EORTC 2015 – The ImmunoGraft: A humanized mouse model for translational assessment of immunotherapy in solid tumors
The ImmunoGraft™ : A humanized mouse model for translational assessment of immunotherapy in solid tumors.
Gilson S. Baia1, David Vasquezl1, Daniel Ciznadija1, David Sidransky2, Amanda Katz1, Keren Paz1. Champions Oncology, Baltimore, MD;2 Johns Hopkins University School of Medicine, Baltimore, MD
Therapeutics reactivating the immune system have demonstrated promise, with durable objective responses in patients with a variety of solid tumors. Despite these successes, current animal models do not reliably identify immunotherapeutic targets with the greatest clinical potential, due in part to differences between human and murine immune systems. Hence, development of robust preclinical tools to test such drugs against human tumors in the context of an allogenic immune system remains an imperative. We have previously demonstrated the generation of its ImmunoGraft™™ platform, whereby technologies, the patient-derived xenograft (PDX) and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform. We now report on the utility of the ImmunoGraft for assessing the effect of immune-modulating agents in solid tumors.
Immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted with human CD34+ cells and monitored for the expansion of human immune cells (humanized). Humanized mice were engrafted with solid tumors that had been subjected to histocompatibility typing and characterized for a number of molecular markers, including PD-L1 expression. Tumor growth in the ImmunoGrafts was compared against non-humanized counterparts, as well as the level of immune reconstitution. Finally, ImmunoGrafts were treated with drug blocking immune checkpoints CTLA4 and PD1 and human immune activation and tumor growth inhibition evaluated.
The ImmunoGraft is an innovative preclinical model enabling immunotherapeutic agents to be evaluated for efficacy in solid tumors. This platform is more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and may one of the most translationally-relevant models to date for screening therapies targeting the immune system. To gauge the clinical potential of the ImmunoGraft, a retrospective analysis is ongoing using PDX models developed from patients treated with immuno-oncology agents. The ImmunoGraft has the potential to revolutionize translational drug discovery and development for immunotherapeutic agents in oncology.