Scientists at the University of Ottawa, The Ottawa Hospital, and collaborators say they have developed a virus that infects and kills cancer cells without harming normal cells, while also sending out signals to prepare nearby uninfected cancer cells for viral attack.
Their new study (“Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy”), published in Nature Communications,” demonstrates that this approach can shrink tumors and significantly prolong survival in several cancer models in mice.
The strategy relies on extracellular vesicles, tiny particles that pinch off from a cell and fuse with other cells. The research team created a virus that causes infected cells to produce extracellular vesicles filled with a specific RNA that blunts the antiviral defenses of nearby cancer cells. They found that this novel virus can work with other forms of immunotherapy, as well as with small-molecule drugs, to enhance cancer-killing even further.
“Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumor on multiple fronts. Oncolytic or “cancer-killing” viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer,” write the investigators.
“In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodeling, as an important player in resistance to OV replication.
“Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumor cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo.
“Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.”
“Cancer cells are constantly evolving new ways to evade our therapies, so we designed this therapy to target cancer on multiple fronts at the same time,” said senior author Carolina Ilkow, PhD, assistant professor in the faculty of medicine and senior scientist at The Ottawa Hospital. “We believe these observations are transformative for the fields of oncolytic viruses, miRNA therapeutics and exosome-based therapies.”
The researchers note that while many groups are investigating therapies based on RNA and extracellular vesicles, these therapies are much more difficult to manufacture and store than viral therapies. This new viral technology could have a broad impact, as it provides an easy and targeted way to “manufacture” and deliver RNA therapeutics and extracellular vesicles right inside the patient, rather than in a lab.
This research used a Maraba virus that has been tested in human clinical trials as a cancer therapy, but the strategy could be applied to other viruses as well. The researchers used several different models of pancreatic cancer (mouse and human) as well as models of ovarian, breast, kidney, and skin cancer.
In addition to the researchers at The Ottawa Hospital and the University of Ottawa, the team includes researchers from the University of Leeds, the University of Tabuk in Saudi Arabia, the University of Oxford, the University of California Los Angeles, the University of Ottawa Heart Institute, and Mount Sinai University.