Long-term CAR-T data bolsters autoimmune argument

2024-02-22

临床结果免疫疗法细胞疗法ASH会议疫苗

After stealing the show at December’s American Society of Hematology (ASH) meeting with promising early data of lupus patients treated with CAR-T cell therapy, a team of German scientists has now published updated results in the NEJM that suggest the one-time treatment can lead to sustained remission for patients with several autoimmune diseases.

At 29 months of follow-up, all eight patients with systemic lupus erythematosus (SLE) had no signs of disease activity.

“Even though it is premature to judge whether these patients are indeed cured from their autoimmune disease, CD19 CAR T cells at least appear to be able to achieve sustained disease- and drug-free remission,” the authors wrote.

While four CD19-directed CAR-T therapies have been approved for various haematological malignancies, Thursday’s study adds to a growing body of evidence that the modality could also be an effective tool to treat autoimmune diseases because they target the same underlying culprit: B-cells. But while the approved treatments attack malignant B-cells in patients with cancer, for those with an autoimmune disease, the goal is a deep depletion of autoreactive B-cells.

The study authors note that antibody treatments targeting B-cells have had modest efficacy in autoimmune diseases, but they’ve yet to achieve long-lasting drug-free remission. The goal with CAR-T therapy is to unleash one powerful treatment that reduces B-cells to a level so low that it can essentially result in a reboot of the immune system.

Resetting autoimmunity

The study enrolled 15 patients who had an inadequate response to at least two previous immune-suppressive treatments, including eight with SLE, three with idiopathic inflammatory myositis, and four with systemic sclerosis.

Each received a single treatment with MB-CART19.1, an experimental CD19-directed CAR-T therapy from Miltenyi Biomedicine. No authors on the paper are affiliated with the German biotech.

At ASH, the researchers announced that all 15 patients had discontinued immunosuppressive drugs at the 15-month follow-up.

In Thursday’s paper, the authors revealed more details they say supports the long-term benefit of CAR-T to treat autoimmune diseases, including autoantibody depletion, B-cell reconstitution, and vaccination response.

All but one of the lupus patients were evaluable for a one-year post-infusion autoantibody test, which found that all of them exhibited a sustained absence of SLE-specific autoantibodies. Additionally, all eight patients showed normal levels of complement factor C3, and seven experienced complete resolution of proteinuria.

Moreover, all patients experienced full B-cell reconstitution for as long as two years without relapse, suggesting a one-time CAR-T treatment can “reset” pathologic autoimmunity. The cell therapy’s potential to be an immune on/off switch was also supported by the appearance of a naive non–class-switched B-cell system, the disappearance of circulating plasmablasts, and the down-regulation of specific disease-associated heavy and light chains.

“Although CAR T-cell therapy is directed to both pathogenic and nonpathogenic B cells, the rebooting of the B-cell system after the disappearance of CAR T cells obviously occurs in the absence of the pathogenic B cells that trigger autoantibody production,” the authors wrote.

Finally, the researchers administered standard vaccines to each lupus patient, including tetanus, measles, mumps, rubella, varicella–zoster virus, and Epstein–Barr virus, and their protective IgG antibody responses remained stable.

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