Cancer treatment makes leukemia disappear but creates more mysteries

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Doug Olson was feeling a little tired in 1996. When a doctor examined him, she frowned.

“I don’t like the feel of those lymph nodes,” he said, prodding his neck.

She ordered a biopsy. The result was terrifying. She had chronic lymphocytic leukemia, a blood Cancer It primarily affects older people and accounts for about a quarter of new leukemia cases.

“Oh my gosh,” Olson said. “I thought it was over.”

He was only 49 years old and, he said, had always been healthy.

Six years passed without the cancer progressing. Then it started to grow. She had four rounds of chemotherapy, but the cancer kept coming back. She had practically reached the end of the line when her oncologist, Dr. David Porter of the University of Pennsylvania, offered her the opportunity to be among the first patients to try something unprecedented, known as CAR T cell therapy.

In 2010, he became the second of three patients to receive the new treatment.

At the time, the idea of ​​such a therapy “was very much out there,” said Dr. Carl June, principal investigator of the trial at Penn, and had tempered his own expectations that the cells he was providing to Olson as a therapy would survive.

“We thought they would be gone in a month or two,” June said.

Now, a decade later, he reports that his expectations were completely dashed. In an article published Wednesday in Nature, June and her colleagues, Dr. J. Joseph Melenhorst and Porter, report that the CAR T treatment caused the cancer to disappear in two of the three patients in that initial trial. All had chronic lymphocytic leukemia. The big surprise, however, was that even though the cancer seemed long gone, the CAR T cells remained in the patients’ bloodstream, circulating like sentinels.

“Now we can finally say the word ‘cure’ with CAR T cells,” June said.

Although most patients will not fare so well, the results offer hope that for some, their cancer will be beaten.

But the mysteries remain.

The treatment involves removing T cells, white blood cells that fight viruses, from a patient’s blood and genetically modifying them to fight cancer. The modified cells are then re-infused into the patient’s circulation.

In the case of chronic lymphocytic leukemia, the type Olson had, the cancer affected B cells, the cells of the immune system that form antibodies. A patient’s T cells are taught to recognize B cells and destroy them. The result, if the treatment were successful, would be the destruction of all the B cells in the body. Patients would be left with no B cells but no cancer either. They would require regular infusions of antibodies in the form of immunoglobulin infusions.

The therapy has helped many people with blood cancers and has been shown to be especially effective in patients with acute leukemias and other blood cancers. By contrast, those like Olson with chronic lymphocytic leukemia, also known as CLL, have had less success. Among those with that cancer, about one-third to one-fifth go into remission with CAR T therapy, but many whose cancers go away later relapse.

“The question is not just why some patients relapse or are resistant to therapy, but why some patients are cured.” said Dr. John F. DiPersio, chief of the division of oncology at Washington University in St. Louis, who was not involved in the study.

CAR T treatment has also caused serious side effects in some patients, including high fever, coma, dangerously low blood pressure, and even death, although alarming symptoms resolve in most patients. It has not yet worked in people with solid tumors found in conditions such as breast and prostate cancer.

As strange as CAR T’s inability to help most cancer patients is the fate of those modified T cells in cured patients.

The genetic modification involved a subset of T cells known as CD8 cells, which are supposed to actually kill cancer. They are the killers of the immune system.

But killers need helpers, and for CD8 cells, the helpers are another group of T cells known as CD4 cells.

At first, the CD8 cells seemed to be acting exactly as expected in June’s study. The modified CD8 T cells almost immediately killed between 3 1/2 and 7 pounds of cancer cells in Olson’s bodies and the study’s first patient, William Ludwig, who was also cured of his cancer but died last year of COVID-19.

After the CD8 cells did their job, they remained in the blood but unexpectedly turned into CD4 cells. And when the Penn researchers extracted CD4 cells from Ludwig and Olson’s blood, they found that those cells could kill B cells in the lab. CD4 cells had become killers or, DiPersio noted, “at least guardians that can keep tumor cells at bay and undetectable in the patient for years.”

Could CD4 cells remain in the blood without cancer cells to kill? Or were they there because the leukemia hadn’t really disappeared but kept trying to come back, only to be attacked by CD4 cells?

“We can’t find any leukemia cells in Doug,” June said. But, she added, maybe they’re still there in small numbers and emerge, only to be killed by CD4 cells, “like a mole,” she said.

However, he suspects that the CD4 cells are more like guards.

“The leukemia disappeared, but they continue to work,” he said.

Whatever the mechanism, Porter said, the result “is beyond my wildest imagination.”

“Oncologists don’t use words like ‘cure’ lightly or easily or, frankly, very often,” he said. “I guarantee you it is not being used lightly. The patients we treated had very advanced disease,” she noted, adding, “the biggest disappointment is that it doesn’t work all the time.”

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