Beginning with the approval of Rituximab in 1997, therapeutics that use the body’s own immune system have become popular in the fight against cancer. Because immune cells are innately capable of sensing something wrong in a cell, researchers are developing strategies to harness this ability to destroy tumors with little to no side effects. But before many of these treatments ever saw a human being, they were developed and tested for efficacy in laboratory mice. Below, I review some of the strategies and mouse models (including humanized NSG mice) that have been used to develop this exciting realm of therapeutic treatments.
Traditional cancer chemotherapy and radiation treatments are toxic and have many side effects because they indiscriminately kill both cancerous and normal cells. One way to increase specificity and reduce off-target effects is through immunotherapy. Cancer cells often express mutant or normal proteins at supra-physiological concentrations on their cell surfaces that can be recognized by the host’s immune system. In this way, the immune system monitors protein synthesis inside cells and directs cytotoxic natural killer (NK) cells and CD8+T cells to eliminate tumor cells that express proteins at the wrong time, concentration or configuration. B cells also play a role in this process by coating the cell expressing aberrant proteins with antibodies. Other immune cells, including macrophages and NK cells, as well as complement, are then activated to induce antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), respectively, to destroy the tumor cell.
Researchers have used several immunity-based strategies to combat cancer. These include: creating synthetic antibodies that target tumor cell antigens; developing cell-based therapies that enhance T and NK cell anti-tumor responses, and cytokine therapies that activate immune cells to target the tumor. These treatments then kill cancer cells by initiating apoptosis, delivering chemotherapeutic drugs (known as antibody-drug conjugates), inhibiting growth factor signaling, enhancing tumor cell recognition by host immune cells, or initiating ADCC or CDC. Rituximab, the first cancer immunotherapy approved for treating leukemia and lymphoma, is an anti-CD20 monoclonal antibody that induces apoptosis in malignant B cells and initiates ADCC and CDC by the patient’s own immune system. Most recently Keytruda, a monoclonal antibody that targets PD-1 receptor (a protein that is overexpressed in several cancers and can inhibit T cell proliferation) was approved last month (September 2014) for treating metastatic melanoma. This development has come a long way since the initial demonstration of PD-1’s role in tumor evasion in mice in 2002– and so have the mouse models used to develop cancer immunotherapies. But it doesn’t stop with PD-1; many other cancer immunotherapies are in development that first need to demonstrate efficacy in mice or another preclinical animal model prior to clinical trials.
Classically, immune competent mouse models such as BALB/cJ, DBA/2J, and C57BL/6J mice have been used to evaluate cancer vaccine efficacy and to evaluate ADCC and CDC in response to immunotherapy delivery (for examples, see Humar et al., Liu et al., and Ramakrishnan et al.). Counter intuitively, however, immune-deficient mouse models have become the new go-to platforms for these studies. This is because immune competent mice are generally poor hosts for human cell engraftment because their mouse immune systems reject the transplanted human cells. Studies performed in inbred mice, therefore, typically measure a therapy’s efficacy against mouse tumors and cell lines. Conversely, immunocompromised strains such as inbred nude mice, NOD scid, NRG, and NSG have all been used to develop new immunotherapies using primary human cancer xenografts. For example, in a study using 48 patient-derived colorectal cancer xenograft models in nude mice, a comparative analysis of two antibody-drug conjugates was performed to determine efficacy in inhibiting tumor growth. In another study, NOD scid mice injected with primary AML cells were used to demonstrate efficacy of an antibody-drug conjugate in reducing tumor load. Finally, in NSG mice injected with primary AML cells, a single dose of an anti-CD33 ADC was effective in inhibiting tumor growth. None of these studies could have been performed in an immunocompetent strain.
Immune deficient models, although useful for investigating cancer cell mechanisms, are not created equal. NSG mice are the best hosts for human immune cell engraftment, due to the absence of NK cells. So while nude mice may support the engraftment of a human tumor, NSG mice not only support tumors, but they also can be engrafted with human immune cells. Nude (both inbred and outbred) mice are poor hosts for human immune cells, and even NOD scid mice have limited ability to engraft these populations (due to NK cell activity). In this way, “humanized” NSG (hu-NSG) mice – NSG mice that express a human immune system – have a distinct advantage over other immunodeficient models. Taking this a step further and engrafting these humanized NSG mice with human tumors are the next best thing to a human patient and are the future of preclinical therapeutic development and testing.
One of the most exciting models to test novel immunotherapies is the combination of mice hosting both the human immune system and patient-derived tumors.
If you’re interested in humanized NSG mice, you’re in luck! We currently have special pricing on our hu-CD34 NSG models (which we routinely engraft to reduce wait-time), in addition to our hu-NSG PBMC and hu-BLT models that are available upon request. And if you are interested in using or learning more about NSG mice, don’t forget to check out the NSG resources page where you can find useful information about housing these mice at your facility, related NSG-based strains and breakthrough research using NSG mice.
Please visit the PDX Resource at the Mouse Tumor Biology database to see our current offerings and characterization studies for many of these models. And if you’re looking to save some time and money, check out our PDX Live program where many of our most popular PDX models are engrafted and ready to be put on study.