Courtesy of New Scientist:
Engineer immune cells to recognise tumour cells they would otherwise overlook and they call a halt to cancers we thought were incurable
Editorial: “Beating cancer by blocking off its escape routes”
“THE results are holding up very nicely.” Cancer researcher Michel Sadelain is admirably understated about the success of a treatment developed in his lab at the Memorial Sloan-Kettering Cancer Center in New York.
In March, he announced that five people with a type of blood cancer called acute lymphoblastic leukaemia (ALL) were in remission following treatment with genetically engineered immune cells from their own blood. One person’s tumours disappeared in just eight days.
Sadelain has now told New Scientist that a further 11 people have been treated, almost all of them with the same outcome. Several trials for other cancers are also showing promise.
What has changed is that researchers are finding ways to train the body’s own immune system to kill cancer cells. Until now, the most common methods of attacking cancer use drugs or radiation, which have major side effects and are blunt instruments to say the least.
The latest techniques involve genetically engineering immune T-cells to target and kill cancer cells, while leaving healthy cells relatively unscathed.
T-cells normally travel around the body clearing sickly or infected cells. Cancer cells can sometimes escape their attention by activating receptors on their surface that tell T-cells not to attack. ALL affects another type of immune cell, the B-cells, so Sadelain takes T-cells from people with ALL and modifies them to recognise CD19, a surface protein on all B-cells – whether cancerous or healthy. After being injected back into the patient, the reprogrammed T-cells destroy all B-cells in the person’s body. This means they need bone marrow transplants afterwards to rebuild their immune systems. But because ALL affects only B-cells, the therapy guarantees that all the cancerous cells are destroyed.
A team led by Carl June from the University of Pennsylvania in Philadelphia used the same technique to treat several children with ALL, including Emily Whitehead (pictured right). He will present the latest results in December at the American Society of Hematology meeting in New Orleans. He will also report on the progress of adults with chronic lymphocytic leukaemia, who were treated with a similar technique that targeted B-cells, including some who are still in remission three years later.
Other teams are developing more targeted forms of immunotherapy, engineering T-cells to recognise markers that only cancer cells possess. What gives T-cells this potential, is that they can home in on what is going on inside cells, as well as outside. This vastly expands the range of potential targets.
Inside all cells, proteins are routinely broken apart and the resultant debris of tiny fragments called peptides are ferried to the cell surface by molecules called human leukocyte antigens (HLAs). These peptides then get inspected by passing T-cells – a process that allows the immune system to routinely check what is going on inside cells.
If the peptide fragment looks normal, the T-cell gives the OK and moves on, but if it is abnormal, perhaps because of a viral invasion or cancer mutation, the T-cell will destroy the cell (see diagram). But sometimes, for unknown reasons, mutated cancer peptides are seen as healthy by T-cells and are ignored.
So now, researchers are reprogramming T-cells to respond specifically to peptides with hallmarks of cancer delivered to the surface from within cells.
Once such peptides are identified, there are two ways to engineer T-cells to seal cancer’s fate. The first involves taking a person’s T-cells and engineering them so they have new genes that make new receptors. These receptors bind exclusively to the cancer peptide, so once they are injected, the T-cells home in on and destroy all cells that contain the peptide.
The second way is to produce artificial T-cell receptors that are primed to recognise a cancer peptide. These receptors contain features that enable them to kill cancer cells once they have bound to them. These features include arms that summon passing native T-cells, or toxic chemicals that kill cells exposed to them.
The first technique has put 16 out of 20 people with myeloid myeloma into remission for two years. They had a T-cell treatment by Adaptimmune in Oxford, UK, that targets a peptide called NY-ESO created inside tumour cells.
It has also put one of two people with a cancer called synovial sarcoma into remission – a first for this kind of cancer. “She was so ill it was a close call whether to go ahead,” says Bent Jakobsen, Adaptimmune’s chief scientific officer. “She had more than 200 secondary tumours in her chest, lungs and lymph nodes – yet she had a complete response and everything disappeared. That was nine months ago, so we’re waiting to see what happens.” The treatment didn’t work for the second person, but the results for the first are good reason to pursue the therapy, says Jakobsen.
The NY-ESO peptide is found in many other cancers, including melanoma, liver, prostate, breast, ovarian and lung cancer. Earlier this year, Adaptimmune began a trial involving women with ovarian cancer.
And there are plenty of other peptides to target. Adaptimmune and another Oxford-based company, Immunocore, have so far identified 25 peptides specific to cancer cells. The big guns are starting to take note: earlier this year, Genentech of San Francisco and British pharmaceutical giant GlaxoSmithKline signed agreements to develop treatments using Immunocore’s targets.
Jakobsen says companies have had to proceed with great care after the catastrophic outcome of a trial of an immune-altering “super-antibody” in 2006 by defunct German company TeGenero. The therapy left six people fighting for life after their immune systems overreacted to the new antibody, triggering massive inflammation and organ failure. Guidelines introduced since then require companies to proceed far more cautiously, increasing doses very gradually.
But the promising results suggest T-cells could be the way forward. “T-cells are smart, living drugs,” says Sadelain. Early next year, he hopes to begin T-cell trials for prostate and lung cancer. “I think it will be a very exciting decade of targeting an increasing array of cancers,” he says.
This article appeared in print under the headline “Cancer meets its nemesis”