ABOVE: © ISTOCK.COM, Meletios Verras
Exosomes are tiny, fluid-filled sacs that are naturally released from cells into blood and other fluids in the body. These nanoparticles facilitate communication between cells by carrying genetic information and proteins, and have long been considered a promising tool for delivering targeted drugs to specific organs. Now, in a scientific first, cancer researchers have developed multifunctional, engineered exosomes for cancer treatment and tested them in mice.
On their surface, the exosomes display four different types of proteins involved in eliciting an antitumor immune response in humans. The engineered exosomes, called GEMINI-Exos, are described in a paper published in the September 7 issue of Molecular Therapy and open up the possibility of reprogramming native nanocarriers, which are safer and less likely to cause long-term adverse effects than synthetic nanoparticles, in many different ways for personalized immunotherapy.
Sonia Melo, a biochemist at the Institute for Research and Innovation in Health in Portugal, says the novelty of this research lies in combining different molecules on the surface of the exosome, each acting on a different mechanism within the antitumor immune response. This offers the opportunity for simultaneously “tackling more than one front to defeat the enemy”—cancer.
To engineer the therapeutic exosomes, Yong Zhang, a biochemist at the University of Southern California (USC), and his colleagues began by identifying exosomes from human cell cultures by looking for a marker naturally present on their surface, known as CD-9. They isolated the exosomes, then fused the marker on each exosome with four molecules, called PD-1, OX40L, CD3, and EGFR, that regulate the immune response and cancer progression.
To test whether these engineered exosomes aid the immune system, Zhang and his team developed humanized mice by introducing human immune cells into immune-deficient animals. These animals were also injected subcutaneously with human breast cancer cells that grew into tumors. The mice were then injected every other day (six times total) with the engineered exosomes, while the control group received native exosomes.
When the researchers mapped tumor growth in mice treated with GEMINI-Exos for 50 days after tumor inoculation, they found that the treated mice had smaller tumors compared to the control group and a stronger antitumor immune response than mice with native exosomes. “This demonstrated to us that the engineered exosomes can lead to [a] sustainable immune response not only for breast cancer, but many other types of cancers that can be treated through immunotherapy,” says Zhang.
See “The Next Frontier of CAR T-Cell Therapy: Solid Tumors”
While Melo says she believes this work could potentially lead to a breakthroughs in cancer immunotherapy, there are safety concerns with engineering exosomes that need to be considered. These particles contain RNA, she says, and scientists have little control over how the engineering will modify the genetic information inside the exosomes. “I don’t know if I would inject these engineered exosomes in myself if I had cancer because I know how little the system is controlled,” says Melo. “That’s a major drawback of not only this work, but the field itself.”
Zhang agrees that this is a barrier and emphasizes the need for further research to evaluate the therapeutic benefits, as well as any risks posed by fusing other proteins to the CD-9 marker. For now, his group is putting those questions on hold, instead testing the efficacy of engineered exosomes in other types of cancers.
