MOUSE “AVATARS” Advance Personalized Medicine

Research into personalized medicine has taken a new turn with the development of a type of mouse model known informally as an “avatar.”

Like avatars in movies and online games, mouse avatars act as stand-ins for real people, enabling scientists to study exactly how and why the cells and tissues of individual patients react to medications. By testing the drugs first on the avatars, physicians may be able to avoid subjecting patients unnecessarily to toxic therapies.

Human cells have been experimentally implanted into mice for many years, of course. But the first mouse avatar—when drugs tested on the implanted tissue of a specific patient were then used to treat the patient— occurred only about a decade ago. The first researcher to use the technique was Dr. Manuel Hidalgo, director of the Centro Integral Oncologico Clara Campal in Madrid and an associate professor of oncology at Johns Hopkins University in Baltimore.

Much of the early work has involved cancer patients, but a few years ago, Dr. Megan Sykes, director of Columbia University’s Center for Translational Immunology, began using mouse avatars to study autoimmune diseases like type 1 diabetes, in which T cells attack and destroy insulin-producing beta cells in the pancreas. Sykes and her colleagues transplanted human bone marrow stem cells from type 1 diabetes patients and healthy individuals into mice with genetically deficient immune systems. Each mouse received cells from either an individual diabetes patient or from a healthy control. Sykes donated her own cells to create the first avatar control, which she dubbed “Mini-Me.” A paper on the study was published in 2012 in the journal Science Translational Medicine.

“This is the first time that a humanized mouse has been created with adult bone marrow stem cells from volunteers,” Sykes said.

Within eight weeks, the mice had a diversity of newly created human immune cells, including T cells, B cells, and myeloid cells (non-lymphocyte cells that generate immune cells). These young cells did not attack healthy tissues.

Sykes and her colleagues are currently studying the mice to determine what occurs differently in the immune systems of people with type 1 diabetes, before the disease develops. They are also beginning to test immunotherapies in these mice. In addition, Sykes hopes to learn more about the genetics of type 1 diabetes. “There are lot of genes that have been identified as predisposed to type 1 diabetes, and a lot of those genes are in the immune system,” she says, “but no one knows how they drive the immune system to create diabetes.”

Sykes and her colleagues are also interested in developing and using mouse avatars to study other autoimmune diseases, such as lupus and rheumatoid arthritis.

“The idea is that you could actually make [human] immune cells in the mice and give them back to the patients,” said Sykes. Immune cells generated in the mice avatars might also be used in other contexts, “such as treating infections in immunosuppressed patients,” she added.

Th is personalized animal-model technique is in its early stages, and the models are being used primarily for research. Experts caution that the technique still poses many practical problems and that randomized clinical trials will be needed to prove that mouse avatars produce better outcomes for patients.

Avatars for Cancer Patients

Scientists are further along in developing avatars for cancer patients. Earlier this year, Hidalgo and his colleagues reported on 14 patients with refractory advanced cancers who were treated with drugs first tested on mice that had been implanted with the patients’ individual tumors. The study found a strong predictivity, both positive and negative, between the drug’s activity in the mouse avatars and clinical outcomes. The researchers also reported that the “treatments selected for each individual patient were not obvious and would not have been the first choice for a conventional second- or third-line treatment.”

“Most of our patients have advanced refractory disease and have an expected survival of six to 12 months, so when patients have responded to our drug combinations and lived for two to three years, we feel that it is likely to add important survival time,” said study co-author Dr. David Sidransky, a professor of oncology and otolaryngology at Johns Hopkins University. “But these results have to be confirmed in a more controlled study.”

A team of Australian researchers, led by molecular geneticist Sean Grimmond of the University of Queensland, reported the results of a similar experiment in which personalized models of a patient’s pancreatic cancer were created by xenografting a piece of the patient’s tumor onto an immune-compromised mouse. They then tested the tumor’s response to a cancer drug that gene sequencing of the tumor suggested could work. The tumors in the mice shrank, although, sadly, the patient died before the drugs could be given to him.

Pharmaceutical companies are also working with personalized animal models. Scientists at Bayer Schering Pharma in Berlin, Germany, for example, have reported using xenograft mouse models derived from the cancer cell lines of 22 patients with non-small cell lung cancer to test and improve the effectiveness of a new anticancer drug.

Mayo Clinic’s Center for Individualized Medicine in Rochester, Minnesota, has launched what may be the largest mouse-avatar project to date: the Breast Cancer Genome Guided Therapy Study (BEAUTY). Its aim is to determine if personalized animal models can help with the development of more effective neoadjuvant chemotherapy for high-risk breast cancer patients.

For the study, the Mayo researchers are obtaining tumor tissue samples from 200 women wiThearly-stage invasive breast cancer who are scheduled to receive standard chemotherapy treatment. These samples are taken twice: before chemotherapy, which shrinks the tumor, and afterward (from any residual cells removed during surgery). Both samples are genetically sequenced, as are the patient’s healthy cells. The researchers then study the pre- and postchemotherapy sequencing to determine how the patient’s tumor cells have mutated in response to the drugs.

Cells from the tissue samples are also being implanted into the fl anks of immune-compromised mice. The Mayo researchers will be able to use these xenograft mice to test the effects of various anti-cancer drugs or combinations of drugs on the tumors—without exposing the patient unnecessarily to those drugs.

“We can analyze the output from the genetic sequencing, identify what pathways are changed in the tumor compared to the host, identify potential drug targets for those pathways, and try those drugs in the xenograft mice,” explained Dr. Judy Boughey, one of the lead investigators with the BEAUTY study. “That will then give us the data to go forward to consider if a drug can be used as a potential therapy for patients with that specific genetic alteration.

Clearing Obstacles

Using mice stand-ins is not without its technical challenges. The tumors often fail to grow in the mice. (The “take” rate in the BEAUTY study is about 40 to 50 percent, according to Boughey.) In addition, it can take several months to produce enough mice to test a sufficient number of drugs. As illustrated by the Grimmond case study, a patient could die waiting for the results. Boughey and her colleagues are confident, however, that these practical obstacles can be overcome.

Although the research to date with mouse avatars has been promising, both Sykes and Boughey stress that it’s still too soon to know what its clinical applications will be.

“We’re at the beginning of exploring this field,” said Boughey. “In the next five years we’re going to see a lot more growth. But will it become part of the standard clinical care that every patient has their own mouse avatar running around? Probably not. It’s more likely that the results of the research using avatars will drive and elevate the care of all clinical patients across the country.”

—Susan Perry is a freelance writer in Minneapolis, MN

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