CAR T-cell cancer therapy
Andy Ewing had never heard of CAR T-cell immunotherapy before it was offered to him as his last hope of beating a relentless form of blood cancer.
“I’d already been through two separate rounds of chemo since 2010 when I was diagnosed with non-Hodgkin’s lymphoma, but the cancer kept fighting back and became impossible to control,” he recalls.
“When I joined a CAR T trial late last year, it was my last chance saloon as far as I was concerned.”
Ewing, 58, from Berwick, south-east of Melbourne, is among the growing number of cancer patients in Australia who have had CAR’s immunotherapy treatment at a point when, as Ewing puts it, “you are waiting around to die”.
Under an agreement between the federal and state governments, CAR T therapy, which costs about $500,000 a patient, is offered free to children and young adults with acute lymphoblastic leukaemia (ALL).
This is to be extended to about 250 adult patients yearly with particular forms of leukaemia, Minister for Health Greg Hunt announced this week.
T cells, known as the foot soldiers of the immune system, normally work to fight infection by patrolling the body looking for foreign protein fragments that indicate a cell might be infected by a bacterium or virus. However, cancer cells are mutated versions of the body’s own cells and therefore T cells do not recognise them as a threat.
CAR T-cell technology changes the dynamics by providing a ramped-up version of a patient’s immune system after extracting their blood then genetically modifying the T cells to recognise and destroy cancer cells.
In the re-engineering process, researchers arm the T cells with two new claws – one to bind onto the telltale protein in the cancer cell, and another to kill it – in a construct called a chimeric antigen receptor (CAR). The DNA instructions are inserted into the patient’s T cells in a laboratory and then delivered back into the patient, where they rapidly multiply into the billions.
Blood cancers such as paediatric and young adult ALL are leading the way for this type of treatment in a broad range of CAR T-cell trials at centres throughout Australia, including Melbourne’s Peter MacCallum Cancer Centre.
“But large cell lymphomas are coming up behind, and multiple myeloma is the next candidate for approval. But there are also groups around the world working on solid cancers, such as breast and lung cancer,” says one of the centre’s senior haematologists, Associate Professor Simon Harrison.
As the epicentre of CAR T-cell research in Australia, Peter Mac, as it is more commonly known, received an $80 million Commonwealth grant last year to upscale its research facility. This included the construction of the country’s first large-scale manufacturing facility for re-engineered T cells, a process that is normally done in the United States.
Peter Mac has been performing CAR T clinical trials since 2010 and its success rate during the past five years has been impressive.
“About 80 per cent of paediatric and young adult ALL patients have responded, and about 60 per cent are in long-term remission,” says Harrison.
“In lymphoma, there is again between 60 and 80 per cent response and about 40 per cent long-term remission. In myeloma there is an 80 to 100 per cent response and the trials are still running to see how many of those convert to long-term disease-free remission.”
This rapidly advancing field of immuno-oncology has been decades in the making. CAR T was developed in the 1990s but the idea can be traced to the late ’60s and American surgeon Dr Steven Rosenberg, who suspected a patient’s remarkable recovery from lung cancer was due to the power of his immune system.
During the next few decades he and several researchers in Israel and the US, including Professors Zelig Eshhar, Carl June and Michel Sadelain, relentlessly advanced the general theme of turbocharging the immune system.
Sadelain, who is now director of the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center in New York, explained the significance of CARs in a 2018 interview:
“CAR therapy is a very novel form of medicine because it uses as the drug not a chemical, not a protein but a cell,” he said.
“It is not a natural cell. It is a cell initially collected from the patient and then modified. It is genetically instructed to acquire new properties.
“CARs have attracted much attention because of the very remarkable results obtained in a number of B-cell malignancies which comprise various leukaemias and lymphomas. And the target we chose named CD19 is found on most of these leukaemias. When the first trials began, those trials like any other trials in oncology focused on patients who had relapsed and refractory disease.
“Those patients have really no other treatment to turn to. They had all exhausted the available treatments. Not only did some of these patients respond to treatment, but most of them … had what is called a molecular response, meaning the disease became undetectable.”
Andrew and Stephnie Ewing, who have been married for 37 years, cried when they received some good news only a month after the procedure at Peter Mac last November.
“The trial requires scans to be done three months after the procedure, but the doctors at Peter Mac told me they like to see if there has been a response after one month,” says Ewing.
“Before the trial my scans were dotted with the black marks of cancer. But just one month later, they were clear.”
Both he and his wife realise it is way too early for an “all clear”, but this rapid response has imbued a sense of hope that had waned with each setback over the years.
“It was not an easy decision to join the trial because a different one that Andy had been on [at a different institution] was cancelled because people worldwide were dying, so that left us with a lot of anxiety,” says Stephnie.
“Andy did suffer two bouts of high temperatures after the procedure but doctors explained that was the result of the T cells doing their work.”
On Ewing’s assessment, CAR T-cell treatment compared with long sessions of chemotherapy “was like chalk and cheese”.
A quantity of blood was taken from him and sent to the US and returned about four weeks later.
“They gave me a short burst of chemo which took about 45 minutes to make way for the re-engineered cells and then they inserted the contents of a small bag that contained my modified T cells, which took about 15 minutes and then it was over,” says Ewing.
“It was nowhere near as invasive as chemo, which is a mix of a lot of chemicals that takes six or seven hours to undergo.”
One of the sticking points with CARs, however, has been and still is the cost of this highly personalised treatment. In Australia the expense has been exacerbated by heavy reliance on shipping patients’ blood to the US for re-engineering.
“This process can take weeks, time that some patients don’t have,” says Associate Professor Harrison.
He says Peter Mac’s proposed manufacturing facility, which is expected to open in 2022, will significantly reduce both cost and waiting time for patients.
“One of the goals towards making the treatment more accessible is to try to transition to an off-the-shelf treatment rather than personalised therapy,” says Harrison.
“There are a number of treatments on trial at the moment that focus on off-the-shelf options, using cell-based therapies from donors rather than individual patients.
“They have been engineered to recognise a patient’s tumour but they are also being engineered so they don’t react against that person.
“There’s a bunch of new things coming on stream in the next 12 months where we will be using more novel technology to try to turn on the immune system in different ways. I think there will be different ways we can achieve that for different diseases.”
Harrison, whose fascination with the immune system’s untapped healing potential began in his student days in Britain, believes CAR T-cell technology has brought a degree of elegance to the treatment of cancer.
And its value in terms of renewed hope and optimism for people such as the Ewings is immeasurable.
“We have patients who have been told this is their last resort and within two weeks there is remission and then a year-plus later they’re back to work,” says Harrison. “So yes, it is a life-changing technology.”
This article was first published in the print edition of The Saturday Paper on Feb 1, 2020 as "Saved by the cell".
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