Reprogrammed cells attack and dominate deadly cancer in a woman

Researchers managed to tame pancreatic cancer in a woman whose disease was very advanced and after other forms of treatment had failed.

The experiment that helped her is complex and highly personalized, and not immediately applicable to most cancer patients. Another patient with a pancreatic tumor who received the same treatment did not respond and died of the disease.

However, the leading journal The New England Journal of Medicine published a report of the study on Wednesday (1st).

Dr. Eric Rubin, the journal’s editor-in-chief, called the proof-of-concept experiment “an important step on the way” to developing similar treatments that could be applicable to lung, colon and other cancers.

The experiment involved genetically reprogramming the patient’s T cells, a type of white blood cell in the immune system, so that they could recognize and kill cancer cells. The technique was developed by doctors Eric Tran and Rom Leidner, from the Earle A. Chiles Research Institute, a division of the Providence Cancer Institute, in Portland, Oregon (USA).

To turn a cancer patient’s T cells into a living drug, the researchers had to overcome serious challenges. Pancreatic cancer is one of the most difficult to treat. While new treatments have allowed patients with other cancers to live longer and have a better quality of life, pancreatic cancer has stubbornly resisted these advances. Less than 10% of patients live more than five years.

For most patients, said Dr. William Jarnagin, a pancreatic cancer specialist at Memorial Sloan Kettering Cancer Center who was not involved in the current experiment, the cancer has already spread by the time it is discovered. Even when tumors are located in the pancreas and surgically removed, about 85% of patients experience recurrences.

“Our treatments are not working,” Jarnagin said.

The technique described in the new paper “is not ready to use,” Dr. Tran said. He added that “specialized facilities and expertise are needed to manufacture T cells.”

But, according to Leidner, “the beauty of it” is that the reprogrammed T cells only attack cancer cells. Other cells are left alone.

The first problem with trying to entice T cells to kill cancer cells is that the mutated proteins that promote cancer growth are hidden inside the cells.

However, there is a hint to the immune system that the cancer cells are abnormal. They contain fragments of mutated cancer proteins on their surface, “like molecular breadcrumbs,” Leidner said. The challenge was getting the T cells to “see” these crumbs.

The solution used was to collect the patient’s own T cells and genetically modify them in the laboratory to recognize and attack these pieces of mutant proteins. Then the T cells were infused back into the patient.

In this case, the target was the mutated KRAS protein, which is involved in 25% of all cancers, including about 95% of pancreatic cancers, 40% of colon cancers, and a third of lung cancers.

“People have been trying to target KRAS immunologically for over 20 years,” said Dr. Robert Vonderheide, a pancreatic cancer specialist and director of the Abramson Cancer Center at the University of Pennsylvania.

The mutated KRAS gene “is such a good target,” said Vonderheide, that killing cancer cells by attacking cells with KRAS mutations has “important implications.”

But the encouraging result comes with some real caveats. To begin with, it is unclear why the other patient who died did not respond to therapy.

Dr Elizabeth Jaffee, a pancreatic cancer specialist at Johns Hopkins Medicine, also highlighted the location of the patient’s metastases, or where the cancer has spread. The metastases appeared only in the patient’s lungs. Most patients with pancreatic cancer have liver metastases, which are more difficult to treat.

“I’d like to see the liver damage go away,” Jaffee said.

Kathy Wilkes, the patient who was successfully treated, is 71 years old and lives in Ormond-by-the-Sea, Florida. It’s too early to know if the cancer will come back. Wilkes’ was serious.

“This lady had all the treatments available and they were failing,” said Jarnagin, who did not treat Wilkes but reviewed her case. Usually, in these cases, the cancer develops resistance to any further treatments.

“For most in this situation, the cancer will win — soon,” he said.

Wilkes first noticed symptoms that were later attributed to pancreatic cancer in 2015. She was tired, lethargic and had bouts of intense pain. At first, the tumors did not show up on exams. But in early 2018, a tumor appeared — a 3.5-centimeter mass in the head of his pancreas.

She had chemotherapy followed by a strenuous operation — the Whipple procedure — in which surgeons remove the head of the pancreas, the first part of the small intestine, the gallbladder and the bile duct. Then she had more chemo, followed by radiation and even more chemo.

The cancer had disappeared from the pancreas, but nodules had appeared in her lungs—metastases. Chemotherapy and radiation continued throughout 2018.

“I just put up with it. I certainly wasn’t ready to die,” Wilkes said. “I had this inner voice that said, ‘You can beat this one.'”

She entered an immunotherapy clinical trial in Pittsburgh in 2020. Her tumors shrank at first, but then grew back. She had the genes for her lung metastases sequenced, and when she learned they were being driven by a specific KRAS mutation, she started looking for clinical trials.

He found Tran, a leader in the use of T cells to attack cancer mutations, and called him. Traveling to Oregon for treatment was no problem, she said. She lived in the state and had family there.

On June 14, 2021, her treatment started. A month later, her lung tumors had shrunk by 67% and were too small to biopsy. In September, they seemed to have shrunk further. She had another exam last week, on May 25th. The stains on her lungs hadn’t changed. Perhaps now they consist of dead cells.

“We are cautiously optimistic,” Wilkes said.

She feels great, like her old self, he added.

^{Translated by Luiz Roberto M. Gonçalves}