Immunotherapy represents one of the next frontiers of treating cancer. First used against lymphoma and breast cancer, immunotherapy is now being used and tested against a wide range of other cancer types.
Yet plenty of obstacles must still be overcome before immunotherapy stands with chemotherapy, radiotherapy, and surgery as a major pillar of cancer treatment. We need to figure out why immunotherapy is effective in only 20 percent to 30 percent of patients. We need to understand why procedures like CAR-T therapy, which reprograms an individual’s own immune cells to track down and kill cancer, can cause serious and occasionally fatal side effects. And we need ways to determine which combinations of immunotherapy and chemotherapy or radiotherapy are best for each individual with cancer.
Complicating these issues is the fact the immune system and cancer are both highly specific to each individual. In fact, two people with seemingly similar tumors growing in the same part of the body can experience vastly different outcomes from treatment.
One of the best ways to explore these differences is to study them in mice.
Mice sometimes get blamed for disappointments in cancer research, such as when treatments that were promising in mouse studies do poorly in clinical trials. However, as we learn more about the complex interactions between cancer and the immune system, the need has grown for simple models that allow research into a limited set of factors in a controlled environment. Studies in mice can be a valuable predictor of clinical success as long as mouse models evolve with the science.
Xenograft mice are mice into which a human tumor has been implanted. These mice have been a valuable tool in cancer research for more than a decade. But their usefulness in immunotherapy is limited. For a human tumor to take root and grow in a mouse, the animal’s immune system must be disabled so it won’t recognize the implanted tumor as foreign and reject it. While that works well for testing chemotherapies, an immunotherapy can’t be tested in a mouse with no immune system.
Fortunately, researchers have developed ways to introduce components of the human immune system into mice genetically modified to have no immune system of their own. These so-called humanized mice don’t reject a human tumor and, with an immune system in place, will respond to immunotherapy.
When implanted with a tumor removed from a patient, humanized mice are in many ways stand-ins for that person. Called patient-derived xenografts, these animals may prove more realistic models than mice implanted with the standardized, dish-grown cancer cells that have traditionally been used for clinical research.
In theory, humanized mice could be used to deliver truly personalized cancer care. Every patient could one day have his or her tumor implanted in several humanized mice, which would then be treated with various combinations of chemotherapy and immunotherapy to determine the most effective one.
In practice, though, most patients won’t have the time or money to follow such a strategy. Instead, researchers are creating hundreds of tumor lines in humanized mice that capture as much of the genetic diversity of human cancers as possible. Because a cancer’s genes are the key to determining whether it will respond to a particular drug, testing a single treatment or combination of treatments on these mice should provide valuable data about what drugs will work for which patients. It heralds an era of truly precision-driven tools.
My company, Charles River Laboratories, is already testing cancer immunotherapies against tumors from more than 550 patients that have been transplanted into lines of humanized mice. These studies will let us see subtle differences in effectiveness, side effects, and dose responses that are caused by the different mutations underlying these tumors and how they interact with the human immune system. They will help us refine CAR-T therapy and other approaches that rely on the immune system and identify genetic markers that indicate a cancer’s susceptibility to a particular treatment.
Humanized mice will increase the success rate of drugs in human trials, decrease the cost of bringing new medicines to market, and expand the arsenal of weapons that doctors can deploy against cancer. They will also give doctors better information about which weapons to choose when faced with a particular foe, increasing patients’ chances of beating their cancer.
The national cancer moonshot has recognized the promise of immunotherapy and the challenges it faces, making it one of 10 priorities for advancement over the next five years. “Current immunotherapy treatments represent only the tip of the iceberg of what is possible,” the moonshot’s blue ribbon panel wrote in September, “and human studies using newly developed, cutting-edge technologies are key to further advances.”
There is no doubt that human studies will be essential to immunotherapy’s progress. But mice also deserve a place in the immunotherapy research agenda.
Aidan Synnott is the executive director of discovery oncology at Charles River Laboratories, where he oversees the company’s oncology discovery services sites.
Seriously disgusted with what I’ve just read. Animal testing is unnecessary and mostly useless. How do you people sleep at night after torturing animals all day?
My bad! Didn’t read all the article till the end.
Still, all research and testing using standard humanized mice is basically flawed and potentially creating really dangerous artifacts
I would indeed object that humanized mice will create the same artifacts as regular mice, if not more misleading ones.
In fact, implanting a patient-derived xenografts in a humanized mice will most likely result in the mouse’s immune system to recognize the graft as foreigner (unless the tumor is a completely undiferentiated non immunogenic mass). Only if the mouse would have the immune system of that very same patient you could recreate a realistic situation to study.
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