Abstract A016: NOG-EXL mice have superior immune cell engraftment and lineage development in the human immune system (HIS) model, the ImmunoGraft
Authors: Verma Bhavna , Mancini Maria , Davies Angela , Sidransky David , Goodwin Neal 
Published: August 2018

Background: The clinical success of immune checkpoint modulators and development of next-generation immune-oncology (IO) agents underscores the need for robust patient-derived models to validate novel IO therapeutics and better predict clinical outcomes and biomarkers of response. The Champions ImmunoGraft® model utilizing humanized NOG mice (PrkdcscidIl2rgtm1Sug) is an innovative preclinical model for assessing the efficacy of IO agents against solid tumors and has been described previously. Improved immunodeficient mouse strains, such as triple transgenic NOG-EXL mice (Prkdcscid Il2rgtm1Sug Tg(SV40/HTLV-IL3,CSF2) expressing huGM-CSF and huIL-3, allow for superior huCD34+ engraftment and lineage development. In this study we compared human immune lineage development and solid tumor engraftment in NOG and NOG-EXL mice and tumor response to checkpoint inhibitors in a humanized mouse platform. Materials and Methods: NOG and NOG-EXL were humanized by intravenous transplantation of 12x104 CD34+ hematopoietic stem cells (HSC). Establishment of human immune components in peripheral blood was evaluated by flow cytometry. At 16 weeks post-transplantation, patient-derived xenograft (PDX) tissue from a NSCLC patient with known response to nivolumab was implanted in humanized NOG and NOG-EXL mice. Treatment with the checkpoint inhibitors nivolumab (α-PD-1; 10mg/kg) and ipilimumab (α-CTLA4; 5mg/kg) and a combination of both agents is planned once tumor implants reach approximately 150-200mm3. Immune cell populations in spleen, blood and the implanted tumor (T cell, macrophages and myeloid and dendritic cells) will be evaluated at the mid- and end-point of the study. Tumor responses will be assessed by changes in tumor volume and with immune-related RECIST criteria applied. Human immune cell proliferation and activation following treatment with the checkpoint inhibitors will be determined by flow cytometry and immunohistochemistry of peripheral blood, spleen and PDX tissue. Results: NOG-EXL mice engrafted human immune components more readily than NOG (take rate of 80% versus 100%, with proportions of huCD45+ cells greater than 25% consistently found in the peripheral blood of NOG-EXL mice. Donor-to-donor variability was observed in both mouse strains, consistent with literature reports. T cell lineage development was equivalent in NOG and NOG-EXL mice 12 weeks post-HSC transplantation. Improved myeloid lineage development was identified in NOG-EXL animals with higher circulating huCD33+ levels observed in comparison to NOG mice. Comparable growth rates have been observed for NSCLC tumor implants in both animal strains. Conclusions: While the ImmunoGraft platform is reflective of the human tumor microenvironment (both immune and tumor cell-based), mouse strains with improved human immune system development promise to further enhance its value for screening IO therapies. We demonstrated that NOG-EXL mice allow better engraftment of human immune components compared to NOG. Importantly, the presence of additional immune lineages in NOG-EXL mice did not adversely affect growth of NSCLC PDX models. A study to evaluate the efficacy of checkpoint inhibitors in NSCLC PDX models in this enhanced ImmunoGraft is ongoing. The NOG-EXL ImmunoGraft has the potential to advance translational IO drug discovery and development.

Citation Format: Bhavna Verma, Maria Mancini, Angela Davies, David Sidransky, Neal Goodwin. NOG-EXL mice have superior immune cell engraftment and lineage development in the human immune system (HIS) model, the ImmunoGraft [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A016.