CAR-T Therapy Preserves Fertility in Lupus; Bispecific Antibodies Show Promise in Autoimmune Diseases

A 24-year-old woman with refractory lupus nephritis has achieved two successful pregnancies following dual-target CAR-T cell therapy, with no evidence of CAR-T cell transmission to either infant. The case demonstrated that the emerging therapy could induce long-term systemic lupus erythematosus remission, while preserving fertility, resulting in the delivery of healthy neonates.

The patient was diagnosed with SLE at age 20 and developed class IV lupus nephritis, receiving initial treatment with immunosuppression. Following relapse, she enrolled in a phase 1 trial of BCMA/CD19 directed CAR–T cell therapy. After achieving sustained molecular remission, the patient became pregnant spontaneously at 6-months and 21-months post infusion.

Throughout both pregnancies, data revealed the patient's lupus activity remained minimal without flares or any new disease activity. Testing of relevant blood markers also showed sustained immunosuppression of autoimmune activity. While some proinflammatory cytokines and inflammation-related cellular markers were elevated late in the second pregnancy, there appeared to be no resulting adverse effects. Both vaginal deliveries of healthy neonates were uncomplicated and to term.

While the patient had low levels of CAR–T DNA detected by quantitative PCR in her peripheral blood at seven months post-infusion, later analysis of the patient's blood, breast milk, and placenta, as well as the infants' blood at birth and during follow-up, were all negative for CAR–T cell DNA. Immunophenotyping of maternal peripheral blood late in the pregnancy and of neonatal blood at 48 hours and one year backed up the absence of CAR–T cell transmission and demonstrated robust immune development in the offspring. Both infants showed normal growth, neurodevelopment, and immune function.

In a separate development, bispecific T cell engagers showed efficacy in treatment-refractory autoimmune connective tissue diseases. Treatment under compassionate use with the CD19×CD3 T cell engager blinatumomab was administered to five patients with treatment-refractory antisynthetase syndrome, while the BCMA×CD3 T cell engager teclistamab was given to five patients with treatment-refractory systemic sclerosis.

Induction therapy with blinatumomab or teclistamab reduced target cells in affected muscle and skin, respectively, and decreased autoantibody titers. Blinatumomab induced rapid clinical, serological and histological improvement of myositis and stabilization of interstitial lung disease in patients with antisynthetase syndrome. Teclistamab improved skin fibrosis, stabilized ILD and resolved tendon friction rubs in patients with systemic sclerosis.

Inhibition of B cell redifferentiation by maintenance therapy with rituximab enabled prolonged disease control, even for patients previously unresponsive to rituximab. Treatment was associated with adverse events including cytokine release syndrome up to grade 3, in two patients with antisynthetase syndrome and in all patients with systemic sclerosis. No immune effector cell–associated neurotoxicity syndrome occurred. Respiratory infections treated with antibiotics occurred in six patients.

Autoimmune-mediated connective tissue diseases such as antisynthetase syndrome and systemic sclerosis have a high unmet medical need. Antisynthetase syndrome is a subtype of idiopathic inflammatory myopathy characterized by autoantibodies against aminoacyl-tRNA synthetases. Anti-Jo1 autoantibodies are the most frequent ASyS-specific autoantibodies, present in approximately 60−70% of patients with antisynthetase syndrome.

Systemic sclerosis is characterized by autoimmunity, vasculopathy and fibrosis. Anti-topoisomerase 1 and anti-fibrillarin autoantibodies characterize subgroups of patients with diffuse-cutaneous systemic sclerosis with severe organ involvement and poor prognosis. Anti-topoisomerase 1 autoantibodies remained detectable in patients with systemic sclerosis treated with second-generation CD19-targeting CAR-T cells, suggesting that CD19-targeting strategies do not eliminate anti-topoisomerase autoantibody-producing B cells.

CD19 is expressed across a broader range of B cell developmental stages than CD20, allowing depletion of additional B cell populations, including plasmablasts. However, long-lived plasma cells are not effectively targeted by CD19-targeted therapies. BCMA is highly expressed on plasma cells. BCMA-directed therapies may, thus, enable more effective targeting of autoantibody production than CD19-directed and CD20-directed therapies.

T cell engagers are bispecific monoclonal antibody derivates that bind to antigens on target cells as well as T cells, leading to T cell activation and killing of the target cell by T-cell-mediated cytotoxicity. Blinatumomab binds CD19 and CD3 and is currently approved for the treatment of acute lymphoblastic leukemia. Teclistamab binds BCMA and CD3 and is approved for the treatment of multiple myeloma.