New Therapies Show Promise for Severe Autoimmune Diseases
Researchers are exploring the potential of T-cell engagers – therapies that harness the body’s own immune system – to treat severe, treatment-resistant autoimmune diseases like antisynthetase syndrome (ASyS) and systemic sclerosis (SSc). A recent compassionate use program at the University Hospital of Düsseldorf, Germany, investigated the use of blinatumomab and teclistamab in patients who had failed multiple conventional treatments, with promising early results.
Understanding the Challenge
Autoimmune diseases occur when the immune system mistakenly attacks the body’s own tissues. ASyS and SSc are particularly challenging to treat, often leading to significant disability and a high unmet medical need. Both diseases involve activation of B cells and the presence of specific autoantibodies, which contribute to inflammation and tissue damage. Traditional treatments, including immunosuppressants like methotrexate, azathioprine, and rituximab (RTX), often prove ineffective in the long term, or are associated with significant side effects.
How T-Cell Engagers Work
T-cell engagers are a relatively new class of immunotherapy. Blinatumomab, for example, is a bispecific antibody that binds to both CD19 on B cells and CD3 on T cells, effectively bringing these two types of immune cells together. This interaction activates the T cells to kill the B cells. Teclistamab targets B-cell maturation antigen (BCMA) on B cells, similarly activating T cells for targeted destruction. The goal is to selectively eliminate the autoantibody-producing B cells that drive the disease process.
Study Details and Patient Characteristics
The compassionate use program involved ten patients – five with ASyS and five with SSc – all of whom had exhausted standard treatment options. All patients with ASyS were positive for anti-Jo1 autoantibodies, and a majority also had antibodies against Ro-52. Patients with SSc were diagnosed with diffuse cutaneous SSc (dcSSc). Prior to the T-cell engager therapy, all patients had failed at least four (ASyS) or three (SSc) immunomodulatory medications.
The ASyS patients presented with symptoms including muscle weakness, shortness of breath, mechanic’s hands (a characteristic tightening of the fingers), and weight loss. Many also had interstitial lung disease (ILD), a serious condition affecting the lungs. SSc patients exhibited widespread skin fibrosis (thickening and hardening of the skin), ILD, and evidence of heart involvement.
Treatment and Outcomes
Patients received either blinatumomab or teclistamab via intravenous infusion or subcutaneous injection, respectively. Treatment protocols included premedication to manage potential side effects, such as cytokine release syndrome (CRS). Following the initial T-cell engager therapy, patients received maintenance treatment with rituximab (RTX) to prevent the re-emergence of autoantibody-producing B cells.
Initial results showed that both blinatumomab and teclistamab reduced the number of target cells in affected tissues – muscle in ASyS patients and skin in SSc patients – and decreased autoantibody levels. In ASyS patients, blinatumomab led to rapid improvements in muscle strength, reduced inflammation, and stabilization of ILD. SSc patients treated with teclistamab experienced improvements in skin fibrosis, stabilization of ILD, and resolution of tendon friction rubs.
Safety Considerations
Treatment with T-cell engagers was associated with adverse events, including CRS, an inflammatory response that can range from mild to severe. Two ASyS patients and all SSc patients experienced CRS up to grade 3 in severity. However, no patients developed immune effector cell-associated neurotoxicity syndrome (ICANS), a potentially serious neurological complication. Respiratory infections requiring antibiotic treatment were also observed in some patients.
The Role of Maintenance Therapy
Researchers found that inhibiting B cell redifferentiation with maintenance therapy using RTX was crucial for prolonged disease control, even in patients who had previously not responded to RTX. This suggests that preventing the replenishment of autoantibody-producing B cells is essential for sustained remission.
Future Directions
These findings, published in in Nature, suggest that T-cell engagers may offer a valuable rescue therapy option for patients with treatment-refractory ASyS and SSc. Further research is needed to confirm these results in larger, controlled clinical trials and to optimize treatment protocols, including the timing and duration of RTX maintenance therapy. The use of advanced techniques like CODEX staining, which allows for detailed analysis of immune cell populations in tissue samples, is helping researchers to better understand the mechanisms of action of these therapies and identify potential biomarkers for predicting treatment response.
The compassionate use program highlights the importance of exploring innovative treatment strategies for patients with severe autoimmune diseases who have exhausted conventional options. While these therapies are not without risks, the potential benefits for carefully selected patients are significant.
