AACR 2015: A humanized mouse model for translational assessment of targeted immune checkpoint blockade
A humanized mouse model for translational assessment of targeted immune checkpoint blockade
Gilson S. Baia1, David Vasquez-Dunddel1, Daniel Ciznadija1, David Sidransky2, Amanda Katz1, Keren Paz1. 1Champions Oncology, Baltimore, MD; 2Johns Hopkins University School of Medicine, Baltimore, MD
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.