CrossLink 2022 - Cover Article

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CrossLink Magazine I Fall 2022

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Engineering the Fight

U F B I O M E D I C A L E N G I N E E R S A R E B U I L D I N G N E W TA C T I C S AN D TOOLS TO ENABLE MORE VICTORI ES OVER C ANCER

D e feating a for mi dable opp on ent i s alway s a g r oup e f for t .

T h e sa m e goes f or b eat i n g ca n c er. Un iv er s it y of F lor i d a bi om e d i ca l en g i n e er s f r om t h e H erb er t Wer t h ei m C ol lege of E n g i n e er i n g ’s J. C ray ton P r u it t Fa m i ly D epa r t m ent of Bi om e d i c a l E n g i n e er i n g a r e t a k i n g t h ei r b es t , m os t i n n o vat iv e s h o t s at c a n c er w it h r esea r c h a i m e d at c r eat i n g n e w r esea r c h pl at f or m s a n d i mp r o v i n g e x i s t i n g t r eat m ent s .

HER E A R E SOME OF 4 4 4 T H E I R S T R AT E G I E S .

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TEXT WRITTEN BY

Laura Mize

BEAT Cancer Lab: : Modeling tumor eco-evolutionary dynamics.

REASSESSING STRATEGY Meghan Ferrall-Fairbanks, Ph.D., an assistant professor in the department, is rethinking the longstanding battle strategy against the deadliest gynecologic malignancy: ovarian cancer. Her Battling Evolution Through Adaptive Therapies (BEAT) Cancer Laboratory investigates “evolutionary medicine approaches and adaptive therapy treatment regimens to better control tumor growth and ultimately develop personalized treatment strategies for cancer patients that leverage an individual’s own tumor ecology to inform their treatment.”

Ferrall-Fairbanks said her team uses “computational, mathematical, and wet-lab experimental techniques to investigate tumor heterogeneity at the molecular, tissue, and systems levels.”

Examining heterogeneity – the differences between cells within the same tumor, or between tumors within the same patient – might be key to gaining more victories against ovarian cancer.

Counterintuitively, proponents of a methodology called adaptive therapy hypothesize that more women would survive ovarian cancer if they were subjected to a less aggressive chemotherapy regimen.

“Firstline therapy includes surgical resection followed by platinum-based chemotherapeutics,

Meghan Ferrall-Fairbanks, Ph.D. Assistant Professor

Quantitative systems biology, mathematical modeling, cancer heterogeneity and evolutionary dynamics

however 80% of patients relapse and from a clinical perspective, a woman diagnosed with recurrent ovarian cancer will die of her cancer,” FerrallFairbanks explained.

She asserts that this grim prognosis “result[s] from the assumption in clinical decision making that all patients are sensitive to platinum-based chemotherapeutics, while only 20% will remain disease free after their initial therapy and there are currently no good biomarkers for stratifying patients based on their platinum sensitivity.”

Borrowing a strategy successful in trials involving metastatic prostate cancer, Ferrall-Fairbanks suggests that lower doses of platinum-based chemotherapy would prevent platinum-resistant tumor cells from taking over the mass. The thought is that high doses of therapy would kill off cells susceptible to platinum-based chemotherapy, leaving a treatment-resistant tumor that is even harder to defeat.

Instead, adaptive therapy aims “to shrink the tumor size, but leave enough sensitive cells that they keep the resistance cells ‘in check,’” she explained.

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11 cells surrounded by blood and lymphatic vessels and immune system cells.

U N D E R S TA N D I N G IMMUNOTHERAPIES

CELLS DESIGNED TO KILL T H E T E A M I S D E V E L O P I N G NA N O PA RT I C L E S T H AT A R E C A PA B L E O F B L O C K I N G C H E M I C A L S I G NA L S T H AT W O U L D O T H E RW I S E D A M P E N T H E S O L D I E R C E L L S’ A B I L I T Y T O H O M E I N O N A N D K I L L T H E I R T U M O R P R E Y.

Blanka Sharma, Ph.D., an associate professor in the department and the Pruitt Family’s Term Fellow, is focused on another immune system weapon: Natural killer cells.

They are designed to essentially poison tumor cells, but instead cancer often neutralizes them.

To understand how this happens and how to combat it, Sharma and her research team are “engineering 3-D models of the tumor microenvironment to [analyze] the biochemical and mechanical cues that impact how natural killer cells migrate

Blanka Sharma, Ph.D.

Associate Professor & J. Crayton Pruitt Family Professor

into tumors and recognize cancer cells.”

Nanomedicine, stem cells, biomaterials, tissue engineering, and targeted drug/gene delivery

Based on what they find, the team is “developing nanoparticles that are capable of blocking” chemical signals that would otherwise dampen the soldier cells’ ability to home in on and kill their tumor prey.

