Review: Humanized Mouse Model Research Symposia


     
Humanized mouse models are critical tools for basic research, modeling of certain human-specific infectious diseases, efficacy testing of immunotherapy approaches, and safety assessment for large molecule therapeutics.

Taconic Biosciences recently hosted the symposium series "Advanced Preclinical Models for Immuno-oncology and Infectious Disease" in several European cities, which focused on the latest research applications of human immune system engrafted mice and the introduction of next generation models. International experts gathered in Norway, France, Germany, and the Netherlands to discuss the impact of the NOG mouse and related mouse models in biomedical research.

All four events featured Dr. Michael Seiler and Dr. Megan MacBride of Taconic Biosciences as the keynote speakers. Supporting speakers, drawn from industry and academia, varied by location.

Mouse Models for Xenografts and Immune System Engraftment

Dr. Megan MacBride discussed the wide range of immune deficient mice currently available, including super immunodeficient mice such as the CIEA NOG mouse®. She provided a thorough look at the key immunodeficient models -- including nudes, scids, Rag2 knockouts and the NOG mouse -- comparing the immune deficiencies of each model. She also covered particular facets of each model relevant to experimental use, such as the limited lifespan of NOD scid mice and the greater sensitivity of all scid strains to radiation and some drugs.

Her talk provided a strong grounding for attendees to rationally choose the most appropriate model for their xenograft experiments and for human immune system engraftment.

Use of Human Immune System Mice in Tumor Immunology Studies

Dr. Michael Seiler introduced existing human immune system mouse models available to researchers, including NOG mice engrafted with human hematopoietic stem cells (huNOG) and human PBMCs (huPBMC-NOG).

He included unpublished data from experiments using huNOG mice in immune checkpoint inhibition studies. Those studies combined mice engrafted with human hematopoietic stem cells (HSCs) as well as patient-derived tumors. Treatment with the immune checkpoint inhibitor ipilimumab induced T cell activation and proliferation of T helper cells and cytotoxic T cells, leading to tumor regression.

Dr. Seiler also discussed next generation mouse models now available to researchers. Further genetic modification of the base CIEA NOG mouse® is intended to generate models with improved engraftment and/or differentiation of particular cell types which are not well represented or have impaired function compared to the base huNOG model.

Mouse models convered in Dr. Seiler's presentation included:

  • huNOG-EXL, which expresses human GM-CSF and IL3 and provides better reconstitution of human myeloid cells following HSC engraftment
  • hIL2-NOG and hIL15-NOG, which support improved human NK cell engraftment
  • hIL6-NOG, which supports improved human monocyte/macrophage engraftment
These newly available models are ideal for study types targeting human immune cells beyond just T cells.

Application of the Humanized Mouse Model in Infectious Disease

Several speakers from TransCure bioServices (Dr. Patrick Nef, Dr. Sebastien Tabruyn, and Dr. Jean-François Mayol) described applications of mice with human immune systems to HIV drug discovery.

HIV is generally not possible to model in traditional animal systems, due to species specificity, but generation of mice with human T cells permits modeling of HIV directly in mice. The Transcure scientists showed experiments examining viral load suppression by anti-retroviral therapy (ART) treatment, followed by recovery of viral load after ART withdrawal. Experimental variations include different HIV isolates and different routes of infection such as intraperitoneal versus vaginal.

Malaria is another agent in which mouse model research is limited by host specificity. Dr. Valérie Soulard of UPMC presented very interesting work on modeling malaria in mice engrafted with human livers.

Her work used the TK-NOG mouse, which permits an inducible liver injury followed by engraftment of human hepatocytes. To fully model the malaria parasite life cycle, including the blood stage, she additionally engrafted human red blood cells by direct repeated injections of mature erythrocytes.

In the liver-engrafted TK-NOG mouse model, Dr. Soulard found P. falciparum schizont formation in the engrafted liver, with sizes similar to those found in humans. In the dual-engrafted model, with both human hepatocytes and red blood cells, she saw transition from liver stage to blood stage with P. falciparum in vivo, showing that hepatic merozoites generated in this model are infectious.

Further, the dual-engrafted mouse model supported differentiation and maturation of malaria gametocytes, thus showing that the full life cycle of the parasite can be modeled in vivo using this system. This represents a major advance in malaria modeling from current malaria research models such as in vitro systems or non-human primate models.

Patient-derived Xenografts for Personalized Cancer Treatment

Dr. Annika Wulf-Goldenberg, of Experimentelle Pharmakologie & Onkologie Berlin-Buch GmbH (EPO), presented ongoing research into patient-derived xenograft (PDX) models. EPO has established large panels of PDX for the testing of novel anticancer agents, detection of novel targets, and to identify and validate predictive biomarkers. Dr. Wulf-Goldenberg presented an interesting case study using these PDX models for identification and validation of potential biomarkers related to treatment response.

She also touched on development of PDX models with functional human immune systems, with some results shown for NOD scid mice co-engrafted with CD34+ human hematopietic stem cells as well as a patient-derived xenograft. Tumors grew successfully in the immune engrafted mice, and infiltration of human leukocytes into the tumor was detected. Treatment with the checkpoint inhibitor ipilimumab resulted in some tumor regression as well as increased numbers of human immune cells in the tumor. Her presentation provided compelling evidence that PDX modeling will be a critical tool for future oncology research.