Kyverna Publishes Promising First Case Reports of CAR-T Cell Therapy in Progressive Multiple Sclerosis

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Overall, the data empower the potential of CAR-T cell therapy for patients with advanced multiple sclerosis that are refractory to conventional antibody-mediated B cell depletion.

Christoph Heesen, MD, professor for clinical and rehabilitative MS research at the University Medical Center, Hamburg-Eppendorf

Christoph Heesen, MD

Recently, Kyverna Therapeutics published the first reports of individual treatment with a fully human CD19 CAR-T cell therapy, KYV-101, in 2 patients with progressive multiple sclerosis (MS). All told, results showed that the therapy was tolerable over a short-term period, with CAR-T cell expansion observed in cerebrospinal fluid (CSF) without neurotoxicity. Intrathecal antibody production also decreased after CAR-T cell infusion in 1 patient.1,2

KYV-101, a first-in-class CD19 CAR-T cell therapy, had its efficacy and safety assessed in 2 patients, a 47-year-old female with a 23-year history of MS and a 36-year-old male who was diagnosed with primary progressive MS (PPMS) in 2019. Each patient received a single dose of 1 x 108 second-generation CD19 CAR-T cells following lymphodepletion with fludarabine and cyclophosphamide. The KYV-101 construct included a C19 binding domain, a CD8a hinge and transmembrane domain, a CD28 co-stimulatory domain, and a CD3ζ activation domain.

Patient 1 was originally diagnosed with relapsing-remitting MS but due to progressive neurological deterioration, B cell-depleting therapy with ocrelizumab was initiated in 2021 and continued until 3 months before CAR-T cell infusion. After receiving KYV-101, the patient developed a recurring rise in body temperature that was consequently treated with 2 sequential doses of tocilizumab and 2 doses of dexamethasone to prevent higher-grade CRS, which conveys increased risk for immune effector cell-associated neurotoxicity syndrome (ICANS).

Days after initiation, the patient continued to see facial and neck swelling and thus was administered a third dose of tocilizumab and another single dexamethasone dose, which transitioned to 10 mg every 6 h at day 6 because of another rise in body temperature. Symptoms rapidly subsided thereafter, dexamethasone was tapered down, and no ICANS occurred. The patient presented with isolated transient worsening of pre-existing spastic paresis of the left side, interpreted as Uhthoff’s phenomenon, which increased the patient’s Expanded Disability Status Scale (EDSS) score to 6.0 before returning to baseline (4.5) by day 29 and remaining stable.

"We are very pleased about offering this potentially paradigm-shifting treatment opportunity to patients that have exhausted other medical recourses,” co-author Christoph Heesen, MD, professor for clinical and rehabilitative MS research at the University Medical Center, Hamburg-Eppendorf, said in a statement.1 "Emerging findings indicating that this approach may affect disease biology in the central nervous system are promising, as preventing disease progression remains one of the most difficult challenges in MS therapy."

A follow-up on day 100 revealed no sign of treatment-related toxicity in patient 1 treated with KYV-101. Of note, there was 1 new T2 lesion detected at the thoracic spinal cord on day 64, which remained unchanged at day 100 on a subsequent MRI. This patient also had their reported walking distance increased from 400 m at baseline to 700 m at day 100 post-CAR-T cell infusion. In addition, there were no noted changes to other assessments of 25-foot walk, 9-hole peg test, and 6-minute walking distance.

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Patient 2 began ocrelizumab after receiving their diagnosis in 2019 and subsequently stopped treatment 4 months prior to receiving KYV-101. Coming into the study, the patient had a 2-year history of worsening gait due to lower limb paraparesis, which limited the patient’s walking distance to 10 m with the assistance of a walker. After CAR-T cell infusion and until the last follow-up (day 28), the patient demonstrated no signs of CRS or ICANS. The patient had no adverse events reported except a transient increase of transaminases, which improved with ursodeoxycholic acid treatment.

"Exploring the safety profile of CAR T administration in this population and hopefully establishing that it compares favorably to hematopoietic stem cell transplant may bring the cell therapy approach to a larger number of patients in need,” co-author Nicolaus Kröger, MD, professor of medicine and medical director of the Department of Stem Cell Transplantation at the University Medical Center Hamburg-Eppendorf, said in a statement.1 "If safe administration can be replicated in other patients and efficacy be formally established in clinical trials, this may bring a relevant therapeutic option to patients with MS."

For patient 2, no new neurological symptoms were observed, and EDSS remained stable throughout observation. Similar to patient 1, lymphocyte counts confirmed sufficient lymphocyte suppression prior to CAR-T cell therapy. In both cases, CAR-T cell presence and target-driven expansion in the CSF relative to peripheral blood was demonstrated by day 14. Consistent with peripheral expansion, this effect was more pronounced in case 1 (>64-fold) than in case 2 (>27-fold).

Despite both patients receiving ocrelizumab before the trial, circulating B cells were only detectable in the peripheral blood of patient 1 but not patient 2. This residual B cell population of patient 1 was depleted by day 2 post-infusion and did not reconstitute as of day 100. Notably, patient 1 saw a decrease in the number of oligoclonal bands from 13 to 6 on day 64, sustained through day 64, whereas patient 2 had no changes in the number of OCBs nor intrathecal immunoglobulin levels.

At the conclusion of the study, the authors wrote that, "These findings empower the potential of CAR-T cell therapy for patients with advanced MS that are refractory to conventional antibody-mediated B cell depletion. Systematic studies will be needed to further assess short- and long-term safety profiles and therapeutic effects with regard to suppression of disease activity. CD19-directed CAR-T cells could not only suppress inflammatory relapses, similar to anti-CD20 antibodies, but at the same time purge the CNS of residing B cells that likely contribute to progression independent of relapses."2

REFERENCES
1. First-in-disease use of Kyverna Therapeutics KYV-101 in patients with progressive multiple sclerosis published in Med. News release. Kyverna Therapeutics. March 29, 2024. Accessed April 1, 2024. https://www.prnewswire.com/news-releases/first-in-disease-use-of-kyverna-therapeutics-kyv-101-in-patients-with-progressive-multiple-sclerosis-published-in-med-302103748.html
2. Fischbach F, Richter J, Pfeffer LK, et al. CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis. Cell Press. Published March 29, 2024. doi:10.1016/j.medj.2024.03.002.
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