TREATING CANCER WITH YOUR OWN CELLS

Immunotherapies may become the final answer to this killer disease

New methods of altering a patient’s own immune cells are helping some cancer patients.

IN 2008, JUST AFTER SHE’D STARTED KINDERGARTEN, Tori Lee was diagnosed with acute lymphoblastic leukaemia (ALL), an aggressive form of blood cancer. Chemotherapy cures most children of the disease, but Tori wasn’t as lucky. A playful little girl who was doted on by her three older sisters, she “was treated with chemotherapy for about two years, and then she relapsed,” says her mother, Dana Lee. “We started a new protocol, with more intensive chemotherapy and radiation. She spent hundreds of days in the hospital.” And still the cancer held on.

With Tori growing weaker, her parents decided to take her to the children’s hospital in Philadelphia for several weeks of chemo in preparation for a bone marrow transplant, a complex and risky procedure. Her doctors told

the Lees that they would also collect Tori’s T cells as a backup plan: if Tori turned out to be too sick to have the transplant, she might be able to participate in an ongoing trial of a promising experimental treatment called CAR T, which takes a patient’s own immune cells and genetically reprogrammes them to kill cancer. CAR T had been used months earlier to cure another little girl, Emily Whitehead, with the same form of leukaemia.

Still, deciding on CAR T therapy wasn’t easy. Several of the children who had followed Emily in the clinical trial at the same children’s hospital had died. Tori would be only the tenth to undergo the treatment. “We finally said, ‘All right, we want to try CAR T.’ We petitioned to be included in the trial. We thought it gave her a better chance of survival [than the bone marrow transplant]”, says Dana.

In April 2013, doctors injected Tori with her own modified T cells. Six weeks later, her cancer was in remission. Five years on, Tori, who turned 15 in September, remains cancer-free.

In August 2017, after 50 more patients in the trial went into remission, the US Food and Drug Administration (FDA) approved the treatment. “With the approval of CAR T, we’re taking a first step towards a new approach to curing cancers that have been incurable,” says Dr Steven A. Rosenberg, chief of the surgery branch at the US National Cancer Institute.

EARLY SIGNS OF HOPE

In the 1980s, a team led by Dr Rosenberg was the first to remove T cells from patients with cancer, multiply them in the lab, and then reinject them in the patients – in essence, turbocharging the patients’ own immune system to fight the disease. In an early study of this treatment, tumours in 11 of the 25 patients shrank by at least half, and one

patient, with malignant melanoma, was cured. Still, in most cases, it wasn’t enough to eradicate the cancer.

But researchers continued to experiment and innovate. Immunologist Zelig Eshhar, a researcher at the Weizmann Institute of Science in Israel, thought he could use a recently developed gene therapy technique to make T cells into better cancer fighters. He engineered T cells to carry a chain of amino acids called chimeric antigen receptors (CARs). These CAR-carrying T cells – CAR Ts – seek out cells that may be cancerous. When the receptors on CAR T cells find cancer cells, the receptors latch on to them like a key fitting into a lock. That connection then acts like a trigger, telling the T cells to multiply like crazy and kill the cancer cells.

“CAR T therapy is something wholly new,” says oncologist Dr David Porter. “It’s not a compound or a chemical. It’s made up of living cells. Once infused into a patient, a single CAR T cell can multiply into 10,000 cancer-fighting cells.”

While drugs, including those used in chemotherapy, are flushed from the body and typically have to be given repeatedly, CAR Ts “go on circulating through the bloodstream, in some cases for years,” explains Dr Porter.

During that time, they can track down and destroy more cancer cells that may arise. This may explain one of the most promising results of CAR T therapy: of the 52 patients who responded to the therapy, two thirds still showed no signs of cancer a full year after treatment.

In fact, the CAR T model worked so well that in October 2017 the FDA approved a second type, for certain forms of non-Hodgkin lymphoma that, until now, have almost always proved fatal. Of the 101 adults with large B‑cell non‑Hodgkin lymphoma enrolled in the clinical trial, 72 responded, meaning their cancers diminished or disappeared. Over half had no detectable cancer after eight months.

One of the patients was a doctor himself. Diagnosed in 2014, Dr Jeff Backer had developed visible masses of lymphoma cells under his arms and on his face, chest, back and neck. In June 2016, he received the new CAR T therapy as part of the clinical trial. “Within a day or two, the lumps started getting softer, smaller, disappearing,” says Dr Backer, who recently returned to his job as an emergency department doctor. “It was as if a nuclear bomb had been dropped on the cancer.”

Twenty-three months after treatment, Dr Backer’s cancer remains in remission.

THE PROCESS... AND COST

CAR T treatments are tailored for each individual cancer patient, with T cells isolated from the blood and then sent to a facility where new genes are inserted into them. The

cells are then stimulated to grow into a legion of CAR Ts. The resulting cells are frozen, sent back to the patient and then reinjected. The production process can take two to three weeks, and it’s expensive, costing between US$373,000 and $475,000. However, Professor David Gottlieb, from the Westmead Institute of Medical Research, told the Sydney Morning Herald last year that the long-term goal is to make CAR T therapy affordable and widely accessible to patients as quickly as possible. “But there is still a long way to go before we can regard it as routine.”

Like all cancer treatments, CAR T has side effects. The immediate danger is a severe reaction, dubbed a cytokine storm, that begins with flulike symptoms but can escalate into plummeting blood pressure, extreme confusion, hallucinations, tremors and seizures. Today, researchers understand that the reaction is actually a sign the therapy is working. When CAR T cells go after cancer cells in large numbers, levels of immune chemicals called cytokines can rise dangerously.

