Turbocharging patients’ T-cells to kill their own cancer

The young surgeon was mystified. A fist-size tumor had been removed from the stomach of his patient 12 years earlier, but his doctors had not been able to cut out many smaller growths in his liver. The cancer should have killed him, yet here he lay on the table for a routine gallbladder operation.

The surgeon, Dr Steven Rosenberg, examined the man's abdominal cavity – but he could find no trace of cancer.

It was 1968. Rosenberg had a hunch he had just witnessed an extraordinary case in which a patient’s immune system had vanquished cancer. Hoping there was an elixir in the man’s blood, Rosenberg got permission to transfuse some of it into a patient dying of stomach cancer. The effort failed. But it was the beginning of a lifelong quest.

“Something began to burn in me,” he would write later, “something that has never gone out”.

Half a century later, Rosenberg, who turns 76 on Tuesday and is chief of surgery at the National Cancer Institute in Bethesda, Maryland, is part of a small fraternity of researchers who have doggedly pursued a dream: turbocharging the body’s immune system so that more cancer patients can experience recoveries like his long-ago patient’s.

Rosenberg, Dr Carl June of the University of Pennsylvania and Dr Michel Sadelain of Memorial Sloan Kettering Cancer Center have been at the forefront of this research for decades, labouring in separate labs in an intense sometimes-co-operative, sometimes-competitive pursuit to bring to fruition a daring therapy that few colleagues believed would work.

The technique, known as cell therapy, gives each patient an individualised and souped-up version of their own immune system, one that “works better than nature made it”, as June puts it.

The patient's T-cells, the soldiers of the immune system, are extracted from the patient's blood, then genetically engineered to recognise and destroy cancer. The redesigned cells are multiplied in the laboratory, and millions or billions of them are put back into the patient's bloodstream, set loose like a vast army of tumour assassins.

This is an unusual pharmaceutical – a drug that is alive and can multiply once inside the body. June calls these cells “serial killers”. A single one can destroy up to 100,000 cancer cells.

Radical

This radical, science fiction-like therapy differs sharply from the more established type of

immunotherapy

, developed by other researchers. Those off-the-shelf drugs, known as checkpoint inhibitors, release a molecular brake on the immune system, freeing it to fight the cancer much as it fights infections by bacteria or viruses.

Cell therapy, in contrast, is brewed specially for each patient, one of the many challenges the field faces in broadening its use. So far, the number of patients treated with cell therapy is in the range of hundreds, not thousands. And for now it works only for certain types of blood cancers, not common malignancies like breast and lung cancer.

Researchers are also still working out how to control potentially lethal side effects. Just recently, a clinical trial was briefly halted after three patients died of brain swelling.

Still, cell therapy has produced complete remissions in some patients who were out of treatment options, stirring excitement among doctors and patients and setting off a race among companies to bring the treatments to market.

Getting to this point has taken decades of painstaking work, with many false starts and setbacks.

Carl June turned to working with T-cells at the Naval Medical Research Institute in the mid-1980s. He and a colleague, Bruce Levine, found a way to multiply T-cells in huge numbers outside the body, a method still used today.

But when his wife, Cindy, the mother of the couple’s three children, developed ovarian cancer in 1996, June’s research turned personal. (Cindy June died in 2001.)

"A lot of other scientists would have been disillusioned by the failure, in his case the personal tragedy," said Sean Parker, the internet billionaire who is funding some of Carl June's work. Instead, June, who had moved to the University of Pennsylvania, stopped treating patients, and devoted himself to creating cell therapies for cancer.

Experimenting

In the 1980s, scientists began experimenting with

gene therapy

, putting new genes into cells of the body to treat disease. Michel Sadelain, while still a graduate student studying immunology at the University of Alberta, told colleagues that he thought the technique could be used to supercharge T-cells to fight cancer.

After earning his PhD, Sadelain headed for the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to learn how to do gene therapy, using disabled viruses that could not cause disease to deliver genes into cells.

He then moved to Sloan Kettering. In 2003, he and his colleagues – including his partner and now wife, Isabelle Rivière – showed that genetically engineered T-cells could eradicate certain cancers in mice.

How is this done? To fight cancer, T-cells have to recognise cancerous cells. Each T-cell in the body has unique receptors, sort of like claws that jut out from its surface. T-cells patrol the body looking for protein fragments that indicate a cell might be infected by a bacterium or virus. If one of its claws latches on to such a fragment, the T-cell destroys the cell displaying it.

But cancer cells are mutated versions of the body’s own cells, not outsiders. T-cells do not always recognise them as something to kill. So scientists like Sadelain decided to put a new claw on the T-cells, one that could recognise cancer by latching onto a telltale protein on cancer cells.

But the claw was not enough. Once a claw binds to a target protein, it needs a molecule to signal the T-cell to go into killing mode. Yet another signal helps sustain the killing. The DNA instructions for all three components are inserted into the patient’s T-cells.

Concoction

Since this concoction is part antibody and part T-cell, it is called a chimera, like the monster of Greek mythology that is part lion, part goat and part serpent. The claw is called a receptor and the protein it binds to on the cancer cell, the target, is called an antigen. So the whole construct is called a chimeric antigen receptor, or CAR, and the use of it to treat cancer is called CAR T-cell therapy, or CAR-T.

Rosenberg and colleagues published first, in the journal Blood in 2010. They described a single patient with lymphoma whose tumors shrank after treatment. (The patient later received more therapy, and has been free of cancer since.)

But the approach really attracted attention the next year when June reported that two of three patients with chronic lymphocytic leukemia went into complete remission.

Bill Ludwig, a retired captain in the New Jersey Department of Corrections, had already paid for his funeral when he started treatment in August 2010. Once his genetically engineered T-cells were unleashed in his system, Ludwig’s lungs started to fail, his legs ballooned to twice their size, his blood pressure dropped and he began hallucinating.

When he emerged from the ordeal, doctors searched for cancer. Detecting none, they ordered another test, certain of error. But there was no mistake. Five pounds of tumor had been destroyed.

‘Make up for lost time’

Ludwig, now 71, and his wife bought an RV. “We’re trying to make up for lost time,” he said. He has celebrated the high school graduations of five grandchildren and welcomed his first great-grandchild.

As for June, Ludwig said: “It’s hard to describe someone who basically saved your life. He lost the one he loved, and turned around and saved me years later.”

Yet for all the excitement, there are reasons for caution. The CAR therapy works now only for patients with some B-cell lymphomas and leukemias, which account for only about 80,000 of the 1.7 million cases of cancer diagnosed in the United States each year. It has not been successfully used to treat malignancies of the lungs, breast, prostate, colon or other organs.

“The solid tumors that kill over 90 per cent of people do not respond to anything we have now,” Rosenberg said.

The big thrust now is to expand the use of cell therapy to additional types of cancer.

It might turn out that the best target for each patient will be unique to that person. Scientists are now experimenting with using DNA sequencing and other techniques to find the best mutated protein in each person’s tumor at which to aim the claw.

“Think of how dauntingly personalised this is,” Rosenberg said. “We are using their own cells to treat a unique mutation in their own tumor.”

Many other improvements are on the runway.

"We're in the Model T version of the CAR now," said Levine, now the director of the cell production facility at the University of Pennsylvania. "What's coming along are Google CARs and Tesla CARs." – Copyright New York Times 2016