Fred Hutch study: Mangling RNA may extend use of immunotherapy drugs

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Fred Hutch computational biologist Robert Bradley. (Fred Hutch Photo)

Experimental compounds that alter RNA boost the effectiveness of immunotherapy drugs against cancer cells and could potentially extend their use to more patients, suggests a study in mice from the Fred Hutchinson Cancer Research Center.

Immunotherapy drugs known as checkpoint inhibitors, which coax the immune system to turn against a tumor, can yield dramatic, life-saving results in some cancer patients.

But many patients do not respond, and the drugs rarely work for some tumor types, such as breast cancer. The new findings may offer a route to increase the number of treatable patients and tumor types.

The findings build on previous work showing that tumors most susceptible to such drugs are also some of the nastiest, most mutated tumor types. Advanced melanoma is a key example. About half of patients with this highly lethal tumor respond to long-term treatment with checkpoint inhibitors.

One reason melanoma is particularly sensitive to such immunotherapy may be that its DNA is a mess — multiple mutations in the tumor cells encode for a suite of abnormal proteins. Small bits of these abnormal proteins end up on the cell surface, where they are recognized as foreign by the immune system.

The drugs act by giving the immune system a boost, increasing its power to recognize and kill cancer cells. The drugs are called “checkpoint inhibitors” because they turn off molecular “checks” on the immune system, ramping up its activity.

“We normally think of mutations as a bad thing,” said Fred Hutch computational biologist Robert Bradley, co-senior author of the paper, in a Fred Hutch news release. “But once a tumor is there, if it has a lot of mutations it can be a good thing, because it lets us use these new, transformative therapies.”

Some researchers are testing whether drugs that cause DNA damage similarly make cancer cells more responsive to checkpoint inhibitors. But such an approach has drawbacks, such as the possibility of permanently damaging healthy cells, noted Memorial Sloan Kettering physician-scientist Omar Abdel-Wahab. He is the second co-author on the new report, published Thursday in the journal Cell.

In the new study, Bradley and Abel-Wahab turned to RNA, made famous during the pandemic as the building block for the Pfizer and Moderna vaccines. RNA serves as an intermediary between DNA in the production of proteins.

Change the sequence of an RNA molecule and you’ll end up with changes to the protein it encodes. But unlike DNA, RNA is short-lived, so the changes are transient.

Some experimental compounds are known to yield changes in RNA sequences throughout a cell, including two that were the focus of the new study, indisulam and MS023.

The researchers found that indisulam and MS023 induced the production of aberrant proteins by cancer cells, fostering recognition by immune cells. This recognition occurred through a suite of aberrant bits of protein present on the surface of the cells.

In a key experiment, the researchers tested indisulam in mice implanted with a tumor cell type that does not normally respond to checkpoint inhibitors. When they applied indisulam to the mice, tumor growth slowed substantially in response to a checkpoint inhibitor.

The new compounds appear to work by disrupting a tiny cellular machine called the spliceosome, which is involved in accurate production of RNA.

Both drugs are similar to other drugs that do not appear to be toxic in early human studies. The lack of toxicity bodes well for combining the compounds together with immunotherapies for clinical testing in humans, said the researchers, though more preclinical studies are needed.

The researchers are seeking a commercial partner to help move the findings toward the clinic.