Nanometer-sized particles trigger self-destruction of tumor cells

A new twist on a decades-old anticancer strategy showed powerful effects against several types of cancer in a preclinical study led by researchers at the University of Pennsylvania’s Perelman School of Medicine. 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 into more advanced development and testing.

The work is published in the journal Scientific advances.

The researchers describe how they used sEVs, which are made in the laboratory 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 through a self-destructive process called apoptosis.

Researchers have been trying for more than 20 years to successfully develop cancer treatments targeting DR5. The new approach, using engineered sEVs to target DR5, outperformed DR5-targeting antibodies, which have been considered a leading DR5 targeting strategy. sEVs were effective killers of several types of cancer cells in laboratory tests and blocked tumor growth in mouse models, allowing much longer survival than antibodies targeting DR5.

“This new strategy has a number of advantages over previous DR5 targeting strategies and other cancer immunotherapies, and following these encouraging preclinical results, we are developing it further for human clinical trials,” said lead author Xiaowei “George” Xu, MD. , Ph.D., professor of pathology and laboratory medicine and member of the Tara Miller Melanoma Center at the Abramson Cancer Center at Penn Medicine.

“We have seen that many patients have benefited from advances in cancer immunotherapy, but we know there is still more to do. This is our motivation to seek new cell therapy strategies, particularly in solid tumor cancers, such as melanoma, where current immunotherapies only work for about half of patients.

A better way to target DR5

The death receptor DR5 appears to have evolved, at least in part, to destroy malignant or damaged cells. Although DR5 appears to be an attractive target for cancer treatments, those developed so far have failed to control tumor growth. Xu and his team used extracellular vesicles to target DR5 because these nanometer-sized capsules, about a million times smaller than a T cell, are produced and secreted naturally by virtually all cells. Extracellular vesicles carry molecules capable of transmitting messages to surrounding cells.

For this application, the team used sEVs made by natural killer (NK) cells, a type of immune cell that frequently plays a role in fighting cancer. NK-derived sEVs are effective at infiltrating tumors and usually contain molecules toxic to tumor cells. Xu and his team engineered the NK sEVs so that they have an antibody fragment that binds strongly to and activates DR5.

In laboratory experiments, sEVs specifically travel to and bind to DR5 and rapidly kill types of cancer cells that have high levels of DR5 expression, including melanoma, liver and ovarian cancer cells. In experiments with mouse models of melanoma, breast and liver cancer, sEVs strongly suppressed tumor growth and prolonged survival.

Reversing tumor immunosuppression

Xu and his team observed in their experiments that sEVs contained other anti-tumor attacks: they attacked other DR5-expressing cells, called cancer-associated fibroblasts and myeloid-derived suppressor cells, which tumors use to create an immunosuppressive environment around them.

sEVs also stimulated T cells, providing further impetus to anticancer immune activation. Overall, the apparent ability of sEVs to disrupt the immunosuppressive environment suggests that they may be successful in solid tumors, where the hostile tumor microenvironment has proven a challenge for many forms of immunotherapy.

Xu noted that sEVs can be made and stored relatively easily, making them a potential “off-the-shelf” therapy that could be administered to any patient and would not require harvesting cells from each patient, as is the case with other personalized cell therapies. .

Next, the team plans to refine the manufacturing process to increase production of clinical-grade sEVs and conduct safety studies to prepare for human clinical trials.