About Stanford CIRP
Optimize and validate pre-clinical quantitative imaging methods for TAM imaging
Our preliminary data showed a specific cellular uptake of ferumoxytol in TAM in osteosarcomas in mouse models and corresponding significant tumor enhancement on T2- and T2*-weighted MR images at 24 hours after intravenous nanoparticle injection21. With this aim, we will define the appropriate time window for TAM imaging, determine the reproducibility of quantitative TAM imaging results and identify potentially confounding signal effects. All imaging studies will be performed on a 3T MRI scanner, which resembles the typical clinical situation. The endpoint will be to validate a quantitative TAM imaging test in an established animal model.
Implement the optimized methods in a co-clinical trial
We recently conducted a first-in-human clinical trial, which showed that ferumoxytol nanoparticles cause strong MRI enhancement of bone sarcomas. A hypointense (dark) tumor enhancement on T2-weighted MRI images correlated with the presence and distribution of TAM on histology22. However, it is not known whether this new imaging test can be used to predict response to TAM-modulating therapies. We hypothesize that the degree of ferumoxytol tumor MRI enhancement after TAM-modulating therapy correlates with the quantity of TAM and the extent of tumor necrosis on histology. The endpoint will be to prove that quantitative ferumoxytol-enhanced MRI can serve as a surrogate outcome measure for tumor response to TAM modulating therapies.
Populate a web-accessible research resource
Finally, we will populate a web-accessible research resource with all the methods, data and results collected from the co-clinical investigations such that investigators at other centers can learn about quantitative imaging approaches for TAM imaging, test their ability to estimate tumor TAM content through R2 and R2* maps, implement related imaging protocols at their institution and apply them for monitoring TAM-modulating cancer immunotherapies. We will invite the research community to participate in a software challenge that could further optimize the speed and accuracy of QI methods for TAM quantification.
Optimal integration of TAM-modulating therapies with conventional chemotherapy remains poorly elucidated, despite the fact that clinical implementation will rely on combinations. Ferumoxytol-MRI could represent a significant breakthrough for clinicians as a new means for therapy stratification and gold-standard imaging test for monitoring response to TAM-modulating therapies. Results from this project will directly inform ongoing clinical trials, including a first-in-patient CD47 mAb trial in 2021. Our investigations will be readily translated to the clinic, provide a novel tool to predict tumor response to new immunotherapies, have major and broad health care impact, and ultimately, help to improve long-term outcomes.
The Team
Heike Daldrup-Link, MD, PhD
Co-Principal Investigator
Professor of Radiology at Stanford University
Co-Director of the Cancer Imaging Program at the Stanford Cancer Institute
Dr. Daldrup-Link has over fifteen years of experience in clinical cancer imaging, MR imaging and nanoparticle research. Dr. Daldrup-Link is the recipient of multiple honors and awards for translational research, including the Distinguished Investigator Award of the Academy for Radiology Research, member of the American Society for Clinical Investigation (ASCI, honor society for physician-scientists) and Fellow of the American Institute for Medical and Biomedical Engineering (AIMBE).
Daniel Rubin, MD
Co-Principal Investigator
Professor of Radiology, Biomedical Data Science, and Medicine (Biomedical Informatics Research) at Stanford University
Dr. Rubin is an expert in quantitative image analysis methods in Radiology. He is a Fellow of the American Institute for Medical and Biological Engineering (AIMBE), Fellow of the American College of Medical Informatics (ACMI) and Fellow of the Society of Imaging Informatics in Medicine (SIIM).
Michael Moseley, PhD
Co-Investigator
Professor of Radiology at Stanford University
Dr. Moseley has a PhD in physical chemistry and expertise in novel high-speed MR imaging techniques for cellular imaging. Dr. Moseley published over 380 publications on MR imaging, he was awarded the ISMRM (International Society for Magnetic Resonance and Medicine) Gold Medal in 2001 for his pioneering work in diffusion MRI and he served as the 2003-2004 president of the ISMRM.
Sheri Spunt, MD, MBA
Co-Investigator
Professor of Pediatrics at Stanford University
Dr. Spunt is a pediatric oncologist with Board Certification in Pediatrics and subspecialty certification in Pediatric Oncology. Dr. Spunt directs a Clinical and Translational Research Program focusing on the development of novel therapy approaches for bone and soft tissue sarcomas in children and young adults.
