In a first, immune therapy tames mutation in colon and pancreatic cancers

Celine Ryan learned about her deadly gene mutation the hard way, by having metastatic colon cancer that spread to her lungs, setting her on a desperate quest to qualify for an experimental immune-boosting therapy at the National Cancer Institute.

Mutations in KRAS genes are  believed to cause nearly half of colon cancers and almost all pancreatic cancers. Until now, efforts to develop a therapy that targets mutant KRAS have failed; researchers call it "undruggable."

That's why Ryan's current cancer-free status is so remarkable. The National Cancer Institute's therapy, made with the suburban Detroit woman's own T cells, gradually eradicated six KRAS-driven tumors in her lungs. A seventh tumor grew bigger, but when it was surgically removed and analyzed, researchers discovered the tumor cells had evolved a new mutation that enabled them to hide from the T cell therapy.

Ryan's is a solitary case, but the promise it holds made it worthy of a report in the prestigious New England Journal of Medicine this week.

"This shows T cells can potentially be applied to almost any cancer," said senior author Steven A. Rosenberg, a surgeon and immunotherapy pioneer at NCI.

Another immunotherapy pioneer, the University of Pennsylvania's Carl June, wrote an editorial in the journal that concluded, "The ability to target gatekeeper mutations with engineered T cells has promise for the treatment of a wide variety of cancers."

The big question, June wrote in an email, is whether the success with a single patient can be repeated: "If  this result becomes reproducible, then it is extremely important."

For Ryan,  50, a mechanical engineer from Rochester Hills, Mich., who set aside her career to home-school her five children, the four-year cancer odyssey has morphed into a cause. Now she is using her hard-won knowledge to try to help other patients.

"I'm just so thankful to God and Dr. Rosenberg and the NCI and the friends who helped me," she said. "But now that I'm hooked into the colon cancer community, it's another emotional roller coaster."

'Bar-code' of molecules

The immune system tolerates malignant cells because they arise from healthy cells. The NCI clinical trial is built on fact that some T cells — not a lot — are naturally and powerfully intolerant. They are able to infiltrate tumors by targeting the malignant cells' unique markers, called antigens.

Isolating these "tumor infiltrating lymphocytes," or TILs, from the patient's fresh tumor samples and identifying the target antigens is not easy. The TILs also have to be multiplied by the billions in the lab before being given back to the patient. Still, Rosenberg's team has successfully used TILs to achieve long-lasting, complete remissions in patients with metastatic melanoma.

While TILs are difficult to identify, they are exquisitely precise in their attack because the antigen they home in on is so distinctive and complex —  June calls it a "bar code" of molecules. This precision reduces the chance that the TILs will accidentally target healthy cells or send the immune system into overdrive. Both of those problems have been seen with T cells that are genetically engineered to force them to recognize a particular antigen, the approach that June's team has used with great success in blood cancers.

So far, the NCI team has treated 12 patients with metastatic gastrointestinal cancers using TILs that targeted various tumor antigens.

Two patients, including Ryan, had dramatic tumor regressions, Rosenberg said.

One patient who did not respond had the same KRAS mutation as Ryan, but received a vastly lower dose of the tumor-infiltrating cells.

"One of the exciting aspects of the therapy is that T lymphocytes are long-lived; they live almost as long as we do," Rosenberg said. "TILs now make up almost 10 percent of Celine's circulating cells. They are surviving. They were at undetectable levels before we gave them to her."

'No Evidence of Disease'

Still, it was conventional, invasive surgery that saved Ryan last April, when one KRAS-driven tumor developed a new mutation that evaded the therapy.

"They had to take the lower left lung lobe to get rid of the tumor," she recalled. "I had to do lots of lung function tests to make sure I was healthy enough to undergo it. I was just so thankful that they didn't say, 'Sorry, you're back to progressive disease.' When I woke up in the ICU, I was in so much pain, but I knew I was 'No Evidence of Disease.'"

Ryan's relative youth and good health helped her all along, but also delayed her diagnosis. Colon cancer screening is recommended beginning at age 50. She was 47 when she began having symptoms, notably fatigue, frequent urination, and bloody stools.

"I changed my diet, cut out the sugar and flour. I started walking two miles a day," she recalled. "I'm an expert at rationalizing. Cancer was the last thing on my mind. And there is no colon cancer in my family history that I know of."

By the time she went in for a colonoscopy — at her husband Patrick's insistence — a large tumor had spread to her bladder and lymph nodes. She had surgery, six months of chemotherapy, and radiation. She also discovered an online patient forum where terms like "KRAS" and "T cells" were part of the vernacular.

When it became clear that "spots" on her lungs were cancer, she rejected her oncologist's recommendation of more chemo: "I said I wanted to try immunotherapy."

On her 49th birthday, she began the arduous, iffy process of being evaluated for the NCI trial. She was initially deferred because the tumors that could be readily removed were too small to provide enough malignant tissue.

"How often do you hear a cancer patient say, 'Boo hoo, my tumors are too small,'" she said with a chuckle. "But I knew they would probably grow."

In July 2015, she underwent a week of chemotherapy to wipe out immune cells that might interfere with her TILs,  then 148 billion of them were dripped into a vein.

Now, she mourns the new friends she has lost to colon cancer.  But she rejoices that she and family will celebrate her birthday later this month.

"When I was diagnosed, one of my first thoughts was, 'I'm not even going to make it to 50,"  she recalled. "Fifty was great. Fifty-one is even better."