Key Points
- Dr. Sheybani and her team use focused ultrasound and advanced imaging techniques to help the immune system fight cancer.
- Learn about her current research projects, vision for the future of the technology, views on mentorship, and how she sees patient treatments evolving.
Natasha Sheybani, PhD, is an assistant professor of Biomedical Engineering at the University of Virginia (UVA) and research director of UVA’s Focused Ultrasound Immuno-Oncology (FUSION) Center. In her cancer immunotherapy research laboratory, Dr. Sheybani and her team design and conduct basic and translational experiments using focused ultrasound and advanced imaging techniques to help the immune system fight cancer.
Before launching her laboratory at UVA, Dr. Sheybani earned the NIH Director’s Early Independence Award, which recognizes exceptional young scientists who are ready to lead research programs right out of graduate school and bypass the traditional postdoctoral path. She was also recognized by Forbes 30 Under 30 in Science in 2022.
We recently interviewed this highly awarded early-career investigator for the Curing with Sound podcast to learn more about her current research projects, vision for the future of the technology, views on mentorship, and the evolution of the patient experience.
How did you first learn about focused ultrasound?
I had read about image-guided drug delivery before interviewing with my PhD advisor, Dr. Richard Price. I was hooked right from the beginning when I learned that focused ultrasound was an incision-free way to precisely interact with tissue from outside the body. It utilizes a form of energy that is familiar to all of us: sound waves. As an engineer, I felt like I was stepping into something quite remarkable – a capability to turn physics into biologically and clinically meaningful outcomes.
Why did you want to study cancer immunotherapy?
I had the good fortune of being part of the Focused Ultrasound Foundation’s first immuno-oncology consortium that launched back in 2016. Several teams across North America were charged with assessing the immunological effects of different focused ultrasound regimens in a preclinical model of glioblastoma. That project ended up informing my PhD focus on immunomodulation in cancer – not just in the setting of glioblastoma, but also in breast cancer. Since that time, I have been fascinated with the idea of using sound waves as a noninvasive modality for helping the immune system see and attack cancer.
What mechanisms of focused ultrasound are you using for your research?
I often tell people that our lab uses the physics of sound waves to tune biology. This is a complex task – as there are many ways that we can shape a sound wave – and the downstream implications for biology are vast.
Most tumors are highly adept at evading the immune system, and this can pose bottlenecks for even our best immune-targeted cancer therapies. My laboratory is studying how thermal or mechanical focused ultrasound regimens can sound a local alarm bell in aggressive solid tumors. We study many forms of focused ultrasound in my lab, all of which mirror what we’re doing in the clinic here at UVA and beyond – thermal ablation, histotripsy, sonodynamic therapy, blood brain barrier opening, and more. In order to improve the performance of cancer immunotherapies, we are trying to change the conversation between tumors and the immune system with precisely delivered acoustic stimuli. Mirroring my graduate studies, we are continuing to do this exercise in aggressive brain cancers and breast cancer.
How do you monitor immunotherapy effects on the tumor microenvironment?
Of course, our workhorse techniques continue to be multispectral flow cytometry and microscopy. But these days, we are also using surveillance methods that have the advantage of being noninvasive and longitudinally accessible, like advanced imaging and liquid biopsies. We are pondering new ways to integrate high-fidelity molecular feedback into focused ultrasound paradigms where we currently lack such feedback. If we could identify unique biomarkers or biological signatures that are associated with responses to focused ultrasound immuno-oncology paradigms, those could one day inform the way that we deploy and adapt combination therapy approaches.
What technological or biological barriers do you anticipate encountering when applying focused ultrasound in an immuno-oncology context, in breast cancer or brain metastases?
From the standpoint of technological barriers, we are in a fortunate position. As an early career researcher, I stand on the shoulders of giants who have worked for many decades to bring the technology to where it is today, notably for transmitting and controlling acoustic energy delivery in the anatomical settings my lab studies.
For us, most days, it’s about the biological barriers. We are rooted in the complexities of tumor immunology and its Newtonian nature – simply put, you poke one part of the immune system and another part responds. There is a lot of work we still want to do toward gaining a robust, fundamental understanding of those complexities and achieving true ‘control’ of immune-targeted focused ultrasound paradigms. To become more precise, we need to evaluate which tools are serving us well and devise new tools or instrumentation features that could yield the next generation of focused ultrasound interventions. We are also on an exciting frontier of clinical growth in focused ultrasound immuno-oncology investigations, which is poised to reveal a great deal to us about outcomes in human cancer settings.
What laboratory techniques have been helpful for conducting your research?
We are excited about the power of molecular imaging. Positron emission tomography (PET)-based radiotheranostics have become an empowering asset for us toward monitoring the processes we are trying to manipulate. For example, with PET we can measure real-time metabolic activity inside a tumor, unravel the kinetics of an immunological response, or track the deposition of a therapeutic that we are directing to the tumor with focused ultrasound. I suspect my students would agree this is a little more fun than the all-nighters we routinely pull for those massive endpoint flow cytometry studies.
Looking ahead 5 to 10 years, what are the most exciting new applications of focused ultrasound that are not yet in the clinic?