Robbie Majzner, MD
Co-Investigator
Assistant Professor of Pediatrics,
Pediatric Oncology Division, at Stanford University
Dr. Majzner completed his residency training in pediatrics at New York Presbyterian-Columbia and fellowship training in pediatric hematology-oncology at Johns Hopkins and the National Cancer Institute. His current work focuses on investigating the value of combined GD2 and CD47 mAb therapies for the treatment of neuroblastomas and osteosarcomas.
Frezghi Habte, PhD
Director
Stanford Center for Innovation in In Vivo Imaging (SCI3)
Dr. Habte is a medical imaging instrumentation and image quantification specialist. As a director of the shared small animal imaging facility at Stanford, he provides various services such as instrument management and support, project specific experimental design consultation, and image analysis software support and training. His current research focuses on image data management and quantitative imaging methods.
Raheleh Roudi, PhD
Postdoctoral Research Fellow at Stanford University
Dr. Roudi is a molecular biologist who has worked as a researcher in the Department of Radiology for 2 years. She conducts our pre-clinical imaging studies with a focus on MR imaging and R2/R2* measurements.
Shakthi Kuraran Ramasamy, MD
Postdoctoral Research Fellow at Stanford University
Dr. Ramasamy is a physician-scientist who has worked as a researcher in the Department of Radiology for 2 years. He coordinates and supervises our imaging studies with a focus on MR imaging and R2/R2* measurements.
Lucia Baratto, MD
Research Associate
Dr. Barratto is a physician-scientist who has worked as a researcher in the Department of Radiology for 5 years. Dr. Barratto acquired extensive experience in the conduction of clinical trials for the evaluation of new imaging technologies. She coordinates and supervises our imaging studies with a focus on PET imaging.
Fabrizio Pisani, MD
Research Associate
Dr. Pisani is a physician-scientist who recently joined the Molecular Imaging Program in the Department of Radiology. He coordinates and analyzes our MR imaging studies of osteosarcomas in animal models and in patients.
Laura Pisani, PhD
Research Associate
Dr. Pisani is an MRI physicist and Co-Director of the Stanford Center for Innovation in in vivo Imaging (SCI3). She trains researchers in MR imaging technologies and supervises preclinical MR imaging studies at the SAIF. Dr. Pisani provides monthly Introductory MRI seminars; hands-on training for MRI, micro-PET, fluorescence imaging; and she helps optimize experimental design and image data analysis.
Jarrett Rosenberg, PhD
Biostatistician at Stanford University
Dr. Rosenberg is the biostatistician for the Department of Radiology and has been involved with the experimental design of this project, with respect to sample size determination, development of multiple regression analyses and correlation models for imaging data analyses. Dr. Rosenberg will work with the PIs to develop a statistical model that relates features of our integrated database to determine quantitative imaging predictors of treatment response.
Brittney Williams
Clinical Trial Coordinator at Stanford University
Ms. Williams is a clinical trials coordinator who worked with our team over the past 2 years. Ms. Williams will ensure regulatory compliance of all aspects of this study, obtain and maintain records of patient consents, and assist in managing overall study logistics.
Facilities
The Stanford Cancer Institute focuses the world-class expertise of more than 240 researchers and clinicians on the most critical issues in cancer research and medicine today. These dedicated individuals work together in multidisciplinary teams to unravel cancer’s secrets and to transform the latest detection, diagnosis, treatment and prevention discoveries into the most advanced patient care available. Combining these advances with comprehensive support services, the Stanford Cancer Institute is committed to giving patients every clinical and technological advantage in the prevention and treatment of cancer. The infrastructure and resources of the Stanford Cancer Institute are available free of charge to cancer researchers.
The Lorry I. Lokey Research Building is located on the main campus within the School of Medicine, between the Lucas Center and the Stanford hospital. The Lokey Building is a 200,000-square-foot facility with 550 researchers in 33 different labs, which includes the preclinical facilities of the Stanford Cancer Center. The institute integrates researchers from multiple specialties including cancer biology, stem cell biology, immunology and bioengineering. The building also has 60 hotel benches, where visiting scientists can come and do research as well.
