Network Seeks Genetic Cause of Innate Cancer Immunity

Newswise — Results from a Cancer Research Institute (CRI) funded study at Wake Forest University School of Medicine show that resistance to highly aggressive cancers can be transferred from a strain of cancer-resistant mice into ordinary mice, causing complete destruction of large tumors and life-long protection against future tumor growth. This resistance is based on innate immunity to cancer rather than adaptive immunity based on T and B cells. In an effort to accelerate the translation of this discovery into a potential cancer therapy for humans, the Cancer Research Institute has established a unique collaboration with three other major U.S. research institutions that will work together to unlock the molecular and genetic mysteries behind this mouse's remarkable immunity.

"The amazing thing is that these cancer resistant mice are innately immune to very aggressive cancers that are injected in amounts that would kill just about any other animal," stated Jill O'Donnell-Tormey, Ph.D., executive director of the New York based Cancer Research Institute. "It is a highly unusual phenomenon, but one that strongly suggests something is going on inside these mice that merits further expert investigation."

According to Zheng Cui, M.D., Ph.D., associate professor of pathology at the Wake Forest University School of Medicine and primary author of the study published in the May 8, 2006, issue of The Proceedings of the National Academy of Sciences (PNAS), the immunity is caused by a genetic mutation. "The most critical challenge now," he said, "is to locate the gene mutation that is causing this immunity. If we can find the gene, then we can begin to understand what it does differently in these mice that it doesn't do in other mice."

To help Dr. Cui accomplish this task, the Cancer Research Institute has brokered a collaboration that teams Cui's laboratory with those of Bruce Beutler, M.D., a world-leading immunogeneticist at the Scripps Research Institute in La Jolla, CA, and Robert D. Schreiber, Ph.D., a molecular immunopathologist at the Washington University School of Medicine in St. Louis, MO. Among their many accomplishments, Dr. Beutler is credited with co-discovering which genes allow the mammalian innate immune system to recognize dangerous microbial infections, and Dr. Schreiber has proven that the immune system recognizes and destroys cancer cells in healthy individuals.

With one of the world's largest mutagenesis studies under his supervision, Dr. Beutler will attempt to locate the genetic mutation responsible for the mouse immunity, and Dr. Schreiber will use his new human-like mouse cancer models to further characterize the extent of the mouse immunity, especially its ability to defend against cancers that arise within the mice themselves versus cancers that are transplanted.

"There are many challenges to advancing a discovery like Dr. Cui's into a therapy for humans," Dr. O'Donnell-Tormey said. "It requires the involvement of individuals with many different areas of expertise. No one person can do it alone; work of this complex nature demands collaboration."

CRI understands collaboration. In 2001, CRI joined with the Ludwig Institute for Cancer Research to launch their Cancer Vaccine Collaborative (CVC) and Cancer Antigen Discovery Collaborative (CADC) programs. Like the Cui mouse collaboration, the CVC and CADC bring together experts from diverse fields who work collectively on shared goals. These programs provide a centralized matrix through which participants freely exchange standardized data and materials from parallel, single-variable studies.

"Collaborations like these don't just happen. They have to be encouraged," said Dr. O'Donnell-Tormey." Dr. Cui's mouse studies are worth the effort and expense.

"These studies have revealed a powerful, amazing kind of cancer immunity," Dr. O'Donnell-Tormey said. "If the collaboration CRI has put in place helps Dr. Cui locate the gene responsible for this immunity, we can then search for a corresponding homologue gene in humans. That would open up a world of medical possibilities," she said. "Our goal is to help accomplish this in as short a time as possible."

About Cui's Remarkable MouseZheng Cui, M.D., Ph.D., associate professor of pathology at the Wake Forest University School of Medicine in Winston-Salem, NC, discovered the remarkable spontaneous regression/cancer-resistant (SR/CR) mouse by chance in 1999 and first described its unique abilities in a 2003 PNAS publication. He noted at that time that neutrophils, NK cells, and macrophages—first-line defenses of the innate immune system that respond rapidly to bacterial and viral infections—comprised the bulk of the immune response, strongly suggesting a previously unknown form of innate immunity to cancer. Cancer resistance was correlated with age, with younger mice mounting stronger, faster responses than older. In his 2003 paper, Dr. Cui linked the cause of the remarkable immunity to a spontaneous genetic mutation that he discovered could be transmitted to offspring. In the 2006 PNAS publication, Dr. Cui shows that long-lasting immunity can be conferred from his SR/CR mice into ordinary (wild-type) mice by injecting into them leukocytes from the SR/CR mice.

About the Cancer Research InstituteThe Cancer Research Institute (CRI) is the world's only non-profit, private organization dedicated exclusively to the development of immune-based therapies for the prevention and control of cancer. Guided by a world-renowned Scientific Advisory Council that includes five Nobel Prize winners and twenty-seven members of the esteemed National Academy of Sciences, CRI supports the finest cutting-edge cancer research at top medical centers and universities throughout the world. As the initiator and steward of unprecedented global scientific and clinical collaborations like the Cancer Vaccine Collaborative and the Cancer Antigen Discovery Collaborative, joint programs with the Ludwig Institute for Cancer Research, CRI is ushering in a new era of scientific progress, hastening the discovery of effective cancer vaccines and other immune-based therapies that are providing new hope to cancer patients. On average, nearly 90 cents of every dollar CRI raises goes directly to the support of science, medical, and research programs. This has consistently earned CRI an A grade or higher for fiscal disclosure and efficiency from the American Institute of Philanthropy and top marks from other charity watchdog organizations. http://www.cancerresearch.org