A fresh approach to a long-established cancer-fighting method has demonstrated strong effects against various cancer types in a preliminary study conducted by researchers at the Perelman School of Medicine, University of Pennsylvania. This innovative method employs tiny capsules known as small extracellular vesicles (sEVs), potentially paving the way for a new form of immunotherapy that is ready to advance into further development and testing.
A fresh approach to a long-established cancer-fighting method has demonstrated strong effects against various cancer types in a preliminary study conducted by researchers at the Perelman School of Medicine, University of Pennsylvania. This innovative method employs tiny capsules known as small extracellular vesicles (sEVs), potentially paving the way for a new form of immunotherapy that is ready to advance into further development and testing.
Today in Science Advances, the researchers detailed their use of sEVs—engineered in the lab from human cells—to target a specific cell surface receptor named DR5 (death receptor 5), commonly found on many tumor cells. When activated, DR5 can initiate a self-destruction process known as apoptosis, leading to the death of such cells. For over 20 years, researchers have been striving to create effective cancer treatments that target DR5. However, this new technique, which utilizes engineered sEVs to engage DR5, has surpassed previously developed DR5-targeting antibodies, which were once considered the leading strategy. The sEVs demonstrated impressive capabilities in lab tests, effectively killing a variety of cancer cells and inhibiting tumor growth in mouse models, resulting in significantly longer survival compared to DR5-targeting antibodies.
“This new strategy has several advantages over former DR5-targeting methods and other cancer immunotherapies, and following these encouraging preclinical results, we’re moving forward towards human clinical trials,” stated senior author Xiaowei “George” Xu, MD, PhD, a professor of Pathology and Laboratory Medicine, and a member of the Tara Miller Melanoma Center in Penn Medicine’s Abramson Cancer Center. “We’ve noticed that many individuals have gained from advancements in cancer immunotherapy, but we recognize there’s still much to achieve. This drives our pursuit of new cellular therapy strategies, particularly for solid tumor cancers like melanoma, where current immunotherapies only seem effective for about half of patients.”
A better way to target DR5
The DR5 death receptor seems to have evolved, at least partly, to eliminate malignant or damaged cells. Despite the promising nature of DR5 as a target for cancer treatments, previous attempts have not succeeded in halting tumor growth effectively. Xu and his team opted to use extracellular vesicles to target DR5 because these tiny capsules—roughly one million times smaller than a T cell—are naturally produced and released by virtually every kind of cell. They carry elements that can communicate messages to neighboring cells.
In this case, the team utilized sEVs derived from natural killer (NK) cells, a type of immune cell known for its role in fighting cancer. NK-derived sEVs can penetrate tumors effectively and carry molecules that are harmful to cancer cells. Xu and his team modified the NK sEVs by adding an antibody fragment that strongly binds to and activates DR5.
In laboratory experiments, the sEVs specifically target and attach to DR5, swiftly eliminating cancer cell types with high DR5 levels, such as melanoma, liver, and ovarian cancer cells. Furthermore, in mouse models of melanoma, breast, and liver cancers, the sEVs significantly reduced tumor growth and extended survival times.
Reversing tumor immunosuppression
Xu and his team discovered that the sEVs had additional capabilities: they not only attacked other DR5-expressing cells, like cancer-associated fibroblasts and myeloid-derived suppressor cells—both of which tumors use to create an immune-suppressive environment—but also invigorated T cells, further enhancing immune activation against cancer. This suggests that the sEVs might effectively disrupt the immunosuppressive environments often found in solid tumors, a significant challenge for many current immunotherapy approaches.
Xu pointed out that sEVs can be produced and stored easily, making them a viable “off-the-shelf” treatment that could be administered to any patient without the need to retrieve cells from individual patients, as necessary in other personalized cellular therapies.
The next steps for the team involve refining the manufacturing process to scale up production of clinical-grade sEVs and conducting safety studies in preparation for human clinical trials.
This study received funding from the National Institutes of Health (CA258113, CA261608, CA114046, CA284182). A patent application for this technology has been submitted on behalf of the University of Pennsylvania.
