Therapy flags DNA typos to rev cancer-fighting T cells

Disabled spell-checker identifies patients who may benefit from immune therapy


UNLEASHED  An antibody sold as the drug Keytruda helps turn on cancer-fighting T cells. Tumors (red) can use PD-1 proteins (yellow, orange) to lock onto T cells (white) and shut them down. The antibody blocks PD-1 proteins, freeing T cells to attack the cancer.

Courtesy of Merck & Co.

Mutations that prevent cells from spell-checking their DNA may make cancer cells vulnerable to immunotherapies, a new study suggests.

A type of immune therapy known as PD-1 blockade controlled cancer in 77 percent of patients with defects in DNA mismatch repair — the system cells use to spell-check and fix errors in DNA (SN Online: 10/7/15). The therapy was effective against 12 different types of solid tumors, including colorectal, gastroesophageal and pancreatic cancers, and even tumors of unknown origin, researchers report June 8 in Science.

“Where the tumor started doesn’t matter. What matters is why the tumor started,” says study coauthor Richard Goldberg, an oncologist at West Virginia University Cancer Institute in Morgantown.

People with defective DNA spell-checkers accumulate many mutations in their cells, which can lead to cancer. While mismatch repair errors can spark cancer, they may also be its Achilles’ heel: Some misspellings cause the cancer cells to make unusual proteins that the immune system uses to target tumors for destruction.

Even before treatment, cancer patients in the study had a small number of infection- and tumor-fighting T cells that target these unusual proteins, the researchers found. Treating patients with an antibody called pembrolizumab (sold under the brand name Keytruda) caused these T cells to increase in number, says coauthor Kellie Smith, a cancer immunologist at Johns Hopkins University.

The antibody binds to a protein on the surface of T cells called the PD-1 receptor. Some tumor cells use this receptor to hide from the immune system (SN: 4/1/17, p. 24). Blocking the receptor with the antibody unmasks the tumors. As a result, “immune cells can go to all corners of the body and eradicate tumors,” Smith says. That includes going after notoriously deadly metastatic tumors — ones that have spread from other parts of the body. Once the T cells are primed for action, they may patrol the body for a long time, stopping cancer from taking hold again, Smith says.

All 86 patients in the study had metastatic cancers that had not responded well to other treatments. For 18 patients, the antibody treatment appears to be a complete cure. Their tumors disappeared entirely. After two years of treatment, 11 of those patients were taken off the antibody. Their tumors have not returned even after a median of 8.3 months.

Other patients had tumors that shrank but didn’t disappear, or that remained stable while on — and even after — treatment. Goldberg says scans suggest some of the patients still have tumors, but biopsies show no remaining cancer cells. The “tumors” are really clusters of immune cells that have invaded sites to kill cancer, he says.

Not everyone fared so well. Tumors in five patients initially shrank, but then began to grow again. DNA from three of those people showed that two had developed mutations in the beta 2-microglobulin gene, which helps immune cells track down their targets.

Side effects of the treatment included skin rashes, thyroid problems and diarrhea as the therapy caused the immune system to attack other parts of the body.

Revving up the immune system to combat a wide variety of tumor types may take cancer therapy in a new direction, says Khaled Barakat, a computational scientist at the University of Alberta in Canada, who was not involved in the study. In recent years, scientists have devised drugs to target specific mutations in one type of cancer. “That’s old school,” Barakat says. Immunotherapy “is the future.”

On May 23, the Food and Drug Administration approved pembrolizumab for  cancer patients with mismatch repair mutations for whom other drugs have failed. In the United States, about 60,000 cancer patients each year could be eligible for the immune therapy, the researchers estimate. 

Editor’s note: This story was updated June 21, 2017, to correct the list of side effects of the treatment and to note that it’s not just late-stage cancer patients who might be eligible for immunotherapy.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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