T cell-dependent inflammatory disease
Many severe inflammatory conditions are driven by persistent, pathogenic T cells. These T cells can establish long-lived immune memory, continuously activate other immune and tissue cells, and sustain inflammation even when individual cytokines are blocked. In patients who no longer respond adequately to corticosteroids or targeted biologics, these persistent tissue T-cell populations may represent an important underlying driver of refractory disease with untapped potential. Cell-depleting therapies offer the possibility of addressing disease at the level of the pathogenic immune cell rather than blocking individual inflammatory signals. Much of the current development of in vivo CAR-T therapies for autoimmune disease is focused on eliminating B cells, building on the emerging potential of deep B-cell depletion to reset B cell-dependent autoimmunity. However, many or even most inflammatory diseases are not primarily B cell-driven and instead have a strong T cell-dependent component, including severe refractory asthma, myositis-associated interstitial lung disease and psoriatic arthritis described more thoroughly below.
A T cell-depleting in vivo CAR-M could extend the potential of targeted immune-cell depletion to this broader group of diseases. By generating CAR macrophages directly in the body and directing them against pathogenic T-cell populations, the approach is designed to remove disease-driving cells within affected tissues and potentially disrupt persistent inflammatory circuits that are not adequately addressed by current therapies.
Treatment refractory asthma
Severe refractory asthma is a serious form of asthma which remains poorly controlled despite optimized treatment with corticosteroids and biologic medicines. In a large subset of these patients, activated T cells persist within the airways and lung tissue. These tissue-resident T cells, including memory T cells, resist corticosteroids and continue to drive inflammation even when other inflammatory pathways are effectively treated. Persistent inflammation can contribute to progressive and potentially irreversible changes in the airways. Patients can experience frequent life-threatening asthma attacks, impaired lung function, and major limitations in quality of life. For patients whose disease remains uncontrolled despite currently available therapies, treatment options are limited. A T cell-depleting in vivo CAR-M therapy could offer a new approach by targeting the underlying cellular drivers of the disease. The therapy is designed to generate CAR macrophages directly in the body and enable them to recognize and remove pathogenic T cells within the inflamed lung tissue. By reducing the T-cell population that sustains airway inflammation and potentially replace it by normal T cells, this approach has the potential to break the cycle of chronic inflammation and provide deeper and more durable disease control than therapies that primarily block individual inflammatory signals.
Myositis with interstitial lung disease (ILD)
Myositis-associated ILD is a serious autoimmune condition in which the immune system attacks healthy tissues, causing inflammation and progressive damage in the lungs. One particularly severe form is associated with antibodies against MDA5 and can cause progressive ILD, leading to respiratory failure. T cells are an important component of the abnormal immune response in myositis and associated ILD. Activated T cells can accumulate in affected tissues, where they contribute to inflammation and tissue injury through direct cytotoxic activity and the release of inflammatory signals. Pathogenic T-cell populations in the lung may therefore sustain disease even when other inflammatory pathways are suppressed. MDA5-associated ILD can progress rapidly and remains associated with high mortality despite intensive treatment with combinations of corticosteroids and other immunosuppressive medicines. A T cell-depleting in vivo CAR-M, removing disease-driving T cells within the lungs and other affected tissues, could provide a new way to directly address the underlying causes of disease, and could provide more durable disease control than broad immunosuppression alone.
Treatment refractory psoriatic arthritis
Severe refractory psoriatic arthritis is a chronic immune-mediated disease in which inflammation affects the joints, tendons and surrounding tissues, often together with psoriasis of the skin. While modern biologics can provide effective disease control for most patients, a significant subset continues to have active and progressive disease despite intense treatment. T cells are central to the biology of psoriatic arthritis. Activated T cells, including IL-17-producing and other pathogenic effector and memory T-cell populations, accumulate in inflamed tissues and sustain the inflammatory process, thus contributing to chronic disease, irreversible structural damage, disability and major reductions in quality of life. A T cell-depleting in vivo CAR-M therapy could provide a new approach by directly targeting a key cellular driver of persistent disease. The therapy is designed to generate CAR macrophages in the body that recognize and remove pathogenic T cells within affected tissues. This has the potential to enable deeper and more durable disease control compared to currently available therapies.
B-cell derived cancer: DLBCL
Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma, a fast-growing type of blood cancer. The medical need for DLBCL is significant due to its aggressive nature. Patients often require a combination of chemotherapy, immunotherapy, and sometimes radiation therapy to achieve remission. Despite advancements in treatment, including approved autologous CAR-T therapies, there remains a need for improved and more affordable therapies.