As Harry Potter characters use an invisibility cloak to avoid detection in Hogwarts’ forbidden areas, cancer cells make themselves invisible to the immune system to avoid destruction. The recent advent of immune-directed therapies that remove this “invisibility cloak” from the surface of cancer cells has opened up a new horizon of opportunity, but also a new set of challenges.
A key difficulty has been that previous animal models of cancer depend on wiping out a rodent’s immune system so that it won’t attack tumor cells it sees as foreign. But without an immune system, the models can’t teach us how cancer evades immune surveillance, nor can they test immunotherapies, whose actions depend on the presence of an immune system.
Antonio Jimeno, MD, PhD, has developed potential solutions to this problem. He recently renewed a 5-year NIH R01 grant with a new focus on studying how head and neck cancer stem cells trick the immune system. Nearly simultaneously, Jimeno obtained another R01 grant to develop new animal models of melanoma that allow the study and testing of immunotherapies against cancer. Jimeno is director of the Head and Neck Cancer Clinical Research Program at the University of Colorado Cancer Center, a member of the Gates Center for Regenerative Medicine, and the Daniel and Janet Mordecai Endowed Chair for Cancer Stem Cell Research at the CU School of Medicine.
Jimeno’s solution has been to transplant a human immune system along with human tumor samples to create “humanized” animal models. These models with both cancer and an intact immune system allow researchers to test the ability of new drugs and treatments to turn the immune system against cancer.
Jimeno’s previous R01 grant focused on characterizing head and neck cancer stem cells, resulting in a major paper in the Journal of the National Cancer Institute describing the mechanisms by which cancer stem cells regulate the disease. The renewal and refocusing of this grant extends the work by using Jimeno’s understanding of cancer stem cells to create fully individualized models of cancer, using a patient’s immune and tumor cells to make personalized models of the disease. By comparing the effects of immunotherapies in patients with the effects of immunotherapies in these individualized tumor/immune models, Jimeno hopes to show that drugs have the same effect in mice as they do in humans, suggesting that his models could be used to explore the effectiveness of new therapies as well.
His second R01 grant hopes to develop a similar model for melanoma, a condition that has been at the forefront of developing immunotherapies. Specifically, the grant will allow Jimeno to generate individualized (with a patient’s tumor), humanized (with a patient’s immune system) models from 20 melanoma patients to study how treatment with immunotherapy correlates in the patient and in the model. This effort will be shared as part of a national network of mammalian models to study cancer, firmly establishing Jimeno’s group and CU Cancer Center as leaders in immunocompetent models of human cancer.
“In both head and neck cancer and melanoma there are approved immunotherapies, but unfortunately they only work in a subset of patients,” Jimeno says. “Right now, we do not have biomarkers to best individualize this therapy and only give drugs to patients who will respond. Having good animal models serves three purposes: to discover the factors that predict who will and who will not respond to immunotherapies, to identify the mechanisms that tumors use to evade the immune system and, ultimately, to use these models to test rational combination therapies.”
Jimeno credits the approval of recent grants to a “deeply ingrained collaborative spirit,” including an early partnership with CU immunologist and stem cell biologist Yosef Refaeli, PhD, to develop a first generation of humanized mouse models. As the project transitioned to improving the immune system’s action against tumors, Jimeno’s group worked with CU cancer immunologist Jing Wang, PhD, and CU stem cell biologist Holger Russ, PhD, to model the cells to be implanted on mice. The second R01 award focusing on melanoma was a direct result of preliminary data generated thanks to the enthusiastic collaboration of melanoma specialists Drs. Rene Gonzalez, Karl Lewis, and William Robinson.
R01 grants are not approved on ideas alone. Investigators must complete early studies showing the promise of their line of research. For many researchers, this can prove to be a Catch-22 in which funding for their studies is only available after performing studies. In this case, funding for Jimeno’s early explorations came in the form of seed monies provided by CU Cancer Center and the Department of Defense. In 2010, the Gates Center for Regenerative Medicine, in partnership with the Gates Frontiers Fund, provided early support for Dr. Jimeno’s research. Between 2011 and 2016, Dr. Jimeno also leveraged generous philanthropic gifts from the Daniel and Janet Mordecai Foundation, the Karsch family, and Peter and Rhondda Grant.
“This philanthropic support took us through the difficult times of chasing an idea that seemed novel and difficult to prove. Now these ideas are validated by these simultaneous awards. For us, philanthropy was a fire-starter,” Jimeno says.
This fire-starter, accelerated by the creativity and hard work of Jimeno’s team and collaborators, sparked grants now nearing a five-fold return on investment, and allows the multidisciplinary team led by Jimeno to continue pushing test models for immunotherapies in head and neck cancer and melanoma.
Dennis Roop, PhD, director of the Gates Center for Regenerative Medicine, commented that this is a wonderful example of how philanthropic support can be used to de-risk novel, cutting edge research to the point that it is eventually funded in today’s risk averse funding environment.
About the CU Cancer Center
The University of Colorado Cancer Center, located at the Anschutz Medical Campus, is Colorado’s only National Cancer Institute-designated comprehensive cancer center, a distinction recognizing its outstanding contributions to research, clinical trials, prevention and cancer control. CU Cancer Center is a member of the prestigious National Comprehensive Cancer Network®, an alliance of the nation’s leading cancer centers working to establish and deliver the gold standard in cancer clinical guidelines. CU Cancer Center is a consortium of more than 400 researchers and physicians at three state universities and three institutions, all working toward one goal: Translating science into life.
About the Gates Center
The Gates Center and the Gates Biomanufacturing Facility partner with the Anschutz Medical Campus and center members on leading-edge work in stem cell biology and regenerative medicine, accelerating discoveries from the lab toward clinical trials and cures and therapies for patients.