I am quite excited about what sonogenetics will offer within the next decade. That frontier is just so cool. My colleagues at UVA recently launched a first-in-human trial combining focused ultrasound and engineered T cells (NCT07343986). I suspect we’ll see sonogenetically controllable immunotherapies enter the clinic in due time. And of course, artificial intelligence (AI) is burgeoning in ways that we will only see grow within the focused ultrasound community. The ways that AI could permeate – and hopefully enrich – everything from technology development to clinical decision-making is poised to be transformative. Of course, I hope the next 5–10 years are just as rich with dialogues and guardrails pertaining to ethics and responsible AI implementation in our field.
How many people work in your laboratory, and what are their positions?
Our lab family is comprised of two postdoctoral fellows, six PhD students, one American Cancer Society–sponsored postbaccalaureate fellow, one incoming MS student, one lab manager, and an average of 4–5 undergraduate researchers at any given time. We are also a host lab to two visiting scholars, and I co-mentor one clinical fellow. We also work closely with the UVA FUSION Center’s two talented senior scientists. In the summers, we routinely host additional visiting high school and/or undergraduate researchers through the Focused Ultrasound Foundation’s Global Internship Program.
Your laboratory includes students ranging from middle school to graduate school, along with postdoctoral scholars and medical residents. What drives your commitment to mentorship, and how do you approach guiding the next generation of researchers?
Mentorship is a multiplier, and it is my favorite part of the job. Spreading my excitement for scientific discovery to my students and postdocs, seeing their passions sparked, and challenging them to generate translatable solutions to critical biomedical engineering problems is everything. Our field is inherently interdisciplinary, so we interact and collaborate with trainees, basic scientists, and clinicians from all scientific paths spanning engineering, immunology, oncology, imaging science, and more. I’m proud to have built a laboratory culture that encourages, harnesses, and celebrates curiosity and embraces complexity. Mentoring students and watching them ‘pay it forward’ in mentorship roles of their own has been incredibly rewarding.
What are your research funding sources?
Our funding comes from the National Institutes of Health, US Department of Defense, private foundations, and internal funding sources – of course including the Focused Ultrasound Foundation–supported FUSION Center at UVA. We’re grateful to all of our funders for enabling our lab an early opportunity to think big and foster a ‘high-risk, high-reward’ scientific agenda.
How are you approaching your pediatric brain tumor research?
We are devising precise, safety-first approaches that minimize systemic exposures in pediatric patients, wherein cancer treatment toxicities can bear devastating impacts on early childhood development. For example, we are studying blood-brain barrier opening in pediatric brain cancers to improve targeted therapeutic delivery and modulate the highly immunosuppressed tumor microenvironment. This is the focus of a few of our current collaborative projects in the cell and gene therapy space.
What does your breast cancer research project entail?
As a lab, we were incredibly honored to recently receive a $5.5 million Era of Hope Scholar Award. This award, funded through the US Department of Defense’s Breast Cancer Research Program, is centered on applications of focused ultrasound for primary and metastatic breast cancer. This grant allows us to drill down on mission-critical themes in the lab, with the goal of more quickly delivering solutions to patients. Themes include leveraging focused ultrasound as a local immune primer, improving penetration depth and distribution of complex macromolecular biologics into breast cancer settings with focused ultrasound, and closed-loop implementation of noninvasive monitoring strategies like PET imaging for personalized treatment.
At UVA, we have already developed first-in-class instrumentation for integrating PET with MR-guided focused ultrasound. Secondarily, we have an active biomarker discovery pipeline with preclinical and clinical liquid biopsy specimens that will, in the long term, endow us with insights regarding cancer responses from a simple blood draw.
We have a robust translational pipeline within UVA’s Focused Ultrasound Center of Excellence, and it has already given rise to multiple clinical trials in breast cancer and other solid tumors. This grant assembles a team spanning basic discovery and clinical investigation that will expand the depth and breadth of our lab’s role within the translational enterprise.
Tell us about the patient advocates who advised this project. What did you learn?
As researchers, we can be prone to operating in our own silos. The barriers between us and the community are sometimes more significant than we might realize. I have been fortunate to intersect with a group of breast cancer patient advocates who are willingly volunteering their time to sit at the table with our lab and discuss the harsh realities of cancer care and survivorship. These women, all of whom have survived breast cancer, have been so generous with their insights and vulnerability to share the totality of their experiences. Their contributions will make the work that we are doing all the more accessible and translationally relevant. Our north star as researchers is making immunotherapies substantially more effective, safer, more accessible, and more comfortable for patients. Our patient advocate team has been instrumental in informing and evolving the vision for our breast cancer research program.
What do you hope your work will make possible for the next generation of patients and scientists?
For patients, I hope that our work leads to better treatment options, ideally with fewer side effects. Through our engagement with breast cancer survivors, we are more consistently reminded of not just the harsh impacts of treating cancer, but also the realities of surviving it – not to mention the psychological, emotional, and financial burdens accompanying that journey. Any small role our research can play toward alleviating those burdens would be a win.
For the next generation of scientists, my message is simple: the future is now. I hope that more scientists from different backgrounds and walks of life will become aware of focused ultrasound and choose to engage in this research. In fact, we are already seeing that. Over the past 10 years, I have seen a striking evolution in the backgrounds and schools of thought that are being brought into the field. This evolution, alongside significant recent translational and commercial successes, has brought our field to an exciting inflection point in accelerated adoption and impact.
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