Abstract A8: The ImmunoGraft: A humanized mouse model for translational assessment of immunotherapy in solid tumors

Abstract

Abstract Background: 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 allogeneic immune system remains an imperative. We have previously demonstrated the generation of its ImmunoGraftTM platform, whereby two 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 ImmunoGraftTM for assessing the effect of immune-modulating agents in solid tumors. Materials and Methods: 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 ImmunoGraftsTM was compared against non-humanized counterparts, as well as the level of immune reconstitution. Finally, ImmunoGraftsTM were treated with drugs blocking the immune checkpoints CTLA4 and PD1 and human immune activation and tumor growth inhibition evaluated. Results: Mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and lymphoid organs of humanized mice. Solid tumors, including NSCLC, melanoma, and head and neck cancer, were successfully engrafted in the humanized mice. Moderate to high expression of PD-L1 was found in approximately 80% of these tumors. ImmunoGraftsTM treated with anti-CTLA4 or anti-PD1 antibodies exhibited systemic immune responses characterized by robust proliferation of splenic and circulating huCD3+ T cells, as well as activated huCD4+ Th1 cells. There was also an increase in tumor-infiltrating huCD8+ cytotoxic T lymphocytes and huCD68+ macrophages, along with elevated secretion of human-specific cytokines. Tumor growth inhibition, and in some instances tumor regression, was demonstrated in treated ImmunoGraftsTM. The magnitude of growth inhibition correlated with the level of immune activation. Conclusion: The ImmunoGraftTM is an innovative pre-clinical 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 be one of the most translationally-relevant models to date for screening therapies targeting the immune system. To gauge the clinical potential of the ImmunoGraftTM, a retrospective analysis is currently ongoing using PDX models developed from patients treated with immuno-oncology drugs. The ImmunoGraftTMhas the potential to revolutionize translational drug discovery and development for immunotherapeutic agents in oncology. Citation Format: Gilson Baia, David Vasquez, David Cerna, Daniel Ciznadija, David Sidransky, Amanda Katz, Keren Paz. The ImmunoGraft: A humanized mouse model for translational assessment of immunotherapy in solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A8.