The Richard M. Lucas Center for Imaging was established in 1992 and is the primary, centralized resource dedicated to biomedical imaging research on the Stanford University campus. With its current 37,000 nasf of space dedicated to molecular imaging, nanotechnology, MRI, PET, PET/MR, and spectroscopy research, the Lucas Center is one of the few centers in the world with major centralized resources devoted to research in the radiological sciences where both basic and clinical scientists are housed. The Lucas Center builds on a long-standing and very close working relationship between faculty and students of the Department of Radiology, the Stanford Cancer Institute as well as the Departments of Electrical Engineering, Bioengineering and Chemistry. The Center provides office and laboratory facilities for over 15 full-time faculty and their complement of more than 75 postdoctoral fellows and students. Dr. Moseley’s office is located in the Lucas Center and our team has eight assigned desks for trainees in the Lucas Center. Major imaging devices available for research studies include one 3T Signa PET/MRI scanner (GE Healthcare) as well as two 3.0T and one 7.0T MR scanner(s). Approximately one half of the Stanford Radiology 3D Imaging Laboratory (image data post-processing) is also located in the Lucas Center. With these resources, the Lucas Center is well suited for the preclinical development and clinical translation of novel imaging technologies. The Lucas Center is being used for preclinical imaging studies and clinical PET/MR scans of patients for our project. The Lucas Center is located in approximately 5 minute walking distance to the Children’s hospital. We conducted clinical trials at the Lucas Center for the last eight years and have established workflows to accompany pediatric patients from the Children’s hospital to the Lucas Center.
The James H. Clark Center fosters an unprecedented degree of collaboration between scientists from different disciplines in order to meet some of the most pressing scientific challenges of the coming decades. Such challenges can no longer be met by individuals working in isolation, but require the combined expertise of multi-disciplinary teams. The Clark Center lies at the heart of the Stanford campus between the core campus science engineering buildings and the hospital and medical facilities. Located on primary routes between the campus and the medical center, the building acts as a social magnet encouraging chance encounters and informal meetings between lecturers, researchers and students from diverse academic backgrounds. This provides a unique opportunity for our imaging researchers to interact and collaborate with basic scientists of different disciplines. The lab interiors are a dramatic departure from tradition. The building has been turned inside out, with ‘corridors’ replaced by external balconies, enabling completely flexible lab layouts. The three-story building takes the form of three wings of laboratories centered on an open courtyard overlooked by balconies. The Clark Center is home to approximately one half of the Radiology 3D Imaging Laboratory, the Molecular Imaging Lab, and the small animal imaging. The Clark Center houses the small animal imaging laboratory, which is being used for preclinical imaging studies for this project. The small animal imaging lab comprises a full complement of state-of-the-art small animal imaging equipmentas well as animals’ surgery suites with a variety of surgical devices and micro- and macrotome facilities.
Stanford Center for Innovation in In Vivo Imaging (SCi3) is a state-of-the-art shared preclinical and translational imaging center to enable the understanding of the biology of health and disease, and to facilitate translation from in vitro findings to in vivo applications and clinical practice. Towards these goals, we continue to bring in the most cutting-edge imaging technologies available, including Bruker MRI system (3T, 7T/PET and 11.7T), MicroPET/CT, High resolution MicroCT, Optical imaging, Magnetic Particle Imager and Visual Sonic Ultrasound and photoacoustic systems. The facility also provides other equipment and animal surgery/prep suites that facilitate multi-modality imaging. The Clark Center houses the main small animal imaging laboratory, which is being used for preclinical imaging studies for this project.
Stanford Nanocharacterization lab: Stanford offers several shared facilities for nanoparticle research, including the Stanford Nano Center (SNC) and the Stanford Nanofabrication Facility (SNF), which are part of Stanford’s National Nanotechnology Infrastructure Network (NNIN) program. These core facilities provide access to a wide array of shared instruments, such as mass spectrometers, high-resolution microscopes, X-ray diffractometers and surface science analytical instruments (among many others) that are available for all qualified users in the Stanford community, and for Stanford collaborators both locally and globally. The NNIN program provides an infrastructure for nanoparticle synthesis, generation of high-quality data on nanomaterials and related data analyses and interpretation. This provides a unique resource for our planned nanoparticle biodistribution studies.
The Daldrup-Link Lab is located in the Lokey building and comprises benches and desks for research fellows as well as a fully equipped cell culture lab with three cell culture hoods, two incubators (one low oxygen incubator), one refrigerator, one freezer, two centrifuges, one microscope, an autoclave, and a variety of additional small equipment (see details below). All personnel involved in this research have access to Dr. Daldrup-Link’s laboratory. Preclinical studies for this project are being performed in the Daldrup-Link lab.
