Researchers at Northeastern University and Beam Therapeutics have developed a new method using base editing to prevent solid tumors from disabling CAR-T cell immunotherapy.
While CAR-T cell therapy has successfully treated blood cancers like leukemia since 2017, the treatment has struggled to penetrate solid tumors, including lung, breast, and kidney cancers.
In a study published in Nature Communications, the team demonstrated that they could use precise gene editing to protect immune cells from the harsh environments found in solid malignancies.
Stephen Hatfield, an assistant professor in pharmaceutical sciences at Northeastern’s Bouvé College of Health Sciences, said the primary obstacle is the low-oxygen environment within solid tumors.
This oxygen-depleted setting produces molecules that essentially turn off the cancer-fighting ability of engineered CAR-T cells.
“We want to fortify CAR-T cells,” Hatfield said. “We want to make them resistant to these immune suppressive mechanisms.”
Overcoming tumor defenses
The research team utilized base editing, a technique that allows for targeted changes to molecular DNA by altering a single nucleotide at a time.
Working with colleagues from Beam Therapeutics, the scientists used a process known as multiplexing to knock out six individual genes, including A2A, PD-1, and TGF beta.
These specific genes act as "negative regulators" that suppress immune function when T cells enter a tumor.
In humanized mouse models, the researchers successfully eliminated the ability of these molecules to suppress the immune function of the cells.
Ryan Murray, a co-author of the study and 2024 Northeastern Ph.D. graduate, noted that the results were particularly successful in treating non-small cell lung cancer.
“The potential is massive,” Murray said, adding that the strategy demonstrates the necessity of attacking multiple parts of a tumor's defenses simultaneously.
According to Hatfield, the base editing approach reduces the amount of genetic manipulation required, which limits potential adverse effects.
Beyond increasing efficacy, the researchers believe this method could enable "off-the-shelf" immunotherapy.
This would allow doctors to provide pre-engineered treatments to patients immediately, rather than waiting for a patient's own cells to be harvested and processed in a lab.