CAR-T: A cutting edge cancer therapy 'curing' the incurable

For some patients with extremely aggressive blood cancers which have relapsed and become resistant to conventional chemotherapy regimes, CAR-T has been known to wipe out the disease - possibly for good.

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"What we see is that when patients are treated, if the disease is not progressed or come back within the first six months, then it becomes increasingly less likely that it's going to happen," said Dr Irvine.

"We feel this is a potentially curative treatment for some patients for whom a cure would hitherto not even have been contemplated.

"A proportion of patients who went through this treatment in trials are now five or six years down the line without any evidence of recurrence."

Dr David Irvine, who co-founded the CAR-T service in Glasgow

The QEUH is currently the only centre in Scotland providing CAR-T, and so far the results are remarkable.

Since the service launched on the NHS in November 2019, a total of 46 patients have been referred from across Scotland to undergo the treatment in its 24-bed bone marrow unit.

To date, around 18 (40 per cent) have achieved full remission, although follow-up is still continuing for some patients and the number includes two who are currently receiving CAR-T.

This compares to a survival rate of around 7% from bone marrow transplants, previously the last resort for a minority of blood cancer patients who had exhausted all other options.

"When we compare the outcomes of what happened before to the outcomes of those treated with CAR-T cells, the outcomes are much better," said Dr Irvine, who set up the service with his colleague Dr Anne-Louise Latif, also a consultant haematologist and lecturer at Glasgow University's school of medicine.

"It isn't the solution for all patients. Patients can still relapse after - and it only applies to very specific patients - but in that group the results are much better than we would previously have anticipated."

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One of the big unanswered questions is why the therapy works so well in some patients, but not others.

More than half of patients do not experience long-term survival, and the therapy is prohibitively expensive - costing hundreds of thousands of pounds per patient - although the NHS has negotiated a discount with the drug companies.

The QEUH has treated some patients in their 70s, but the treatment can come with severe side effects which mean it is unsuitable for patients who are frail due to other co-morbidities.

Those with a high volume of disease, or a lymphoma that is spreading very rapidly, also appear less likely to benefit.

At the moment, CAR-T is limited to a very narrow category of blood cancers which have defeated standard treatments and relapsed. 

It covers acute lymphoblastic leukaemia for patients aged 25 and under; an aggressive form of non-Hodgkin lymphoma known as diffuse large B cell lymphoma (DLBCL); and Mantle cell lymphoma.

There is considerable interest in extending it to solid tumours in future, though this remains highly experimental for now.

Dr David Irvine and Lisa Halliday in one of the patient suites at the bone marrow unit with a 'cryoshipper' used to transport cells for transplant at ultra sub-zero temperatures

CAR-T - or 'chimeric antigen receptor T cell' therapy - is unlike any other cancer treatment.

It was pioneered in the US by Carl June, a professor of immunotherapy who made medical history when six-year-old Emily Whitehead, who was terminally ill with leukaemia, became the first child in the world to receive CAR-T in 2012.

Ten years on, she is alive and well.

The process begins with apheresis, where blood is extracted from a patient and passed through an apparatus to remove the T cells, a type of white blood cell - or lymphocyte - involved in the body's immune response.

These are sent abroad to be "customised" at laboratories specialising in CAR-T manufacture.

There are currently sites in the Netherlands, France, Switzerland, Germany, and the US, but none in the UK.

The T-cells are genetically engineered to produce a new protein on their surface called chimeric antigen receptors (CARs), which recognise and bind to specific proteins found on cancer cells.

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This is done using a virus vector which "injects" a new DNA sequence into the T-cell's existing genome, enabling it to code for CAR - a receptor which is not found in nature, and which has been designed specifically to attack cancer cells.

Once completed, the revamped T cells are scaled up into millions and returned for transplant back into the patient.

The whole cycle takes around three to six weeks.

In the meantime, patients undergo chemotherapy so that their immune system is primed to "re-grow" with the new T cells.

In Scotland, the cells are initially stored in specialist laboratories at the Beatson cancer centre in Glasgow, before being transferred to the QEUH in "cryoshippers" - tanks of liquid nitrogen designed to keep the samples at minus 180°C - where they are eventually unpacked by nurses clad in protective gloves to avoid frostbite and cold burns.

Prior to transplant, the bag of cells is defrosted in an incubator-like water bath which heats the sample to 37°C.

Senior charge nurse Lisa Halliday with a water bath used to defrost cells for transplant

Once infused into the patient, the CAR-engineered T cells multiply rapidly.

They begin attacking white blood cells expressing the CD19 protein, a biomarker found in healthy as well as cancerous B cells - another form of lymphocyte.

It is a hallmark for lymphoma and some types of leukaemia.

Dr Irvine said: "When the [the re-engineered T cells] catch CD19 they start to activate, and go from small numbers to huge numbers in the space of five or six days.

"They crescendo up to the point where they may be the dominant immune cell that's circulating, and they're destroying millions of B cells very quickly in a way that wouldn't happen with other treatments."

CAR-T therapy has been described as a "living drug", in the sense that the T cells carry on working indefinitely.

It is also a one-off.

"You come in, you go through the process, and it either works or it doesn't," said Dr Irvine.

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The side effects can be life-threatening, however.

As well as destroying cancerous cells, the T cells flood the bloodstream with cytokines - chemical messengers that stimulate an immune response.

This can cause patients' temperatures to soar or their blood pressure to drop. Organ function can be compromised, and some patients require intensive care.

The phenomenon, known as cytokine release syndrome (CRS), can be fatal in severe cases.

It has become more common during the pandemic when some Covid patients experienced an extreme immune response to the infection.

Lisa Halliday said most patients 'feel lucky' to be given the option of CAR-T, despite the risks

As with Covid, however, the effects can be dampened down in CAR-T patients using the anti-inflammatory arthritis drug, Tocilizumab.

Other CAR-T patients suffer neurotoxicity, characterised by confusion, cognitive impairment, sensory disturbance and sometimes hallucinations.

Overall though, patients who have reached the 'last chance saloon' in their cancer journey are grateful for new hope.

"Most people who come in are just glad to have been accepted onto the list," said Lisa Halliday, senior charge nurse for the QEUH bone marrow unit.

"A lot of the time there wouldn't be another treatment available at the stage that they're at, so this is something that could give them good quality of life for a long time.

"It comes with risks and it's a big undertaking, but most people feel very lucky to have a treatment that wouldn't have been there for them five or six years ago."