CD19-Directed CAR T Cell Therapy in 4 Patients with Refractory Multiple Sclerosis
Authors: Richter Johanna , Fischbach Felix , Pfeffer Lena Kristina , Fehse Boris , Berger Susanna Carolina , Reinhardt Stefanie , Schäfersküpper Mathias , Marquard Franziska Elisabeth , Rathje Kristin , Gagelmann Nico , Badbaran Anita , Lück Catherina , Janson Dietlinde , Wolschke Christine , Borie Dominic , Seibel Johann , Ayuk Francis A. , Friese Manuel , Heesen Christoph , Kroeger Nicolaus 
Published: December 2024

In multiple sclerosis (MS) disease progression is driven by chronic low-grade neuroinflammation leading to neuronal dysregulation. B cell directed monoclonal antibodies are effective, yet fail to halt disease progression, likely because of their inability to access, compartmentalization of neuroinflammation in the central nervous system (CNS). In the cerebrospinal fluid (CSF) of &gt; 95% of MS patients isolated oligoclonal bands (OCBs) produced by clonally restricted immunoglobulins are detectable. These immunoglobulins are secreted by CSF-derived meningeal or parenchymal B cells. CD19-directed CAR T cell therapy recently successfully entered the field of autoimmune diseases and may contribute to a deeper B cell depletion by the ability to infiltrate tissues.
We report on the individual treatment of CD19-directed CAR T cell therapy in 4 patients with refractory MS: One female patient with secondary progressive MS (SPMS; n=1), one male patient with primary progressive MS (PPMS; n=1) and 2 male patients with relapsing-remitting MS (RRMS; n=2). Disease courses ranged from 2 to 23 years. Prior to CAR T cell therapy all patients had received CD20-directed antibody therapy, which was discontinued 3 or 4 months before infusion. Before CAR T infusion, B cells were detectable at low level (29-5/µl; n= 2) or undetectable (n = 2) in the peripheral blood. A single dose of 1 x 108 second-generation anti-CD19-directed CAR T cells (KYV-101, Kyverna Therapeutics) was administered following lymphodepletion with fludarabine (30 mg/m2 on day -5, -4, -3) and cyclophosphamide (300 mg/m2 on day -5, -4, -3). The mean follow-up time after CAR T infusion was 151 days.
CAR T cell expansion was measured by digital PCR in blood and CSF. All 4 patients displayed a CAR T cell expansion within peripheral blood as well as a relative enrichment of CAR T cells in the CSF compared to peripheral blood. Patients 1, 3 and 4 exhibited a significant higher peak expansion than patient 2. CAR T cells remained detectable within the peripheral blood until the second month follow up for patient 2 to 4. Patient 1 presented a longer CAR T persistence past the month 3 follow up. All 4 patients showed reappearance of B cells after a mean of 88 days.
After CAR T infusion 3 of the 4 patients experienced reoccurring CRS grade 1 requiring treatment with tocilizumab, dexamethasone or anakinra. One patient presented with opioid refractory headaches without signs of intracranial pressure and received dexamethasone in suspicion of ICANS grade 1. A transient transaminitis (CTCAE grade 1 to 3) in all patients proved mostly self-limiting and was successfully treated with ursodesoxycholic acid in one case. Additionally, hematotoxicity was observed including neutropenia (CTCAE grade 2 to 4) requiring G-CSF treatment.
In the CSF of patients 1, 3 and 4 a rapid initial decrease of OCBs was observed, which was followed by a subsequent slight increase. In one of these patients OCBs where temporarily undetectable at day 14. These patients all displayed a single new spinal cord lesion within MRI-imaging at different timepoints of the early follow up period. Clinically one of these patients experienced an increase of the Expanded Disability Status Scale (EDSS) in form of a walking distance reduction 6 months after CAR T cell infusion. For all other patients the EDSS remained stable without clinical worsening. Patient 2 showed no reduction in OCBs and remained stable as measured by EDSS and MRI.
In conclusion, we present the first case series of CD19-directed CAR T cell therapy in 4 patients with refractory MS demonstrating an acceptable safety profile in spite of selective CAR T cell enrichment within the CNS. Short term follow-up indicates temporary target effects with at the same time signs of new inflammation in MRI imaging as well as clinical progression in one patient although long term data is needed.
Further data will be presented.