CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis

Felix Fischbach; Johanna Richter; Lena Kristina Pfeffer; Boris Fehse; Susanna Carolina Berger; Stefanie Reinhardt; Jens Kuhle; Anita Badbaran; Kristin Rathje; Nico Gagelmann; Dominic Borie; Johan Seibel; Francis Ayuk; Manuel A Friese; Christoph Heesen; Nicolaus Kröger

doi:10.1016/j.medj.2024.03.002

CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis

Med. 2024 Mar 22:S2666-6340(24)00114-4. doi: 10.1016/j.medj.2024.03.002. Online ahead of print.

Authors

Felix Fischbach¹, Johanna Richter², Lena Kristina Pfeffer¹, Boris Fehse², Susanna Carolina Berger², Stefanie Reinhardt¹, Jens Kuhle³, Anita Badbaran², Kristin Rathje², Nico Gagelmann², Dominic Borie⁴, Johan Seibel⁵, Francis Ayuk², Manuel A Friese¹, Christoph Heesen⁶, Nicolaus Kröger⁷

Affiliations

¹ Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
² Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
³ Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
⁴ Kyverna Therapeutics, Emeryville, CA 94608, USA.
⁵ Institute for Transfusion Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁶ Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: heesen@uke.de.
⁷ Department for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: nkroeger@uke.de.

PMID: 38554710
DOI: 10.1016/j.medj.2024.03.002

Abstract

Background: Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases.

Methods: Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS.

Findings: CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection of CD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64.

Conclusions: CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19⁺ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted.

Funding: Both individual treatments as well the generated data were not based on external funding.

Keywords: CAR-T cells; CRS; ICANS; Translation to patients; autoimmune disease; multiple sclerosis; neurotoxicity.