In addition, Sharma collaborates with Rinaldi-Ramos “to establish

Sharma Lab: Cancer and natural killer cells interacting in 3D.

clinically viable cell-tracking methods for natural killer cells.”

“The cancer immunotherapy field is progressing very rapidly and there is a lot of excitement around [immunotherapy’s] impact in treating what have been historically very intractable cancer types,” Sharma said. “Natural killer cells are at the forefront of cancer immunotherapies because they could bypass some of the safety and cell-sourcing issues associated with T-cell therapies which are currently in use; this could allow for broader use and lower costs.”

CrossLink Magazine I Fall 2022

which circulating lymphocytes Another UF biomedical engineer (a type of immune cell) are creating models of the tumor exposed during external beam microenvironment is Walter radiotherapy. The reference Lee Murfee, Ph.D., an associate organ and blood vessel professor and models produced at the department’s UF can be reshaped to associate chair “THE OVERALL GOAL OF OUR match each patient’s for undergraduate WORK IS TO DEVELOP NOVEL unique organ anatomy studies. He leads E X P E R I M E N TA L M O D E L as captured through the Microvascular imaging.

Dynamics P L AT F O R M S T H AT E N A B L E Laboratory.

I N V E S T I G AT I O N O F C A N C E R C E L L S , Following radiotherapy, some patients have “The overall goal B L O O D V E S S E L S , LY M P H AT I C abnormally low of our work is to VESSELS AND IMMUNE CELLS lymphocyte counts. develop novel AT T H E S A M E T I M E .”

MGH physicians have experimental model Walter Lee Murfee noted that these people platforms that have poorer longenable investigation term outcomes than of cancer cells, blood patients with normal vessels, lymphatic lymphocyte counts. Because of vessels and immune cells at the Murfee envisions the model as a this, the researchers propose same time,” Murfee said. “lab-on-a-chip” that could easily that these vulnerable immune be used by cancer researchers. cells should be labeled Walter Lee Murfee, Ph.D. While Sharma and Murfee Associate Professor & Associate Chair ”organs-at-risk.” for Undergraduate Studies work on living models, other Cell dynamics, microcirculation, UF researchers are creating angiogenesis, lymphangiogenesis and neurogenesis computational models.

Currently, there is no way to view these all simultaneously, which Murfee calls “a big challenge in the cancer world.”

Overcoming this hurdle would allow scientists to study, for example, the known phenomenon of “tumor cells secreting something, causing lymphatic vessels and blood vessels to remodel.”

They could also examine how tumors respond when the number of attached blood vessels decreases. Big picture goals include discovering new traits of tumors and providing an environment for testing anticancer drugs on human tumor

Wesley Bolch, Ph.D., a distinguished professor and UF term professor, and his team are busy creating computer models of specific organs and tissues so radiation oncologists planning their attack can more accurately and effectively protect cancerfree tissues from radiation toxicity.

They are collaborating with researchers from Massachusetts General Hospital to create a library of computer models of blood and lymphatic vessel networks within organs of virtual adult male and female cancer patients. UF biomedical engineers create the models, which MGH scientists can use to assess the radiation dose to

Wesley Bolch, Ph.D. Distinguished Professor & UF Term Professor

Dosimetry, computational medical physics and dose assessment

After approximating how much radiation this patient’s lymphocytes can endure, the radiation oncologists will strategize how to best deliver the right dose.

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Bolch Lab: (A) Three-dimensional 1-cm3 histology-based computational model of the renal cortex for assessment of alpha-emitter radiopharmaceutical dose (showing proximal and distal convoluted tubules), (B) Three-dimensional model of the blood vasculature within the adult liver (hepatic arterial, hepatic venous, and portal venous systems) needed for assessment of radiation dose to circulating lymphocytes during external beam radiotherapy, (C) Representative members of a broad library of human computational phantoms – 65 kg of total body weight but at different standing heights – from 155 to 185 cm.

“Can we deliver fewer radiation treatments, each with a higher dose? Are there better angles for the radiation beam so we can avoid the major blood vessels feeding the organ?

Our tools will eventually allow physicians to redesign the external beam radiotherapies to minimize the dose to the circulating blood cells,” Bolch explained.

In a similar collaboration with Johns Hopkins University, Bolch and his team are working to create models of other organs-at-risk, such as the salivary and lacrimal glands, liver, bone marrow and kidneys.

The team uses finely detailed histology images provided by John Aris, Ph.D., from the UF College of Medicine’s Department of Anatomy and Cell Biology

to create the comprehensive models.

These models will help to improve radiopharmaceutical therapy, which Bolch described as “a pharmaceutical chemically linked to a radioactive atom which then decays, emitting charged particles.”

