A lupus diagnosis turned German teenager Janina Paech’s life on its head. Once a keen horse rider and an aspiring doctor, Paech’s heart, liver and kidneys were failing by the time she turned 21.
Running out of hope, her father Stefan reached out to Professor Georg Schett, a doctor on the other side of Germany, who was testing a gene therapy approved to treat blood cancer patients on lupus sufferers.
Paech became just the third patient to receive Car-T, or chimeric antigen receptor cell therapy, as a treatment for an autoimmune disease such as lupus, which is caused by the immune system attacking healthy cells. Within days of receiving the infusion, the crippling fatigue and joint pain that had blighted Paech’s early adulthood had dissipated. Three years later, she is still in remission.
“Dr Schett saved my life,” said Paech, who is about to qualify as a doctor herself. “Sometimes I forget I was even ill.”
The early findings offer hope to millions of autoimmune disease patients — four in every five of whom are women, probably due to genetic abnormalities associated with the X chromosome — who do not respond to conventional steroid treatment and face the threat of multiple organ failure.
They have also renewed excitement about Car-T’s potential — and reignited debates about safety, manufacturing constraints and cost surrounding the treatment.
“It’s really changing the landscape,” said Schett, a rheumatologist at University Hospital Erlangen in eastern Germany. “Most people thought that when you have an autoimmune disease, you have to suppress the immune system for ever. Now, we have a single shot that looks a lot like a cure.”
With only one of the 15 patients treated so far having experienced a mild recurrence of the disease, Schett has boosted the prospects for a treatment that was first approved for some blood cancers in 2017 but had fallen out of favour due to manufacturing hurdles and concern over side- effects.
“Schett has breathed new life into Car-T,” said Yatin Suneja, a biotech analyst at financial services firm Guggenheim, comparing him to US immunologist Carl June, a pioneer of the treatment. “If what we are seeing right now turns out to be true, it will be a very big deal.”
Twenty-nine different Car-T treatments for autoimmune diseases, ranging from the muscle inflammation condition myositis to multiple sclerosis, are now being tested in clinical trials by drugmakers including Novartis and Bristol Myers Squibb, according to Beacon Intelligence.
But barriers to its wider rollout persist. Only 35,000 lymphoma and leukaemia patients have been treated with Car-T in the US since its approval seven years ago. In comparison, an estimated 204,000 Americans have systemic lupus erythematosus, a severe form of the disease.
The treatment, which can cost as much as $530,000 and must be produced and delivered in under a fortnight, relies on a complex procedure whereby a patient’s T-cells are extracted, chemically re-engineered and then reintroduced to attack the cells causing disease.
Peter Maag, chief executive of Kyverna Therapeutics, which has treated 30 autoimmune patients with its Car-T, likened the treatment to heart transplants. “Your heart is giving in. What do you do? You need another heart,” said Maag.
Compared with Professor Schett’s near-perfect trial results, Kyverna has experienced some hiccups. About a third of the 30 trial participants still required steroid treatment after receiving the Car-T; almost all patients experienced some cytokine release syndrome, whereby the immune system overreacts to the treatment; and three patients were affected by more severe neurological side-effects and one relapsed after six months.
Steven Nichtberger, chief executive of Cabaletta, another biotech testing Car-T for autoimmune disorders, including myositis and the skin disease scleroderma, said the field would “rise and fall on the ability of a medicine to replicate Schett’s data”.
Cabaletta, which is advised by Schett, has treated two autoimmune patients with Car-T, helping both to achieve drug-free remission for several months with no side-effects.
Paech reports twice-monthly respiratory infections that sometimes require antibiotics but largely her life is unencumbered, while Schett’s first patient has now been in drug-free remission for more than five years. Evidence suggests that lupus patients treated with Car-T can still mount an immune response against many vaccines, unlike those regularly taking immunosuppressive steroids to control the disease.
But patients require three chemotherapy sessions to prime their bodies for Car-T, leaving them with fevers or fatigue. Cabaletta is testing the treatment in patients not exposed to chemotherapy, which could open the treatment up “to almost every autoimmune patient, not just the severely ill”, predicted Nichtberger.
He added: “If the worst case happens and this treatment is approved for use in only 10 per cent of patients with lupus, myositis and scleroderma, that’s still several orders of magnitude bigger than the number of cancer patients currently eligible.”
With supply constraints limiting availability of the treatments for blood cancer patients, expanding capacity to offer Car-T to millions more patients will not be easy.
“It’s really tragic. There is a cell therapy on the market that would most likely cure [patients] and they still die because the pharma companies can’t supply sufficient batches,” said Fabian Gerlinghaus, chief executive of Cellares, a start-up that has a $380mn manufacturing supply deal with Bristol Myers Squibb.
Another manufacturing method, known as allogeneic Car-T, used by Pfizer-backed Allogene, among others, cuts out one step as it uses donor cells, but its efficacy is unproven. Early data also showed that Amgen’s cancer-targeting T-cell engager drug Blincyto showed efficacy in six rheumatoid arthritis patients, which would not face the same supply chain challenges as Car-T.
Cellares’s main technology, the cell shuttle, attempts to integrate the manufacturing process into one piece of equipment. It can produce Car-T doses for 16 patients at the same time, while reducing manufacturing costs by up to 50 per cent compared with conventional outsourcers. Another start-up, Ori Biotech, has also developed a similar module to speed up Car-T manufacturing.
Meanwhile, Schett’s patients, almost all of whom are young women, hope that this treatment can be approved and made available to more patients.
“For now, the therapy is very expensive . . . but I would love to see this therapy used not only to treat lupus but also other diseases,” said Paech, now 24. “I want other young women with lupus to receive that blessing.”
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