Fouad Kandeel, M.D., Ph.D.
In the 1970s, scientists first observed cells shedding tiny buds and thought they were simply waste debris. Only recently have we learned that these extracellular vesicles
(EVs) are actually packed with molecular information and function as an important intercellular communications system throughout the body.
It’s a discovery that promises to revolutionize medical treatment and diagnosis, and may even help us detect cancer at least seven years earlier than we can today.
City of Hope and TGen
, a City of Hope affiliate, have now joined forces, combining their formidable research and genomic mapping resources to bring the benefits of EV technology to patients. As part of this collaborative effort, clinical trials for cancer, type 1 diabetes and graft-versus-host disease are currently being prepared.
HOW EVs WORK
“EVs are kind of like FedEx packages,” said Derek Cridebring, Ph.D., director of the Molecular Medicine Division of TGen. “Each EV carries a tiny cellular cargo and has its own ‘ZIP code,’ which directs it to a particular part of the body.”
Some EVs go to adjacent cells; others are carried through the bloodstream to distant locations. When they arrive, they communicate their messages through genetic material, proteins and lipids. These messages might stimulate a cell to grow, transform a cell into something else or convey protection to a cell — to name just a few of the many processes EVs are involved in.
They also carry messages that can create and spread disease in the body. For example, in cancer, EVs from certain tumors can produce metastases, and in type 1 diabetes, EVs play a role in the autoimmune reaction that inhibits insulin production.
This knowledge has led to new technologies for treatment and diagnosis. We can now replace the “cargo” in EVs with medications, engineer them as we do with CAR T
cell therapy and infuse them with imaging agents for more precise diagnosis. We can also infuse EVs with both a treatment and imaging agent to trace medication delivery in real time.
TREATMENT WITH NO SIDE EFFECTS
Side effects are the bane of most treatments, and EVs are expected to eliminate many of them. For one thing, EVs have such specific destinations that whatever treatment they are carrying, even chemotherapy, will affect only targeted cells.
What’s more, EVs are inert organelles, not living cells like CAR T or stem cells. This means they can’t be rejected or cause antigenic reactions or form tumors. And because EVs are not living tissue, they can be used off the shelf and for any patient.
Another advantage is that these applications use only the tiniest EVs (sometimes called exosomes). They are less than 100 nanometers in diameter, too small to block even the narrowest blood vessels.
DIAGNOSING CANCER 7 YEARS EARLIER
EVs also serve as biomarkers that can be used to detect disease, and they will hopefully allow us to diagnose cancer seven years earlier than is now possible.
“Cancer can take years to grow, and we are working on techniques to detect it as early as possible. We are finding hints that eight years before cancer is diagnosed, there are detectable changes,” Cridebring explained. “We believe the EVs circulating in your bloodstream can tell us if you have cancer and pinpoint where it is.”
This means we will be able to catch cancer when it is at a more treatable stage, before the tumors have evolved escape mechanisms to our current therapies.
UPCOMING CANCER TRIALS
A clinical trial is being developed for refractory, or treatment-resistant, cancers using EVs loaded with an immunotherapy treatment called exoSTING that was developed by Codiak Bioscience
ExoSTING is an immune checkpoint inhibitor
, and Cridebring explained how it works. “Certain tumors have a way of cloaking themselves so the immune system can’t recognize them,” he said. “This drug essentially removes the cloak so that the immune system can go in and destroy the tumor.”
EVs may also be the key to healing pancreatic cancer. One reason this disease has been so difficult to cure is that the tumors are very dense, and previous treatments have not been able to penetrate the tumor. EVs have a targeting mechanism and membrane that can fuse with cancer cells so they can hopefully overcome this problem.
FIRST-IN-HUMANS TRIAL FOR TYPE 1 DIABETES
On the opposite end of the spectrum from the immune suppression of certain cancers are autoimmune diseases, such as type 1 diabetes, in which an activated immune system attacks the insulin-producing cells of the pancreas.
In early 2020, City of Hope/TGen will launch a first-in-humans trial for type 1 diabetes. It will use EVs extracted from umbilical cord mesenchymal cells, a type of stem cell. Kandeel, who is currently setting up this trial, expects these EVs to reverse the autoimmune attack on insulin-producing cells and restore their proper functioning.
He will also be principal investigator in a future trial, using similar technology, for graft-versus-host disease
, an autoimmune condition that occurs in a large number of stem cell transplant patients.
ALMOST LIMITLESS POSSIBILITIES
EVs have exciting applications in many other areas of medicine, too — repairing damaged heart muscles after a heart attack, reversing the early stages of kidney disease and healing wounds. They also hold great promise for neurological diseases.
“This is a field that is just taking off. The science is going very, very fast,” Kandeel said. “And the potential of it, if you think about it, is enormous.”
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