Ken Shefveland’s body was swollen with cancer, treatment after treatment failing until doctors gambled on a radical approach: They removed some of his immune cells, engineered them into cancer assassins and unleashed them into his bloodstream.
Immune therapy is the hottest trend in cancer care and this is its next frontier – creating “living drugs” that grow inside the body into an army that seeks and destroys tumours.
Supercharged immune cells
Looking in the mirror, Shefveland saw “the cancer was just melting away”. A month later doctors at the Fred Hutchinson Cancer Research Center couldn’t find any signs of lymphoma in the Vancouver, Washington, man’s body.
“Today I find out I’m in full remission – how wonderful is that?” said Shefveland with a wide grin, giving his physician a quick embrace.
This experimental therapy marks an entirely new way to treat cancer – if scientists can make it work, safely. Early-stage studies are stirring hope as one-time infusions of supercharged immune cells help a remarkable number of patients with intractable leukaemia or lymphoma.
There have been other cancer treatment successes recently, like Xeloda, which, in a study, improved the odds of survival. It cut patients’ risk of relapse or death by 30% over five years.
In another approach, German researchers are presenting a “Trojan horse” method of attacking cancer, sneaking virus impersonators into the human body to unleash an anti-tumour immune offensive.
“It shows the unbelievable power of your immune system,” said Dr David Maloney, Fred Hutch’s medical director for cellular immunotherapy who treated Shefveland with a type called CAR-T cells.
New cellular immunotherapy approach
“We’re talking, really, patients who have no other options, and we’re seeing tumours and leukaemias disappear over weeks,” added immunotherapy scientific director Dr Stanley Riddell. But, he acknowledges that there’s still lots to learn.
T cells are key immune system soldiers. But cancer can be hard for them to spot, and can put the brakes on an immune attack. Today’s popular immunotherapy drugs called “checkpoint inhibitors” release one brake so nearby T cells can strike. The new cellular immunotherapy approach aims to be more potent: Give patients stronger T cells to begin with.
Currently available only in studies at major cancer centres, the first CAR-T cell therapies for a few blood cancers could hit the market later this year. The Food and Drug Administration is evaluating one version developed by the University of Pennsylvania and licensed to Novartis, and another created by the National Cancer Institute and licensed to Kite Pharma.
CAR-T therapy “feels very much like it’s ready for prime time” for advanced blood cancers, said Dr Nick Haining of the Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard, who isn’t involved in the development.
Now scientists are tackling a tougher next step, what Haining calls “the acid test”: Making T cells target far more common cancers – solid tumours like lung, breast or brain cancer. Cancer kills about 600 000 Americans a year, including nearly 45 000 from leukaemia and lymphoma.
According to data from the National Cancer Registry (NCR), South African males have an overall age standardized incidence rate of cancer of 135.89 per 100,000 and a lifetime risk of developing cancer of 1 in 7, whereas South African females have an age standardized incidence rate of 115.53 per 100,000 and an lifetime risk of developing cancer of 1 in 8.
Potentially life-threatening side effects
“There’s a desperate need,” said NCI immunotherapy pioneer Dr Steven Rosenberg, pointing to queries from hundreds of patients for studies that accept only a few.
For all the excitement, there are formidable challenges.
Scientists still are unravelling why these living cancer drugs work for some people and not others.
Doctors must learn to manage potentially life-threatening side effects from an overstimulated immune system. Also concerning is a small number of deaths from brain swelling, an unexplained complication that forced another company, Juno Therapeutics, to halt development of one CAR-T in its pipeline; Kite recently reported a death, too.
And, made from scratch for every patient using their own blood, this is one of the most customised therapies ever and could cost hundreds of thousands of dollars.
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“It’s a Model A Ford and we need a Lamborghini,” said CAR-T researcher Dr Renier Brentjens of New York’s Memorial Sloan Kettering Cancer Center, which, like Hutch, has a partnership with Juno.
‘Your imagination can run wild’
In Seattle, Fred Hutch offered a behind-the-scenes peek at research underway to tackle those challenges. At a recently opened immunotherapy clinic, scientists are taking newly designed T cells from the lab to the patient and back again to tease out what works best.
“We can essentially make a cell do things it wasn’t programmed to do naturally,” explained immunology chief Dr Philip Greenberg. “Your imagination can run wild with how you can engineer cells to function better.”
The first step is much like donating blood. When leukaemia patient Claude Bannick entered a Hutch CAR-T study in 2014, nurses hooked him to a machine that filtered out his white blood cells, including the T cells.
Technicians raced his bag of cells to a factory-like facility that’s kept so sterile they must pull on germ-deflecting suits, booties and masks just to enter. Then came 14 days of wait and worry, as his cells were reprogrammed.
Bannick, 67, says he “was almost dead”. Chemotherapy, experimental drugs, even a bone marrow transplant had failed, and “I was willing to try anything.”
The goal: Arm T cells with an artificial receptor, a tracking system that can zero in on identifying markers of cancer cells, known as antigens. For many leukaemias and lymphomas, that’s an antigen named CD19.
Targeting different antigens
CAR-Ts cause collateral damage, killing some healthy white blood cells, called B cells, along with cancerous ones because both harbour the same marker. Finding the right target to kill solid tumours but not healthy organ tissue will be even more complicated.
“You can live without some normal B cells. You can’t live without your lungs,” Riddell explained.
Early studies against solid tumours are beginning, targeting different antigens. Time-lapse photos taken through a microscope in Riddell’s lab show those new CAR-T cells crawling over aggressive breast cancer, releasing toxic chemicals until tumour cells shrivel and die.
CARs aren’t the only approach. Researchers also are trying to target markers inside tumour cells rather than on the surface, or even gene mutations that don’t form in healthy tissue.
“It’s ironic that the very mutations that cause the cancer are very likely to be the Achilles heel,” NCI’s Rosenberg said.
The hope of any cancer patient
And studies are beginning to test CAR-Ts in combination with older immunotherapy drugs, in hopes of overcoming tumour defences.
If the FDA approves Novartis’ or Kite’s versions, eligible leukaemia and lymphoma patients would be treated at cancer centres experienced with this tricky therapy. Their T cells would be shipped to company factories, engineered, and shipped back. Gradually, more hospitals could offer it.
Because only certain patients would qualify for the first drugs, others would have to search for CAR-T studies to try the treatment. A drug industry report lists 21 CAR-T therapies in development by a dozen companies.
“This is the hope of any cancer patient, that if you stay in the game long enough, the next treatment’s going to be just around the corner,” said Shefveland, the Hutch patient.
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