Claire Mutchnik

How can we enable immune cells to selectively recognize and kill tumors? Yale scientists may have found an answer.

Published in the Journal of Experimental Medicine on Oct. 10, a Yale-led study reported the discovery of a method in which an RNA molecule, when injected into the body of mice, can trigger immune cells to reduce tumor size and prevent the spread of tumor to other tissues.

The scientists found that an intravenous injection of a special RNA molecule with a unique structure can be recognized by the body’s immune cells as a viral infection. This allows the immune system to selectively target tumors without harming normal cells. The new therapy sidesteps a long-standing problem in cancer research, since most treatments that kill tumor cells are often toxic to healthy cells.

“We are fooling the immune system into thinking that a viral infection has occurred in the tumor,” said Akiko Iwasaki, professor of immunology at the School of Medicine and senior author of the paper.

The study utilizes the molecular pathway of the immune response called the RIG-I pathway, which is the immune system’s way of recognizing viral RNA in the cytosol. According to Iwasaki, this method takes advantage of the immune system’s ability to fight viral infections by injecting tumors with an RNA molecule.

Because RNA is one of the most diverse biological molecules in existence, the process of identifying this particular RNA molecule required extensive understanding of RNA structural biology, according to Iwasaki.

Anna Pyle, professor of molecular, cellular and developmental biology and an RNA expert, collaborated with Iwasaki in determining plausible structures for the RNA molecule. Pyle identified this RNA’s structure and optimized it for its binding ability to the RIG-I molecule that recognizes the RNA as a viral infection.

Iwasaki said that after an injection of this RNA molecule, mice become immune to tumor relapse. Creating this immunological memory could have powerful implications for cancer patients, since relapses are a significant challenge to current therapeutic options, according to Iwasaki.

She said the RNA molecule developed by the Yale researchers can be delivered through blood circulation with help from an FDA-approved reagent called Jetpl, which added promise to its safety and efficacy.

First author and Yale research scientist Xiaodong Jiang said future research will determine RNA dosage for targeting specific tumors.

“We would like to do clinical trials, and to do this, we will need to get [FDA] approval,” said Jiang. “Since we already have data on melanoma and colon cancer models, we are hoping to test for other tumor models like breast cancer or lung cancer.”

Iwasaki added that testing for potential toxicity of the RNA molecule can be followed up with trials with patients who have exhausted all other treatment options including chemotherapy and radiation.

As of 2018, the FDA approval rate for a preclinical study to progress to a Phase 1 clinical trial is 32 percent.

 

Viola Lee | kyounga.lee@yale.edu