Research on immunotherapies against cancer dates back over a century ago, when Paul Ehrlich hypothesized that tumor cells could be controlled using the immune system. Since then, our knowledge of the human immune system has steadily increased. We have discovered the enormous potential of monoclonal antibodies (mAb), developed cancer vaccines and CAR-T cell Therapies.
The 2018 Nobel Prize in Physiology or Medicine that was awarded to two researchers working on immune checkpoint inhibitors CTLA-4 and PD-1, seems to mark the beginning of a new era. It is an era, in which we are closer to defeating cancer than we have ever been before, and although there is still a long way to go from where we are now, the immuno-oncology field is brimful with potential.
The importance of full human immune system mouse models
For centuries, mouse models have allowed researchers to test the impact, efficacy and toxicity of novel drug candidates. But the benefits of using mouse models in the field of immuno-oncology only surfaced with the reconstitution of the full human immune system mouse (hu-mouse) with a fully functional set of human immune cells which enabled researchers to study the interaction of the human immune system with human tumor cells.
There are two ways of generating hu-mouse models: First, “transient” engraftment of mice with adult peripheral blood mononuclear cells (PBMCs), and second, engraftment with human hematopoietic stem cells from cord blood.
“In order to see the impact of a drug in preclinical immuno-oncology studies, researchers have often injected PBMCs into immunodeficient animals,” explains Sebastien Tabruyn, Chief Scientific Officer at TransCure bioServices. “But there is a huge disadvantage to that, because the engrafted PBMC’s will not only recognize and attack the tumor, but also attack all other cells in the host body and develop a reaction called Graft versus Host Disease (GvHD).”
This PBMC side-effect prevents researchers from observing a full natural immune response upon injection of the drug candidate, because cytokines and other inflammation markers are overexpressed in this model. Also, due to GvHD, the animals will die rapidly, which results in a very short study window and prevents the observation of long-term effects of the drug on the tumor, or even to develop model diseases like HIV, which would need at least a four to six month study period.
Generating a mouse with a fully functional human immune system
“The main challenge that researchers face in preclinical immuno-oncology research is to have human tumor cells in an environment that mimics the natural habitat, because, of course, the tumor cells interact with other cells in the body,” Tabruyn says. “These are very complex underlying mechanisms, and based on this observation it is important to have models that allow us to create a microenvironment which perfectly mimics human immune cell responses.”
With this in mind, Tabruyn and his team of researchers at the CRO and biotech company TransCure bioServices have developed hu-mouse models with a fully developed and stable human immune system. Their Fully Human Immune System hu-Mouse Model not only allows researchers to study the natural interaction of the human immune system with the tumor, but also the effects of various immuno-oncology treatments on the immune system and tumors such as immunotherapy.
At four weeks of age, hu-mice are treated with a chemoablation agent, to deplete the endogenous mouse immune system from the bone marrow. The young animals are then engrafted with human CD34+ hematopoietic stem cells from cord blood. The engrafted human stem cells mature and develop a fully functional human immune system containing all the cells found in the normal human immune system: dendritic cells, granulocytes, macrophages and monocytes, B and T lymphocytes, as well as natural killer (NK) cells.
After about 14 weeks, the hu-mice undergo a quality control with the help of flow cytometry and cell biology. Tumors cells are then injected from that moment onwards using cancer-type cell lines or patient-derived tumor cells (PDX).
Improving immuno-oncology research with this humanized mouse model
“Many of our customers profile drug candidates that boost the hu-mouse immune system or release the brakes,” explains Patrick Nef, the CEO and Founder of TransCure bioServices. “Very often they use the drug candidate in combination with immune checkpoint inhibitors; they check for antibody-dependent cellular cytotoxicity (ADCC), work with new immune checkpoint inhibitors, oncolytic viruses or cancer vaccines in powerful combination strategies.”
Using flow cytometry the team at TransCure bioServices is able to characterize human immune responses by analyzing small quantities of the peripheral blood, which reflects the systemic effect of a compound, and the tumor. “Our customers ask us to observe the number and type of immune cells involved, such as CD8+ T-cells and regulatory T-cells, macrophages M1 and M2, and NK cells that are involved in ADCC,” says Tabruyn, the CSO.
Furthermore, to analyze the outcome of their preclinical studies, Tabruyn and his team measure the volume of the tumor before, during and after drug candidate treatment. “This year, we are also implementing new imagery techniques to assess the volume of the tumor and whether it has metastasized. Also, until now, the tumors we were testing were subcutaneous, but now we are also providing orthotopic tumors, such as breast cancer cells,” he says.
Looking for the right hu-mouse model to mimic the full human immune system and study your novel immuno-oncology drug candidate therapy? Then get in touch with the experts at TransCure bioServices! They will gladly help you out. You can also request a quote directly to them!
Images via royaltystockphoto.com, Chamaiporn Naprom, Juan Gaertner/Shutterstock.com & TransCure bioServices
Author: Larissa Warneck, Science Journalist at Labiotech.eu