This compound is designed to follow biochemical signals from the tumor, taking the radiation straight to even the tiniest tumors. In a patient with advanced cancer, there

might be hundreds of such tumors. Because this therapy typically is administered intravenously into the blood stream, the radiation can also accumulate at lower levels in some tumor-free tissues. As with the external radiation used for the glioblastoma patients, the physician must determine a dose that will be effective against the tumor but safe for the organs-at-risk. Eventually, these models can be used in human clinical trials.

Murfee Lab: Screening of molecular treatments on cancer cell migration in real microvascular networks with blood vessels, lymphatic vessels, fibroblasts, macrophages, and extracellular matrix.

TRACKING THE ATTACK Carlos Rinaldi-Ramos, Ph.D. Chemical Engineering Dept. Chair & Dean’s Leadership Professor Nanomedicine and magnetic nanoparticles

Pairing magnetic nanoparticles with immune cells makes them trackable via magnetic imaging. Then, scans reveal where the loaded immune cells travel and give clues to how well the immune system is ramping up to fight the tumor cells.

Carlos Rinaldi-Ramos, Ph.D., the Dean’s Leadership Professor and chair of the Department of Chemical Engineering; and Jon Dobson, Ph.D., the Department of Biomedical Engineering’s J. Crayton Pruitt Family Professor are both working to attach various types of nanoparticles to immune cells, then track the migration of these cells via magnetic imaging methods.

Modifying immune cells to battle cancer is called immunotherapy.

One of Dobson’s projects in this area focuses on dendritic cells from mice that have a central nervous system cancer called glioblastoma.

A dendritic cell “boosts immune responses by showing antigens on its surface to other cells of the immune system,” according to the National Cancer Institute. This makes dendritic cells a

CrossLink Magazine I Fall 2022

key component of immune system response to vaccines.

After creating “multifunctional Jon Dobson, Ph.D. J. Crayton Pruitt Family Professor RNA-loaded magnetic Magnetic micro- and liposomes,” the scientists nanoparticle-based biomedical applications vaccinate the mice with them. The RNA in the nanoparticles is from the tumors and meant to provoke an immune system response against the cancer.

Dendritic cells pick up these nanoparticles and, ideally, carry them to the lymph nodes. Two days following vaccination, magnetic resonance imaging shows how many of the nanoparticles the dendritic cells have carried to the lymph nodes.

Rinaldi-Ramos collaborates with Duane Mitchell, M.D., Ph.D., the Phyllis Kottler Friedman Professor in the UF College of Medicine’s Department of Neurosurgery to modify and track immune cells called antigen-specific T cells. These are one of several types of T cells that scientists are working to enhance for battling cancer. After the T cells have been modified, the researchers load them with a superparamagnetic iron oxide nanoparticle, or SPION, to allow for tracking.

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15 As with the dendritic cells in the lymph nodes, if imaging shows inadequate accumulation of the T cells in the tumor, the oncology team can quickly pivot the patient to another treatment strategy.

CrossLink Magazine I Fall 2022

One advantage of SPIONs is that they tend to allow for clearer images than other types of nanoparticles.

accumulation two days after injection saw significant tumor shrinkage and survived the longest after vaccination.

Tracking movement of modified T cells and post-vaccine dendritic cells is important primarily for previewing immunotherapy effectiveness.

The researchers believe the same would be true for humans receiving a cancer vaccine containing magnetic nanoparticles.

In Dobson’s work, accumulation in lymph nodes of the dendritic cells bearing the magnetic liposome allowed the scientists to predict which of the mice models would respond most positively to the vaccine.

The group with the greatest

“This has significant

Pushing Toward Victory

implications … as it has

C A N C E R I S A F O R M I D A B L E E N E M Y.

the potential to allow

With UF biomedical engineers and their collaborators innovating novel strategies and creating new tools for the fight, more patients may be closer to earning their victories.

clinicians to make a very early determination of the efficacy of the immunotherapy,” Dobson explained, “and to adjust the therapeutic regimen

“For many cancers,

accordingly.”

waiting weeks is a

A similar principle seems to be true for T cells.

matter of life and death.

“There’s some evidence in the literature that suggests that if the T cells get into a tumor within 24 to 48 hours, there’s going to be a positive outcome,” Rinaldi-Ramos explained. “Okay.

But we don’t have a good way to do that in humans, to noninvasively track whether they [the T cells] get there.”

That’s where SPIONs and an innovative, still-emerging method known as magnetic particle imaging come in.

Though MPI is not yet widely used, its advantage lies in its ability to produce 3-D images clear of “background noise” from surrounding tissues.

Being able to determine whether the therapy is effective early on will be extremely valuable.”

Carlos Rinaldi-Ramos