Lucile Salter Packard Children’s Hospital (LPCH), ranked as one of the nation’s top pediatric hospitals, is a 361-bed hospital for children and expectant mothers, located next to the Stanford Hospital on the University campus. With over 750 physicians and 5000 staff support and volunteers, Packard Children’s Hospital is a world-class, non-profit hospital devoted entirely to medical and surgical care of babies, children, adolescents and expectant mothers, offering the full range of health care of pediatric and obstetric services, from preventive and routine care to specialized services. Supported by the academic resources at the Stanford University School of Medicine, Packard Children’s brings world-class medicine right to the bedside.
The Division of Pediatric Hematology and Oncology at LPCH is one of the largest and most active in the country with 20 full time faculty members. All members of the division are actively involved in research. The division has more than 50 active research projects with peer-reviewed funding. Senior faculty members play key roles in the Children’s Oncology Group and in other national and international research consortium.
References
- Bernthal NM, Federman N, Eilber FR, et al. Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer 2012; 118(23): 5888-93.
- Rodriguez-Galindo C, Navid F, Liu T, Billups CA, Rao BN, Krasin MJ. Prognostic factors for local and distant control in Ewing sarcoma family of tumors. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2008; 19(4): 814-20.
- Zhu L, McManus MM, Hughes DP. Understanding the Biology of Bone Sarcoma from Early Initiating Events through Late Events in Metastasis and Disease Progression. Frontiers in oncology 2013; 3: 230.
- Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children’s Cancer Group Phase II Study 9457–a report from the Children’s Oncology Group. J Clin Oncol 2006; 24(1): 152-9.
- Cangir A, Vietti TJ, Gehan EA, et al. Ewing’s sarcoma metastatic at diagnosis. Results and comparisons of two intergroup Ewing’s sarcoma studies. Cancer 1990; 66(5): 887-93.
- Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 2010; 28(20): 3284-91.
- Miser JS, Krailo MD, Tarbell NJ, et al. Treatment of metastatic Ewing’s sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide–a Children’s Cancer Group and Pediatric Oncology Group study. J Clin Oncol 2004; 22(14): 2873-6.
- Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 1998; 9(3): 275-81.
- Bakhshi S, Radhakrishnan V. Prognostic markers in osteosarcoma. Expert Rev Anticancer Ther 2010; 10(2): 271-87.
- Mialou V, Philip T, Kalifa C, et al. Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome–the French pediatric experience. Cancer 2005; 104(5): 1100-9.
- Xu JF, Pan XH, Zhang SJ, et al. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models. Oncotarget 2015; 6(27): 23662-70.
- Zhao XW, van Beek EM, Schornagel K, et al. CD47-signal regulatory protein-alpha (SIRPalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A 2011; 108(45): 18342-7.
- Chao MP, Weissman IL, Majeti R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012; 24(2): 225-32.
- Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009; 138(2): 286-99.
- Chao MP, Alizadeh AA, Tang C, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 2010; 142(5): 699-713.
- Edris B, Weiskopf K, Volkmer AK, et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proc Natl Acad Sci U S A 2012; 109(17): 6656-61.
- Chao MP, Jaiswal S, Weissman-Tsukamoto R, et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med 2010; 2(63): 63ra94.
- Chao MP, Alizadeh AA, Tang C, et al. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res 2011; 71(4): 1374-84.
- Edris B, Weiskopf K, Volkmer AK, et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proceedings of the National Academy of Sciences 2012; 109(17): 6656-61.
- Herrmann D, Seitz G, Fuchs J, Armeanu-Ebinger S. Susceptibility of rhabdomyosarcoma cells to macrophage-mediated cytotoxicity. Oncoimmunology 2012; 1(3): 279-86.
- Mohanty S, Yerneni K, Theruvath JL, et al. Nanoparticle enhanced MRI can monitor macrophage response to CD47 mAb immunotherapy in osteosarcoma. Cell Death and Disease 2019; 10: 1-14.
- Aghighi M, Theruvath AJ, Pareek A, et al. Magnetic Resonance Imaging of Tumor Associated Macrophages: Clinical Translation. Clin Cancer Res 2018.
- Daldrup-Link HE, Golovko D, Ruffell B, et al. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clinical Cancer Research 2011; 17(17): 5695-704.