CAR T-cell therapy remains the 'hottest story' in lupus, autoimmune disease
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DESTIN, Fla. — Positive results for chimeric antigen receptor T-cell therapy in systemic sclerosis and myositis have added fuel to the fire of recent landmark data in lupus, said a speaker at the Congress of Clinical Rheumatology East.
“The hottest story in lupus and perhaps in autoimmune diseases in general are CAR T cells,” Ronald van Vollenhoven, MD, PhD, chair of the department of rheumatology and clinical immunology at the Amsterdam Medical Center, and director of the Amsterdam Rheumatology Center Academic Medical Center, told attendees. “It is an extremely complex treatment from a technical point of view.”
According to van Vollenhoven, positive data have been emerging from the first five patients with lupus who were treated with this approach in the study published by Mackensen and colleagues.
“Their results were very good,” he said. “Disease activity very much disappeared and the patients did very well.”
More such data have surfaced recently. Eight patients with lupus along with four patients with SSc and three with idiopathic inflammatory myositis are experiencing similar results. In his talk, van Vollenhoven focused specifically on the lupus group, which were “technically” juvenile patients with systemic lupus erythematosus and active disease in many organs, he said.
“Some with nephritis,” van Vollenhoven said. “They had been treated with many other things and failed or had severe recurrent disease.”
Results showed that SLEDAI “dramatically goes down to zero” following CAR T-cell therapy, according to van Vollenhoven.
“These patients really did do very well,” he said. “That by itself is great for the patients, their doctors and their family. However, that by itself is not sensational.”
What is perhaps more impressive is that the patients, at least so far, no longer require treatment of any kind and have not experienced a recurrence.
“Three months after treatment, they still had no B cells,” van Vollenhoven said.
At 6 months, the B cells returned, along with “healthy” immunoglobulins and antibodies to measles and other infections, he added.
“The autoantibodies stay away and clinical manifestations stay away,” van Vollenhoven said. “This has gotten people very excited. An essential mistake in developing lupus has been corrected.”
Although the long-term data from the first cohort of patients is encouraging, van Vollenhoven noted that patients in the second group are only a few months out from the CAR T-cell procedure.
“We will have to see how it plays out,” he said.
Looking ahead to how CAR T therapy will potentially fit into future lupus treatment paradigms, van Vollenhoven stated that re-treatment is likely not an option.
“This is not something you want to have to do every year,” he said.
However, this hurdle has not deterred pharma, according to van Vollenhoven. He noted that as many as 16 companies are pursuing CAR T cells for lupus and other autoimmune diseases.
Some critical questions should be considered as these trials get underway.
“Are these really lasting remissions and how long do they last?” van Vollenhoven said. “Or is this a cure? Is that possible?”
Even if the answer is yes, then the role of pretreatment with cyclophosphamide and fludarabine should be investigated, he added, noting that all of the patients in the two studies were pretreated with one or both of these medications.
“Is it really necessary?” van Vollenhoven said.
Meanwhile, other experts have suggested that investigation of CAR T-cell therapy may lead to other B-cell depleting approaches that are not so expensive and complicated.
“Is this exciting result possible with simpler means?” van Vollenhoven said.
He noted that although B-cell depletion with rituximab (Rituxan, Genentech) has not lived up to expectations, obinutuzumab (Gazyva, Genentech) has proven better in the lupus space.
Further, it may be possible to develop a monoclonal antibody like rituximab that not only binds to a target but also involves a T cell, he added.
“It could give a T cell a nudge and say, ‘Hey, go do something about this cell,’” van Vollenhoven said. “It could bring the T cell over to kill the B cell.”
Such approaches are currently in development in the hematology space.
“They have very promising results,” van Vollenhoven said. “It could be that with a monoclonal of this type, you could have the same degree of B cell depletion with T cells. The enterprise of doing CAR T cell replacement may not be necessary.”
The next issue to consider is patient selection. Questions remain about whether early stage or late stage patients, or patients who have failed other therapies, are ideal candidates for complete B cell depletion.
“There is no blueprint for how to do this,” van Vollenhoven said. “A lot of thinking is being done about this theme. Hopefully, we will get answers to these questions in the next couple of years.”
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van Vollenhoven R. Targets for Biologics in SLE: Precision Medicine in the Works. Presented at The Congress of Clinical Rheumatology East; May 9-12, 2024; Destin, Florida (hybrid meeting).
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