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

Fred Hutch computer biologist Robert Bradley. (Fred Hutch photo)

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

Immunotherapeutic agents called checkpoint inhibitors, which induce the immune system to turn against a tumor, can have dramatic, life-saving results in some cancer patients.

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

The results build on previous work showing that tumors most susceptible to such drugs are also some of the most vicious and mutated tumor types. An important example is advanced melanoma. About half of the patients with this highly fatal tumor respond to long-term treatment with checkpoint inhibitors.

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

The drugs work by strengthening the immune system and increasing its ability to recognize and kill such mutilated cells. The drugs are called “checkpoint inhibitors” because they switch off molecular “checks” of the immune system and increase its activity.

“We usually think mutations are a bad thing,” Fred Hutch’s computer biologist Robert Bradley, the newspaper’s co-senior writer, said in a Fred Hutch press release. “But once a tumor is there, it can be good if it has many mutations, because it enables us to use these new, transformative therapies.”

Some researchers are testing whether drugs that cause DNA damage similarly make cancer cells more susceptible to checkpoint inhibitors. However, such an approach has drawbacks, such as the potential to permanently damage healthy cells, noted Omar Abdel-Wahab, a medical professional and scientist at Memorial Sloan Kettering. He is the second co-author of the new report, which was published in Cell magazine on Thursday.

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

When you change the sequence of an RNA molecule, you will change the protein it encodes. Unlike DNA, however, RNA is short-lived, so the changes are temporary.

Some experimental compounds are known to cause changes in RNA sequences in 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, which promoted recognition by immune cells. This recognition was due to a number of aberrant pieces of protein that were present on the surface of the cells.

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

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

Both drugs are similar to other drugs that appear non-toxic in early human studies. The lack of toxicity is a good sign of combining the compounds with immunotherapies for clinical testing in humans, the researchers said, although more preclinical studies are needed.

The researchers are looking for a commercial partner to bring the results to the clinic.

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