Abstract 5031: A humanized mouse model for translational assessment of targeted immune checkpoint blockade

Abstract

The blockade of immune checkpoints is a promising therapeutic avenue for cancer therapy, with durable objective responses observed in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, robust preclinical tools to test these drugs directly against human cancers in the context of a human immune system are required. Champions Oncology has now developed the ImmunoGraft, whereby two innovative technologies, the patient-derived xenograft and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform. Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted (humanized) with human CD34+ cells and twelve weeks after humanization, mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and secondary lymphoid tissues of the now humanized animals. Growth of NSCLC tumors implanted into humanized NOG animals was comparable to those in non-humanized counterparts, and when humanized animals harboring NSCLC tumor implants were treated with ipilimumab, tumor growth was slowed, exhibiting marked regression. Systemic immune activation was observed in humanized mice following treatment with ipilimumab, characterized by robust proliferation of huCD3+ T cells and activated huCD4+ Th1 cells, as well as an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes (all relative to vehicle controls). We have developed an innovative new preclinical cancer model, the ImmunoGraft, which will enable novel immunotherapeutic agents to be accurately evaluated for efficacy against virtually any cancer indication that can be engrafted. As a proof-of-concept of the utility of the ImmunoGraft, we demonstrated how effectively ipilimumab restricted the growth of NSCLC implants engrafted in humanized animals. This translational platform is, therefore, more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and is the most clinically-relevant model for screening immune system-targeting therapies, as single agents or in combination with standard-of-care drugs and other immuno-modulators. The ImmunoGraft has strong potential to revolutionize the application of immunotherapy to both personalized oncology and translational drug discovery. Citation Format: Gilson Baia, David Vasquez-Dunddel, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz. A humanized mouse model for translational assessment of targeted immune checkpoint blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5031. doi:10.1158/1538-7445.AM2015-5031

Patient‐derived xenografts as tools in pharmaceutical development

“…The Jackson Laboratory (Bar Harbor, ME) has demonstrated the antitumor efficacy of immunotherapeutic antibodies, such as pembrolizumab or ipilimumab, against various human cancers in humanized NSG mice (http://www.nature.com/webcasts/event/pre-clinical-models-immuno-oncology). Although this is an elegant model to evaluate and compare the antitumor efficacy of immunotherapeutic agents against several types of patient‐derived tumors, current approaches for immunograft generation are still technically challenging, time‐consuming, and difficult to implement in large‐scale drug screening studies. The development and optimization of PDX models in mice, including further genetic modification of the mouse strains that allow reconstitution of even broader cell linage, will improve the preclinical evaluation of immune‐oncology therapeutics and predictive accuracy of all PDX models.…”

“…Several strategies for generating mouse models that recapitulate elements of the human immune system have been proposed to circumvent this limitation (discussed above). Implanting tumorgrafts into immunodeficient mice reconstituted with homologous or even autologous human immune system through engraftment of human hematopoietic stem cells is a promising approach that would provide a new model for studying anticancer immune responses and evaluating efficacy of immune therapeutics in the PDX setting. Although this approach is technically challenging and may not be suitable for patients with aggressive, rapidly progressing disease, further development and optimization of this system may contribute to an improved cancer therapy in the coming years.…”