Off-the-Shelf Drug Matches CAR-T Effects in Refractory Lupus

A new chapter may have begun in the exciting story of “immune reset” therapy for difficult-to-treat autoimmune diseases, with a patient with severe refractory lupus obtaining drug-free remission after treatment with an antibody product normally used in multiple myeloma.

The drug, teclistamab (Tecvayli), is a bispecific agent that targets both the CD3 protein and the B-cell maturation antigen (BCMA). Tobias Alexander, MD, and colleagues at Charité-Universitätsmedizin Berlin tried it in a female patient, age 23, with systemic lupus erythematosus (SLE) who had not responded to a wide variety of conventional treatments.

She received teclistamab injections in the recommended step-up dosage sequence over a period of 5 weeks, Alexander’s group reported in a letter to the New England Journal of Medicine.

SLE biomarkers quickly dropped to normal or near-normal levels, and most impressively, “a complete resolution of mucocutaneous and musculoskeletal manifestations [was] also observed after the completion of teclistamab treatment,” they wrote. Remission lasted to the end of follow-up, which was just 16 weeks in this preliminary analysis.

“The response in our patient was remarkable and could position bispecific BCMA-directed antibodies as a future off-the-shelf treatment, potentially with incidences of response similar to those obtained with anti-CD19 CAR T-cell therapies,” Alexander and colleagues enthused. “However, a longer follow-up period, particularly until the occurrence of B-cell repopulation, and treatment of a larger patient population are needed to determine the incidence and duration of response.”

In the last couple years, reports of almost miraculous responses to chimeric antigen receptor (CAR) T-cell therapy, first developed as cancer treatments, in patients with SLE and certain other autoimmune conditions have galvanized the rheumatology community. These experiences have engendered hopes of actual cures for these patients, many of whom have suffered for years without meaningful help from standard treatment, including the newest targeted therapies.

CAR T-cell treatment, in which patients’ T-cells are extracted and modified ex vivo to target certain B-cell antigens, is used in oncology to treat B-cell lymphomas. In rheumatology, the goal is to eliminate the subpopulation of B-cells that produce autoantibodies and otherwise trigger autoimmune attack, thus yielding an “immune reset” in which disease pathology is eliminated at the root. Early experiences in a few dozen patients have shown that this is highly effective, with remissions lasting as long as 3 years and, thus far, only one relapse.

But Alexander and colleagues noted that CAR T-cell therapies are expensive and require conditioning regimens that expose patients to serious infection, problems that “preclude their widespread use.” The group hypothesized that teclistamab would have the same effect: its mechanism of action should stimulate “CD3-positive T-cell activation and the subsequent destruction of target cells,” in this case B-cells responsible for autoimmunity.

Their initial patient had a 6-year history of SLE and was experiencing active lupus nephritis with autoimmune hemolytic anemia, vesiculobullous lesions, and polyarthritis, the researchers explained. Six different conventional drugs and two biologics typically used in SLE had been tried without substantial relief.

Per the drug’s label, teclistamab was started with subcutaneous injections of 0.3 and 0.6 mg/kg, then a third dose of 0.8 mg/kg on day 7. The full 1.5-mg/kg dose was then given at weeks 2 and 5. The woman had been taking mycophenolate mofetil and oral prednisolone; the former was stopped prior to commencing teclistamab, and the steroid was discontinued at week 6.

Anti-double stranded DNA antibody titers dropped rapidly and remained undetectable through week 16, the investigators reported. Other SLE biomarkers likewise normalized or nearly so: urinary protein/creatinine ratio, blood hemoglobin, and antiglobulin test results. Peripheral B-cell counts also declined rapidly along with “a vast eradication of bone marrow plasma cells and B-cells,” the researchers wrote.

Clinically, SLE Disease Activity Index-2K scores fell from 20 at baseline to zero at week 6, where they remained through the end of current follow-up at week 16.

All these good things did come with some not so good. The patient experienced grade 2 cytokine release syndrome (CRS), pneumonia, sinusitis, and hypogammaglobulinemia. The CRS was treated with tocilizumab (Actemra), and Alexander’s group said the gamma globulin deficiency may warrant a new round of vaccinations for infection prevention. These effects, they noted, have also been reported with teclistamab in myeloma patients. Some others reported in that population, such as neutropenia, anemia, and neurotoxicity, did not appear in the lupus patient.

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