Chimeric antigen receptor (CAR) T-cell therapy for rheumatologic disease is now expanding out of academe into the commercial space, with encouraging new data reported here from a U.S.-based industry program.
A CAR T-cell treatment under development by Philadelphia-based Cabaletta Bio for systemic lupus erythematosus (SLE) aimed at reconstituting patients' B cells appeared highly effective, according to Saira Sheikh, MD, of the University of North Carolina at Chapel Hill, although follow-up so far has been relatively short.
Three of four patients with refractory non-renal SLE achieved complete remission, she told attendees at the European Alliance of Associations for Rheumatology's (EULAR) annual meeting. She added that the one who didn't qualify failed only on a technicality.
Also, the first patient with lupus nephritis with enough follow-up to judge renal remission did indeed obtain it, she said.
All seven patients treated thus far, with follow-up of 12 to 52 weeks, have stopped all immunomodulator and corticosteroid treatment, Sheikh noted.
CAR T-cell therapy has excited the rheumatology field like no other treatment approach since the advent of tumor necrosis factor inhibitors and other antibody-based drugs. By engineering patients' T cells ex vivo to destroy their autoantibody-producing B cells, the idea is that when B cells eventually grow back, they will be normal again -- essentially providing a "reset" to the immune system. This approach originated in oncology, where the aim is to eliminate B-cell cancers such as lymphoma.
Probably the leading exponent in rheumatology has been Georg Schett, MD, of Friedrich-Alexander-Universität in Erlangen, Germany, whose program has now treated 20 patients with SLE, systemic sclerosis, and idiopathic inflammatory myositis (IIM). Originally, this group was doing the ex-vivo engineering in-house, but it now has a commercial tie with a German firm, Miltenyi Biomedicine. At EULAR, Schett reported that all patients evaluable for efficacy have obtained remission or major clinical responses.
Numbers of other groups have jumped on board as well. At last year's EULAR meeting, highly favorable results from another commercial sponsor, iCell Gene Therapeutics in Stony Brook, New York, were reported, and this year's meeting features more.
Sheikh was the first to take the podium in an oral presentation here, discussing early results from an ongoing phase I/II trial called RESET-SLE. Eight lupus patients have been treated thus far, including four with nephritis and four without. Sheikh presented findings from those who had at least 1 month of follow-up, which excluded one of the nephritis patients.
They ranged in age from 18 to 44, and two were men. Their disease was long established, with symptoms poorly controlled despite standard therapies including corticosteroids, antimalarials, immunosuppressants, and, in most cases, biologic agents. Two patients had tried seven drugs without lasting benefit. SLE Disease Activity Index-2K (SLEDAI-2K) scores prior to undergoing Cabaletta's CAR T-cell therapy ranged from 8 to 26, indicating moderate to severe disease.
Six of the patients, of whom four had non-renal SLE, had follow-up of at least 24 weeks. Of those, five showed dramatic clinical responses, and one with lupus nephritis and exactly 24 weeks of follow-up had a substantial but not miraculous improvement.
The SLE patient with a full year of follow-up had achieved remission at week 48 but had to go on cyclosporine for an episode of macrophage activation syndrome, Sheikh explained, and thus did not qualify as having remission at the most recent formal follow-up. She said that the episode was most likely from a viral infection and probably not related either to lupus or the CAR T-cell therapy, at least directly. Moreover, Sheikh said, she learned after preparing her EULAR data presentation that the patient had fully recovered and stopped the cyclosporine.
Among the lupus nephritis patients, the one with longer follow-up (44 weeks) saw SLEDAI-2K scores plummet from 22 to zero, and met other criteria for complete clinical and renal response. The patient with 24 weeks of follow-up hadn't yet seen such a steep decline (from 14 to 6), and the estimated glomerular filtration rate remained at baseline level. Urine protein-creatinine ratio did fall somewhat (4.9 to 2.7).
Only one participant had serious adverse events. That was the lupus nephritis patient with 44 weeks of follow-up, who experienced grade 4 immune effector cell-associated neurotoxicity syndrome and grade 4 pancytopenia, as well as mild fever and a grade 1 case of cytokine release syndrome (CRS). These did resolve. One other patient also had grade 1 CRS. No participants developed serious infections.
Sheikh also reported that the treatment appeared to succeed on the lab-test level as well: B cell counts fell rapidly to zero after the CAR T-cells were infused, and began to recover about 2-3 months afterward.
In addition to SLE, Cabaletta is also targeting IIM and hopes to file a marketing application in 2027 for that indication, according to a recent company statement; data from the firm's IIM trial are slated for presentation at EULAR on Friday. Systemic sclerosis is also in Cabaletta's sights.
Disclosures
The study was funded by Cabaletta Bio; most co-authors were its employees. Sheikh reported relationships with the company and with GSK, AstraZeneca, Biogen, and Aurinia Pharmaceuticals. Other academic authors also reported relationships with multiple commercial entities.
Primary Source
European Alliance of Associations for Rheumatology
Source Reference: Sheikh S, et al "RESET-SLE: clinical trial evaluating rese-cel (resecabtagene autoleucel), a fully human, autologous 4-1BB anti-CD19 CAR T cell therapy in non-renal SLE and lupus nephritis" EULAR 2025; Abstract OP0202.
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