‘Unprecedented’ results for CAR-T cells in lupus may signify new era in treatment
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SCOTTSDALE, Ariz. — Chimeric antigen receptor T-cell therapy had “unprecedented” and “astonishing” results in lupus, but whether it will truly revolutionize rheumatology care remains to be seen, according to a speaker.
“Everybody is jumping on the CAR-T cell bandwagon,” William Rigby, MD, vice chair of the department of medicine and professor of medicine and microbiology at the Geisel School of Medicine at Dartmouth in Lebanon, New Hampshire, told attendees at the Basic and Clinical Immunology for the Busy Clinician symposium. “It may be the newest, greatest thing since sliced bread. It looks awfully good. But there is a very limited number of patients who have been in trials.”
Rigby provided an overview of the findings by Mackensen and colleagues published in Nature Medicine that caused a shockwave across the rheumatology community. The study included five patients with lupus. “There was unprecedented efficacy in refractory lupus,” he said. “Astonishing things happened.”
Not only did the patients show a complete B-cell response across the body — from the spleen to the bone marrow — but they experienced almost complete disappearance of fatigue and other clinical factors, as well. “In other words, it looked really good,” Rigby said.
But for Rigby, the initial response may not be as important as the long-term impacts. He noted that at around 110 days of follow-up, the B cells returned, but with improvements.
The B cells that returned retained immunologic responses to measles, mumps, rubella and other pathogens to which the patients had been previously vaccinated. “We are mystified,” Rigby said. “How is it that memory B-cell responses were maintained even after total B-cell depletion? We have restored immunologic naivete.”
Looking deeper into the mechanism, the B cells that were destroyed largely contained immunoglobulin A. “We made them clinically better, because they swapped from IgA majority rule to IgM,” Rigby said.
The findings raised questions about other B-cell depleting therapies such as rituximab (Rituxan, Genentech). “They deplete B cells similarly,” he said. “The difference is that rituximab does not have the efficacy that CAR-T cells have.”
The next phase of trials may illuminate exactly why the CAR-T approach is so much more effective.
Use of CAR-T cells in anti-synthetase syndrome may be one area that could be useful to this end. However, findings in this disease showed “divergent results” related to the duration of B cell depletion. Specifically, the depletion was more transient, according to Rigby. “CD19 CAR T-cell targeting works, but we do not know why it works in these patients,” he said.
Case report data exists for the CAR T-cell approach in systemic sclerosis. However, comparing these findings in rituximab may not prove fruitful, according to Rigby. “This is not an area where there are immensely robust rituximab data,” he said.
He added that while there has been a “dramatic effect” of CAR-T cells in scleroderma, the biochemistry remains unknown.
Looking to the future, early data for the anti-CD20 T-cell agent obinutuzumab (Gazyva, Genentech) show that it may be more potent than rituximab, but whether it can match other CAR T-cell approaches remains to be seen.
Further questions about the feasibility of CAR T-cell therapy also must be considered. “Are we really going to engineer specific T cells for every single patient with every single rheumatic disease?” Rigby said.
Regardless of these obstacles, Rigby believes that the data from the lupus trial are strong enough to warrant further investigation “The implications for rheumatic disease therapy are enormous,” he said.
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Rigby W. To B or Not B Depleted-CAR T Cells Enter the Treatment Arena of IMIDS. Presented at Basic and Clinical Immunology for the Busy Clinician, Feb. 17-18, 2024; Scottsdale, Arizona (hybrid meeting).
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