Nanoparticle-Based MRI for First-In-Man Immune-Therapy Trials in Brain Tumor Patients
Samuel Cheshier, M.D., Ph.D.
Stanford University School of Medicine, Stanford, CA
Clinical Neuroscience Research
October 2013, for 3 years
Paving the way for testing and assessing malignant brain tumor immunotherapies
This neurosurgeon and neuroradiologist team will determine whether a new non-invasive MRI imaging technique can reveal innate immune cells’ presence in deadly brain tumors in children and adults, and can be used to assess responses to an experimental immunotherapy that is soon to undergo human clinical testing.
Prognoses for malignant brain tumors in children and adults remain stubbornly poor, with a life expectancy of about one year, despite decades of vigorous research on experimental treatments. Prior research has demonstrated that innate (first line of defense) immune cells called “macrophages” infiltrate brain tumors; in fact, they make up 30-70 percent of brain tumor tissue. The degree of macrophage infiltration has been found to relate to overall survival in a few types of cancers including breast cancers and Hodgkin’s lymphoma, and in a type of brain tumor called malignant-astrocytoma. Despite the abundant macrophage presence in brain tumors, no current immunotherapy has employed the use of macrophages to directly attack cancer cells. The Stanford neurosurgeons, working with Stanford professor Irving Weissman M.D., have demonstrated that these innate immune cells can be activated to attack tumor cells when a molecule (called CD47) on the tumor cell surface is blocked.
They showed in mice that developed brain tumors (generated by stem cells taken from human brain tumors) that the activated macrophages essentially eat up (phagocytize) the tumor cells. The investigators are readying for human clinical trials an immunotherapy (called a monoclonal antibody) designed to block the CD47 molecule and stimulate macrophage attacks on malignant brain tumors in children and adults. What they need, though, is a noninvasive imaging technique that can quantify the degree of macrophage infiltration of the tumor initially and then determine whether the experimental treatment increases this infiltration of attacking macrophages.
A microscopic “nanoparticle”-based imaging agent, called ferumoxytol (Feraheme®) to be used with MRI may be the agent that they need. Ferumoxytol is approved by the Food and Drug Administration as an intravenous iron supplement to treat people with iron deficiency. The investigators have found that this iron-oxide nanoparticle can be used as a contrast agent with MRI to measure signals indicating that changes have occurred in degree of macrophage infiltration in a tumor. Now they will establish the characteristics of ferumoxytol in 20 adults and 20 children with deadly brain tumors and then validate this imaging technique by correlating the MRI findings with actual macrophage infiltration seen in tumor tissue removed during surgical treatment. Thereafter, they will use this MRI agent in mice to track macrophage anti-tumor responses that occur following administration of the experimental anti-CD47 monoclonal antibody treatment to establish its utility for assessing the treatment’s effects in the planned human clinical trial.
Significance: This new noninvasive MRI imaging agent, if successful, would become the gold standard tool for assessing the efficacy of this and other experimental brain tumor immunotherapies.
Samuel Cheshier, M.D., Ph.D.
Dr. Cheshier is a pediatric neurosurgeon who specializes in surgical-neuro oncology. His laboratory was initiated to study the stem cell developmental biology of brain tumors with an emphasis of discovering basic biological principles that will translate into novel treatments. As a neurosurgeon at Lucile Packard Children’s Hospital at Stanford, Dr. Cheshier is a main source of tissue procurement as well as clinical follow up on the patients. Dr. Cheshier is also a fully trained scientist with over two decades of research experience in stem cell biology. Dr. Cheshier received his M.D. and Ph.D. in Immunology from Stanford University. His thesis work elucidated the in vivo cell cycle kinetics of hematopoietic stem cells, and determined how cell proliferation is coordinated in order to meet the huge and constant demand for hematopoietic cells. After graduate school, Dr. Cheshier completed a residency in neurosurgery. During this time, he conducted his post-doctoral studies, where he discovered that Wnt pathway activation promotes self-renewal in central nervous system stem cells. The residency was followed by a fellowship in stem-cell transplantation in Lund University, Sweden. Dr. Cheshier finished a fellowship in Pediatric Neurosurgery at the Hospital for Sick Children, University of Toronto, Canada, after which he matriculated onto the faculty at Stanford University School of Medicine as an Assistant Professor of Pediatric Neurosurgery. The current research efforts in Dr. Cheshier’s laboratory focus on the prospective isolation of cell populations within brain tumors of both adult and pediatric patients. The hope is to understand the cellular milieu within the tumor and establish cell lineages from the tumor stem cells to their immediate progenitors, and finally differentiated tumor cells. The direct isolation of brain tumor cell populations will allow for a better understanding of the molecular events mediating cell fate decisions, as well as, the activities leading to the perpetuation and spread of these diseases. His laboratory also studies multiple immune and molecular based therapies for brain tumors in preclinical animal models with an emphasis of rapidly translating the research findings into potential treatments for human disease. The most promising immune-therapy currently studied in his laboratory utilizes a monoclonal antibody to block the cell surface molecule, CD47, which then stimulates macrophages to enter the tumor and “eat” the cancer cells. With his collaborators, he is utilizing the nanoparticle, Ferumoxytol, as a biomarker for macrophage entry into tumors; with the ultimate goal of real-time visualization of macrophage mediated anti-tumor responses in both preclinical animal models of brain tumors, as well as, in patients undergoing immune-therapy. These studies will establish the utility of Ferumoxytol in monitoring treatment effects in planned human clinical trials for anti-CD47 treatment of brain tumors.