When T-cells attack

"IN 2010 AN American girl called Emily Whitehead developed a form of leukaemia that is usually terminal. She was five years old. Two years later, she became the first paediatric patient to be offered a form of treatment called CAR-T, in which the body’s immune system is reprogrammed to attack cancerous cells. The treatment worked. A documentary film about her journey, released in 2022, was called “Of Medicine and Miracles”.

Researchers do not use the second of those m-words lightly. But CAR-T therapy seems to justify the excitement. A decade on from Emily’s treatment, its proponents are finding that the cells driving many other diseases, from asthma to heart conditions, share similarities with cancer cells that could allow them to be targeted in the same way. Early results from clinical trials are encouraging.

CAR-T therapy works because many harmful cells have specific protein markers called antigens on their surfaces. T-cells in a patient’s immune system are extracted, genetically tweaked to possess “chimeric antigen receptors” (the CAR in CAR-T) [1] that can spot these antigens, and then returned to the patient’s body. Several CAR-T cell therapies licensed to treat leukaemia and lymphoma, for example, use T-cells engineered with CARs that can recognise a protein called CD19, which is found on the outside of those cancer cells.

“When you hear CAR-T cell therapy you think cancer,” says Scott Lowe, a researcher at the Memorial Sloan Kettering (MSK) Cancer Centre in New York. “But what we’re learning is that this approach of engineering immune cells to target disease has much broader possibilities.”

Take asthma. Although medicines allow millions of people to control their symptoms, severe asthma attacks still kill three people in Britain every day. That is often down to a misfiring immune system, which triggers what is called a type 2 inflammation response. Intended as a defence against parasites, the body releases aggressive white blood cells called eosinophils which can cause inflammation in the airways, making it hard for people with severe asthma to breathe.

Asthma treatments, including inhaled steroids and injected antibodies, aim to lower the number of circulating eosinophils and so reduce inflammation and symptoms. Researchers in China have now shown that CAR-T cells can be engineered to do a more thorough job, at least in mice. In a study published in May in Nature Immunology, they described how a single dose of the cells injected into animals bred to mimic the symptoms of asthma in effect cured them of the condition.

The researchers could do this because they identified a distinctive antigen on the surface of the eosinophils: a receptor for the signalling molecule interleukin-5. To design a therapy that could target eosinophils, the Chinese group, led by Peng Min at Tsinghua University in Beijing, added a CAR protein to the T-cell surface tailored to recognise this specific antigen. When the T-cells find a match, they release toxins that act to destroy the eosinophils, thereby dampening the body’s inflammation response. Dr Peng’s team has already shown that anti-asthma human T-cells can be prepared in the same way.

Some CAR-T cancer treatments have unintended consequences. The treatment that targets CD19 antigens, for example, can also attack the body’s B-cells, which produce antibodies and maintain vital memory of immunity against pathogens. But this need not be a disaster. In fact, some researchers now see this as a way to treat medical problems caused by overactive immune systems. A series of small clinical trials have suggested that the licensed technique to produce CD19-directed T-cells can also help treat people with systemic lupus erythematosus (SLE), an autoimmune disease that attacks a person’s own organs. Earlier this year, European researchers reported in the New England Journal of Medicine that eight patients with severe SLE were symptom-free two years after a single infusion of CAR-T cells.

In principle, pathogenic cells across the body could be attacked with CAR-T cells, provided that scientists can identify a distinct antigen to target. In recent years, researchers have found such an antigen on heart cells weakened by fibrosis, a common and sometimes deadly stiffening of cardiac muscle caused by acute injury, chronic disease or ageing. Labelled (a little unimaginatively) fibroblast activation protein, the antigen has inspired CAR-T cells that reduce fibrosis and improve heart function in mice.

Some even argue that CAR-T cells can take aim at ageing itself, sweeping away cells that have undergone an age-related loss of function. Similar versions of this clearing process, called senolysis, have been shown to help tackle many chronic diseases associated with ageing, including cancer and liver damage. Importantly for CAR-T therapy, scientists have found an antigen: many cells as they age produce more of a protein called urokinase plasminogen activator receptor (uPAR). In a study published in January in Nature Aging, researchers in America, again working in mice, showed that CAR-T cells engineered to bind to uPAR could boost senolysis, with various benefits including improved metabolism and exercise capacity.

CAR-T therapies are not cheap: a course of treatment for cancer could cost several hundred thousand dollars. Customisation is partly responsible, explains Ying Huang, CEO of Legend Biotech in New Jersey, which produces an approved CAR-T therapy for myeloma patients. Traditional pharmaceuticals and newer biological therapies are manufactured on assembly lines, “But we have to do one batch production for one patient. So technologically it is actually very difficult,” he says.

The company is doing what it can to make the process more efficient—such as investing in larger reaction vessels to engineer and grow the modified cells—but is still looking at a near-month-long process to make a specific therapy for each individual patient. And that same bespoke bottleneck would apply to all CAR-T therapies made from a patient’s own T-cells, including those that aim beyond cancer.

Better, faster, cheaper

Other firms are working out ways to trim costs, from cheaper labour and materials to scaling up production. These efforts are paying off, up to a point. In October 2023 the Indian government approved a cut-price domestic CAR-T therapy for B-lymphomas and B-acute lymphoblastic leukaemia, where one or more lines of treatment have failed. Produced by a company called ImmunoACT in Mumbai, the therapy costs about $40,000, a tenth of the price of the American version but still beyond the reach of most Indians.

At the moment the treatments can’t be made any other way: only T-cells taken from a patient can be safely returned to them, given the risk of immune rejection. But researchers are busy experimenting with other techniques. Other immune components could be used, for example, as could so-called allogeneic CAR-T cell therapies, in which the natural rejection processes are overcome. And, inspired by the protection that mRNA vaccines offer against covid-19, some researchers are seeking to encourage T-cells to generate the antigen-spotting mechanism while they are still inside the patient’s body. In a field looking for its Henry Ford moment to streamline production, such an advance could see a new generation of CAR-T miracles roll off the assembly line." [2] 

 

1. "Chimeric antigen receptors

The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

CAR T cell therapy uses T cells engineered with CARs to treat cancer. T cells are modified to recognize cancer cells and destroy them. The standard approach is to harvest T cells from patients, genetically alter them, then infuse the resulting CAR T cells into patients to attack their tumors."

2.  When T-cells attack. The Economist; London Vol. 452, Iss. 9416,  (Sep 28, 2024): 71, 72.