In Vivo generation of anti-CD19 CAR-T cells for the treatment of B-cell mediated autoimmune diseases

作者：Eli Pasackow, Camille Khairallah, Joshua Ferrell, Adrianna Graziano, Mengmeng Zheng, Jennifer Tian, Daniel Kong, Jamie Yuan, Srujan Gandham, Shreya Mukherji, Suzeeta Bhandari, П. В. Макаров, Nikita Prajapati, Venus Sahu, Aidan O'Willey, Sanmit Adhikari, William Brinton, Mansi Deshmukh, Clarissa Esmeralda Halim, Elizabeth Belcher, Stuart Cole, Allison I. Jasa, Israel Rivas, Jared Martin, Heather Lopes, Husain Attarwala, Felipe Bendezu, Robert Dorkin, Lukasz Sweich, Scott Barros · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-4106 · 被引用次数：6 · 研究领域：CAR-T cell therapy research、Monoclonal and Polyclonal Antibodies Research、Virus-based gene therapy research

Abstract Emerging clinical data demonstrate the transformative potential of B cell-depleting CAR-T therapies for patients with autoimmune diseases. However, despite their promise, the broad clinical deployment of ex vivo CAR-T therapies remains limited by several key challenges including manufacturing complexity, high cost, the need for lymphodepleting chemotherapy, and safety risks related to cytokine release syndrome. In addition, the persistence of administered CAR-T cells can lead to prolonged B cell aplasia, leaving patients immunocompromised long after the clearance of pathogenic B cell clones. To overcome these limitations while preserving efficacy, we have developed a novel, transient in vivo T cell engineering platform that utilizes our targeted lipid nanoparticle (tLNP) to deliver mRNA encoding an anti-CD19 CAR specifically to cytotoxic CD8+ T cells. This targeted delivery system drives rapid and precise in vivo engineering of T cells without the need for ex vivo manipulation or pre-conditioning. The resulting CAR-T cells exhibit potent cytolytic activity and high specificity across in vitro assays and preclinical in vivo models. Following a single two-dose treatment cycle in studies of CD34+ humanized mice and non-human primates, we observe potent and durable B cell depletion from the periphery and B cell rich tissues, including the spleen, bone marrow and lymph nodes at doses as low as 0.3 mg/kg. Importantly, this depletion encompasses differentiated B cell popula...