The Jackson Laboratory (JAX) has received $2.5 million from The Mark Foundation for Cancer Research to study in mice the influence of host genetics on response to immunotherapy. The goal of this project is to generate insights that will empower future decisions about the best treatments for cancer patients based on their genetic backgrounds.
Immunotherapy, which uses the body’s own immune system to fight cancer, is one of the most promising approaches to cancer treatment today, and expanding its effectiveness to a wider population of patients is a high priority for researchers across the globe.
The project, “Dissecting the Genetic Control of Response to Immune Checkpoint Inhibitors in Cancer,” has major implications for how oncologists may be able to predict whether their patients will respond positively to immunotherapy before prescribing a treatment regimen.
A unique opportunity
Immunotherapy has resulted in some remarkable outcomes for patients whose cancers would have otherwise been fatal. Nonetheless, the overall efficacy rates for this class of treatment are not high, and many patients experience serious or even life-threatening side effects. The determination of which patients will respond well to immunotherapy is still uncertain. Probing factors that may influence response to immunotherapy, such as the personal genetics of each individual, tumor characteristics, and the cross-talk among these profiles is a critical step toward designing immune therapies that will have broader impact.
JAX President and CEO Edison Liu, M.D.Conducts research focused on the functional genomics of breast cancer through an exploration of the entire genomic space.Edison T. Liu, M.D. and Associate Professor Laura Reinholdt, Ph.D.Dr. Reinholdt’s research focuses on comparative and functional mammalian genomics, reproductive development and stem cell biology. Laura Reinholdt, Ph.D., co-principal investigators of the study, will use genetically diverse JAX mouse models to untangle the relationship between genetics and response to immunotherapies.
“This research may one day allow doctors to use genetic sequencing to predict patient response to immunotherapy, as well as help scientists develop more effective anti-cancer drugs that fight tumors by activating an immune response,” said Liu. “We are so grateful to The Mark Foundation for enabling this extraordinary opportunity, which we hope will have a significant impact on patients and the field of immunotherapy,” said Liu.
The mission of The Mark Foundation for Cancer Research is to support scientists tackling the toughest challenges in cancer research. Multi-disciplinary groups such as the JAX team, which brings together experts in genetics, bioinformatics, mouse models, and immunology, are well positioned to take on these challenges. By funding this type of collaborative project, The Mark Foundation ensures that the right expertise is brought to bear on a substantial unmet need, ultimately accelerating cancer research to the benefit of patients.
“This project addresses critical limitations in cancer research. First, most mouse models for studying therapeutic response lack the genetic diversity that exists in the human population, often leading to disappointment when treatments that show promise in these models are deployed broadly in patients. Second, the biology of how genetics impact tumor response is not well understood due to a lack of adequate experimental systems for uncovering new knowledge”, said Michele Cleary, Ph.D., CEO of The Mark Foundation. “Solving both of these issues requires the type of complex and nuanced work in mouse genetics for which JAX is world-renowned.”
The power of genetic diversity
The grant to the Jackson Laboratory research team, which also includes Assistant Professor Chih-Hao "Lucas" Chang, Ph.D.We love to study metabolic events in immune cells and tissue microenvironments that govern their immune function and contribute to disease outcomes. Chih-Hao “Lucas” Chang, Ph.D., Associate Research Scientist John Graham, Ph.D. I am interested in how genetic background influences the function of the immune system in tumors and visceral fat. John P. Graham, Ph.D., Professor Karolina Palucka, M.D., Ph.D.Conducts research to understand how vaccines work and to define precisely the immune mechanisms that underlie vaccination, with a focus on cancer immunotherapies.Karolina Palucka, M.D., Ph.D., and Research Scientist Daniel Skelly, Ph.D.Biologist and data scientist harnessing single cell functional genomics and genetically diverse mice to study complex traitsDaniel Skelly, Ph.D., will examine four different tumor lines: a melanoma tumor, a triple-negative breast cancer tumor, and two types of colon cancer tumors. The tumor types were chosen to represent a wide range of responses to immunotherapy. For example, melanoma tumors tend to respond quite well to immunotherapy, whereas triple-negative breast cancer tumors typically do not.
The scientists will use JAX’s The power of genetically diverse mice in complex disease researchNew genetically diverse mouse populations mirror human genetic variation, providing a powerful new experimental platform to complement human data insights, particularly for complex trait and complex disease research. genetically diverse mouse strains in their studies, which will allow them to identify the genetic differences that underlie the variation in response to immunotherapy. Such an approach is inordinately difficult to achieve in human clinical trials.
“The increasing adoption of genetically diverse mice in biomedical research is really a paradigm shift driven by new technologies and biological resources, and by the recognition that an inbred mouse strain only represents one genome,” said Reinholdt.
“This project is providing a unique opportunity to harness natural genetic variation in laboratory mice to more accurately model the biological complexity of cancer treatment response. The power of these genetically diverse mouse strains is that they facilitate genetic discovery and they provide tractable in vivo systems for dissecting molecular pathways, which are essential for the identification of biomarkers and potentially new therapeutic targets.”
The research team plans to map the genetic differences found in the mice to specific genetic variants in humans. Ultimately, they hope that doctors will be able to test and determine a given individual’s likely response to immunotherapy to help guide the selection of a treatment regimen.
About The Jackson Laboratory
The Jackson Laboratory is an independent, nonprofit biomedical research institution with nearly 2,300 employees. Headquartered in Bar Harbor, Maine, it has a National Cancer Institute-designated Cancer Center, a genomic medicine institute in Farmington, Conn., and facilities in Ellsworth, Maine, Sacramento, Calif., and Shanghai, China. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.
About The Mark Foundation
The Mark Foundation for Cancer Research supports scientists tackling the toughest challenges in cancer research. Launched in 2017, The Mark Foundation pursues its mission by funding a global portfolio of groundbreaking research that will lead to new and better ways to prevent, diagnose, and treat cancer. Since its launch in 2017, the Foundation has awarded over $80 million in grant funding to over 50 institutions across 19 U.S. states and 4 countries.