PHILADELPHIA – A new twist on a decades-old anticancer strategy has shown powerful effects against multiple cancer types in a preclinical study from researchers in the Perelman School of Medicine at the University of Pennsylvania. The experimental approach, which uses tiny capsules called small extracellular vesicles (sEVs), could offer an innovative new type of immunotherapy treatment and is poised to move toward more advanced development and testing.
Today in Science Advances, the researchers describe how they used sEVs, which are engineered in the lab from human cells, to target a cell-surface receptor called DR5 (death receptor 5) that many tumor cells have. When activated, DR5 can trigger the death of these cells by a self-destruct process called apoptosis. Researchers have been trying for more than 20 years to develop successful DR5-targeting cancer treatments. The new approach, using engineered sEVs to target DR5, outperformed DR5-targeting antibodies, which have been considered a leading DR5-targeting strategy. The sEVs were efficient killers of multiple cancer cell types in lab-dish tests, and blocked tumor growth in mouse models, enabling much longer survival than DR5-targeting antibodies.
"This new strategy has a number of advantages compared to previous DR5-targeting strategies and other anticancer immunotherapies, and after these encouraging preclinical results, we're developing it further for human clinical trials," said senior author Xiaowei "George" Xu, MD, PhD, a professor of Pathology and Laboratory Medicine, and member of the Tara Miller Melanoma Center in Penn Medicine's Abramson Cancer Center. "We've seen that many patients have benefited from advances in cancer immunotherapy but know there's more to work to do. This is our motivation for seeking new strategies for cellular therapies, particularly in solid tumor cancers, like melanoma, where current immunotherapies only work for about half of patients."
A better way to target DR5
The DR5 death receptor appears to have evolved, at least in part to destroy cells that are malignant, damaged. Although DR5 has seemed an attractive target for cancer treatments, those developed so far haven't been successful in controlling tumor growth. Xu and his team used extracellular vesicles to target DR5 because these nano-sized capsules—about a million times smaller than a T cell—are naturally produced and secreted by virtually all cells. Extracellular vesicles carry molecules that can deliver messages to surrounding cells.
For this application, the team used sEVs made by natural killer (NK) cells, a type of immune cell that frequently has a cancer-fighting role. NK-derived sEVs are good at infiltrating tumors and typically contain molecules that are toxic to tumor cells. Xu and his team engineered the NK sEVs so that they have an antibody fragment that strongly binds to and activates DR5.
In lab-dish experiments, the sEVs specifically move towards and bind to DR5 and quickly killed cancer cell types that have high levels of DR5 expression, including melanoma, liver and ovarian cancer cells. In experiments with mouse models of melanoma, breast and liver cancers, the sEVs strongly suppressed tumor growth and prolonged survival.
Reversing tumor immunosuppression
Xu and his team observed in their experiments that the sEVs packed other antitumor punches: they attacked other DR5-expressing cells called cancer-associated fibroblasts and myeloid-derived suppressor cells, which tumors use to create an immune-suppressive environment around themselves. The sEVs also stimulated T cells, giving another boost to anticancer immune activation. Overall, sEVs apparent ability to disrupt the immunosuppressive environment suggests that they might succeed in solid tumors, where the hostile tumor microenvironment has proved challenging for many forms of immunotherapy.
Xu noted that sEVs can be manufactured and stored relatively easily, making them a potential "off-the-shelf" therapy that could be given to any patient and would not require retrieving cells from each patient, as is the case with other personalized cellular therapies.
Next, the team plans to refine the manufacturing process to scale production for clinical-grade sEVs and conduct safety studies to prepare for human clinical trials.
The study was funded by the National Institutes of Health (CA258113, CA261608, CA114046, CA284182). A patent application for this technology has been filed on behalf of the University of Pennsylvania.
