliferation marker and at least 9-fold upregulation of interferon gamma release, indicative of cytotoxic activity. This result indicated that the hPBMCs were healthy and responsive, but the extent of activation varied by donor. Investigation of human T cell infiltration into human tumors following treatment with pembrolizumab are currently being performed.

Despite the lack of response of pembrolizumab against A549 or MiaPaCa-2, these models are promising translational tools for assessing efficacy of novel therapeutics using rational combination strategies with pembrolizumab. This humanized mouse model represents a powerful preclinical platform to examine the effects of novel agents that harness human T cells to direct anti-tumor activity both as monotherapy and in combination with FDA approved or investigational agents.

Citation Format: Sheri Barnes, David Draper, Stacey Roys, Philip Lapinski, Maryland Rosenfeld Franklin. Modeling pancreatic and non-small cell lung cancer using a humanized mouse platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2711.