CAR-T Treatment Continues to Astonish in Rheumatologic Diseases

VIENNA — New data reported here reinforce the idea that chimeric antigen receptor T-cell (CAR-T) therapy can be an out-and-out cure for many rheumatologic diseases.

One new study showed that all patients with systemic lupus erythematosus (SLE) receiving a proprietary CAR-T therapy were free of disease biomarkers, as well as clinical symptoms, after 6 months or more, as described by Greg Deener of iCell Gene Therapeutics in Stony Brook, New York.

Also, Georg Schett, MD, of Friedrich-Alexander-Universität in Erlangen, Germany, provided an update on his group’s closely watched program in which patients with a variety of rheumatologic conditions have been treated with a house-made CAR-T regimen, with follow-up now extending past 3 years in one case.

The presentations were among the first delivered at the European Alliance of Associations for Rheumatology (EULAR) annual meeting, which began Wednesday.

CAR-T treatments were first developed for certain cancers, the concept being that, with the aid of viral vectors, a patient’s own cells can be transformed ex vivo to express receptor proteins that bind to a specific antigen on other cells that need to be eliminated. These transformed T cells are then re-injected into the patient, where they hunt down and kill the target cells. Initially, the targets were rogue B cells in non-Hodgkin lymphoma and lymphoblastic leukemia.

But with B cells also playing an important role in lupus and some other rheumatologic diseases, Schett and others thought the same approach could be helpful in that sphere too, hopefully leading to immune system reconstitution that eliminates all autoimmune activity.

Schett first began reporting findings with CAR-T treatment a couple years ago, with a publication in Nature Medicine describing positive results in five SLE patients followed for up to a year. Further updates came at meetings in June and November of last year, with increasing numbers of patients, as well as continued follow-up with the initial five.

This week, he gave new results for a total of 15, with diagnoses of inflammatory immune myositis (n=3) and systemic sclerosis (n=4). These were also the subject of the report from last November, but with additional follow-up.

All of the SLE patients remain in clinical remission, Schett said. As well, all of those with systemic sclerosis have shown marked reductions in European Scleroderma Trials and Research Group Activity Index (EUSTAR AI) scores, with no need for corticosteroids or immunosuppressants.

Meanwhile, two of the three myositis patients have also shown durable remission. The exception is one patient with a strong initial response who then relapsed about 16 months after treatment. While the precise reason for the late failure isn’t clear, Schett noted that myositis is heterogeneous and it may be that some forms will be more responsive to CAR-T therapy than others.

He said that the relapsed patient was re-treated with frozen CAR-T cells that then failed to expand after injection; his group’s interpretation is that the patient’s native T cells — which “are not touched” in his group’s protocol — had mounted an attack on the CAR-T cells, which would then block any benefit from them. (At a separate presentation here, he remarked that relapses following CAR-T therapy in some patients must be expected, as “every therapy will have relapses.”)

One possible solution to this issue was the subject of Deener’s talk. His company’s product, dubbed cCAR, adds another component to the standard CAR-T concept: targeting long-lived plasma cells as well as B cells. This is done by crafting CAR-T cells that home in on a plasma-cell antigen called BCMA, along with the CD19 antigen on B cells.

His group has now completed a phase I trial with efficacy results for 12 SLE patients, including 10 with lupus nephritis, with up to 478 days of follow-up. (Deener and colleagues published some results just 2 weeks ago, but without as much follow-up.) A 13th patient was excluded on account of receiving a suboptimal CAR-T dose, given as compassionate use, who then failed to respond fully.

The first patient in the group’s program was treated in September 2019 and the last in February 2023. The lupus nephritis patients were required to have kidney biopsies to confirm disease activity at baseline, with additional biopsies as time goes on.

As of now, Deener said, all patients no longer show elevated levels of lupus-type autoantibodies, and in most they became undetectable. With at least 1 year of follow-up, 11 of the 12 have achieved SLE Disease Activity Index-2K scores of 0; the 12th has not yet had post-1 year biopsy to confirm a zero score, but all clinical symptoms and other key biomarkers show complete remission. Patients were taken off all their normal lupus medications just prior to undergoing cCAR therapy, and no patients have needed to have them restarted. Renal function has improved in all patients with nephritis and seven now show completely normalized renal function.

One important question with the iCell approach is whether vaccine-related immunity to infection is retained after treatment. Because the company hopes to sell its product in China, where hepatitis B virus (HBV) is a major public health concern and vaccination is common, the study examined anti-HBV antibody titers before and after cCAR treatment. Antibody titers did decrease over the short term with treatment, but then recovered to levels considered adequate, Deener said. There were no other notable safety concerns with cCAR, he added.

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