“In some patients with widespread disease, CAR T cells destroy up to three kilograms of malignant cells,” says Dr Porter. The more extensive a patient’s cancer, the more likely a cytokine storm will follow the treatment.

When Emily Whitehead, the first child to receive CAR T therapy, had a life-threatening reaction, doctors ordered blood tests that showed soaring levels of a cytokine called interleukin- 6 (IL- 6). Fortunately, oncologist Dr Carl June, the lead investigator in the clinical trial, knew about a drug that lowers IL- 6, because his daughter was taking it for juvenile rheumatoid arthritis. By a lucky chance, the hospital had a supply of the drug, called tocilizumab. Within hours of receiving it, Emily began to recover. Tocilizumab is now routinely used to blunt the effects of cytokine storms.

CAR T therapy also has another long-lasting but manageable side effect. The cancers they treat, leukaemia and lymphoma, occur when B cells – a type of immune cell that guards against infections – mutate and become malignant. Because the CAR T therapy destroys both cancerous and healthy B cells, patients may be more vulnerable to infections such as pneumonia after receiving treatment. To bolster their defences, they must receive periodic injections of antibody-rich gamma globulin, a substance made from human blood plasma, possibly for the rest of their lives.

Despite the steady progress in perfecting the treatment, doctors have not been able to explain why it fails to help some people, even those who would seem to be ideal patients. CAR T seemed to be working as expected on Sophia Kappen, a fiveyear-old girl who hadn’t responded to chemotherapy. “This little girl who was in pain, who couldn’t walk because of the cancer, began to get some of her sparkle back,” says her mother, Amy Kappen.

But the cancer fought back. Doctors added another experimental drug, pembrolizumab, which makes cancers more vulnerable to attack, hoping it might give the CAR Ts a better chance. It wasn’t enough. Malignant cells surged in her bloodstream. Sophia Kappen died on April 5, 2017. She was six years old.

After her death, doctors were able to figure out what had gone wrong. Sophia’s B cells had mutated so that the CAR Ts could no longer recognise them; unable to hook onto the cancerous cells, the CAR T receptors couldn’t unlock the explosion of cancer-fighting cells. The same phenomenon has been seen in other patients. And in some patients who suffered a recurrence of cancer after treatment, the CAR Ts had died off before the disease was completely eliminated.

Researchers are working to perfect the CAR T model, to create cancer-fighting cells that attack multiple molecular targets and therefore make it tougher for malignant cells to hide. They’re also devising ways to keep T cells fighting longer. Some cancer cells have learned how to shut down immune attacks. New drugs, called checkpoint inhibitors, have been developed to block cancer cells from doing this. Clinical trials are under way to test whether combining checkpoint inhibitors with CAR Ts will improve the odds of wiping out cancer.

THE ROAD AHEAD

To date, CAR T therapy has been approved for only a handful of blood cancers and – because the treatment is so expensive – only after other treatments, such as chemo and radiation, have failed to stop them. Yet clinical trials are already showing that CAR T cells can work against another blood cancer, called multiple myeloma. And

there’s hope that before long, CAR Ts and similar immune-cell therapies will be able to target solid tumours, such as breast, lung, colorectal and prostate cancers. Those make up about 90 per cent of all cancers.

There are obstacles, however. CAR T cells have to be genetically engineered to go after a specific target. Choosing the right one is critical so that these aggressive cells kill cancer – and not the patient. Researchers tackled leukaemia and lymphoma first because the defective B cells that cause them are expendable. “People can live without B cells. So even though the treatment kills both cancerous and healthy B cells, patients survive and get along pretty well,” explains Dr Rosenberg. Similar ‘safe’ targets have been much harder to find on solid tumours. “Any of the targets we might use on lung cancer cells are shared by healthy lung cells as well. Destroy them, and you destroy a patient’s lungs.”

FUTURE STRATEGIES

One st rategy that might target malignant cells more precisely is a variation of CAR T called T- cell receptor therapy. Cel ls become cancerous as a result of hundreds of mutations, some of which cause small changes in proteins on the surface of the cel l. “The goal of T- cell receptor therapy is to create T cells, using a process like CAR T, that can recognise those changes and attack cancers but leave healthy cells alone,” explains immunologist Dr Frederick L. Locke.

Another approach uses naturally occurring T cells that have learnt on their own to find cancer cells. These tumour- infiltrating lymphocytes (TILs) aren’t numerous or powerful enough to destroy tumours. But in experiments at the National Cancer Institute, Dr Rosenberg and his colleagues have removed small numbers of TILs from tumours in patients, grown them in the lab into large numbers, and then reinjected them – much as they did with CAR Ts. In early clinical trials, the treatment has been shown to shrink and in some cases eliminate a wide range of solid tumours, including advanced melanoma, cervical cancer, colorectal cancer and other malignancies.

“Most of our patients don’t respond,” admits Dr Rosenberg. “But in some cases, we have seen complete and lasting remissions. We know this can work. Eventually, we think TILs could be the blueprint for treating almost all kinds of cancers.”

That won’t happen overnight, says Dr J. Leonard Lichtenfeld, chief medical director of the American Cancer Society. “It took ongoing commitment, basic research and a lot of courageous patients willing to enrol in clinical trials to test promising new therapies. CAR T therapy is saving patients who couldn’t be saved before. But the battle against cancer is far from over.”