CA(A)R T Cell Therapy and Neuroimmunology: From Understanding Toxicity to Identifying New Target Antigens

• Applicant: Dr. Leonie Müller-Jensen
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569527324

Chimeric Antigen Receptor (CAR) T cell therapy is a personalized, antigen-specific immunotherapy that has transformed the treatment landscape for hematologic malignancies. Encouraged by promising results in rheumatologic autoimmune diseases, its application is now being explored in neuroimmunological disorders such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis. Despite its clinical efficacy, CAR T cell therapy is frequently associated with severe side effects, many of which involve the nervous system. In particular, the mechanisms, risk factors, and immunological features of neurotoxicity following B-cell maturation antigen (BCMA)-directed CAR T therapy remain poorly understood. One promising strategy to improve the safety of CAR T cell therapy is the development of autoantigen-specific approaches using chimeric autoantibody receptor (CAAR) T cells, which selectively eliminate autoreactive B cells while sparing protective immunity. This translational research project will be conducted at the Weill Institute for Neurosciences at the University of California, San Francisco (UCSF), under the mentorship of host researcher Dr. Scott Zamvil and co-mentor Dr. Michael Wilson. It aims to advance mechanistic insights into CAR T cell-related neurotoxicity and to develop novel CAAR T cell therapies for neuroimmune diseases. In the first part of the project, I will generate murine CAAR T cells to target autoreactive B cell receptors implicated in two model diseases: Kelch-like protein 11 (KLHL11) encephalitis and autoimmune vitamin B12 central deficiency (ABCD), which are linked to pathogenic B cells specific for KLHL11 and CD320, respectively. The therapeutic efficacy of these CAAR T cells will be assessed in vitro using cytotoxicity assays and in vivo in a Nalm6-based mouse model. The second part of the project will focus on immunoprofiling of patients who developed neurological complications—such as movement disorders, cognitive deficits, and neuropathies—following BCMA-directed CAR T cell therapy. Using advanced methods including single-cell RNA sequencing, multiparameter flow cytometry, and phage display immunoprecipitation sequencing (PhIP-Seq), immune signatures in the peripheral blood and cerebrospinal fluid will be compared to matched CAR T-treated patients without neurological toxicity. Additional analyses will include human leucocyte antigen (HLA) typing and quantification of neurodegenerative markers such as neurofilament light chain (NFL). By integrating preclinical innovation with clinical investigation, my overarching goal is to improve the safety of existing CAR T cell therapies and advance the development of targeted CAAR T cell treatments for patients with neuroimmune diseases.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Scott Zamvil, Ph.D.