A Study of Kyv-101, a CD19 CAR T Cell Therapy, in Participants with Treatment Refractory Progressive Multiple Sclerosis

Background Progressive forms of multiple sclerosis (MS) are characterized by accumulation of neurologic deficits leading to disability and impairment in quality of life. Currently approved treatments include siponimod, an S1P receptor modulator, and ocrelizumab, an anti-CD20 monoclonal antibody. These agents have modest efficacy with many patients experiencing worsening symptoms on therapy. Progression of MS after peripheral B-cell depletion is likely due to persistence of pathogenic CNS-resident B-cells. This is evidenced by detection of clonally expanded immunoglobulin G (IgG) and oligoclonal bands (OCB) in the cerebrospinal fluid (CSF), and continued presence of ectopic meningeal lymphoid aggregates after treatment with anti-CD20 monoclonal antibodies (Monson 2005). CD19-directed chimeric antigen receptor (CAR) T-cells have been shown to penetrate into the CNS, and may achieve more robust depletion of CNS-resident B-cells. In this investigator-initiated trial (NCT06451159), we hypothesize that KYV-101, a fully human autologous CD19 CAR T-cell, will achieve CNS penetration in patients with progressive forms of MS, and that this treatment will be safe and effective in this disease. Objectives The primary objectives of this phase 1b study are (1) to evaluate CNS penetration of KYV-101 as measured by detection in the CSF, and (2) to characterize the preliminary safety of KYV-101 as measured by incidence and severity of adverse events and dose limiting toxicities (DLTs). The secondary objectives of this study include (1) characterizing target engagement within the CNS as measured by reduction of CSF OCB and/or IgG index; (2) additional safety measures including incidence of disease reactivation, detection of replication competent lentivirus, and immune reconstitution; (3) pharmacokinetics of KYV-101; and (4) pharmacodynamics of KYV-101 including immunophenotyping of peripheral blood and CSF CAR T-cells using 10X immune profiling, flow cytometry, and other measures, cytokine profiling, and other biomarkers. Additional objectives and endpoints include efficacy measures such as changes in Expanded Disability Status Scale (EDSS), and patient-reported outcomes (PROs). Methods This is an open-label, phase 1b, single-center, single ascending dose study of KYV-101, an autologous CD19 CAR T-cell product. Eligible participants must have a diagnosis of primary or secondary progressive MS based on the 2017 International Panel Criteria (Thompson 2018). Additional eligibility criteria include age 25-70 years, EDSS score 3-7, clinical progression of disability within 2 years prior to enrollment, adequate hematologic and organ function, and absence of infectious or other significant comorbidities. A total of 10 participants will be enrolled. After apheresis and CAR T-cell production, participants will receive standard lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by a single infusion of KYV-101 at one of two dose levels. The first 5 participants will receive 0.33 x108 CAR-positive T-cells. If no DLTs are seen in the first 28 days following CAR T-cell infusion in this cohort, then the subsequent 5 participants will receive 1 x108 CAR-positive T-cells. Participants will be monitored through the follow up period of 48 weeks following KYV-101 infusion. Key study procedures include CSF sampling at baseline and at 14 days, 24 weeks, and 48 weeks after KYV-101 infusion to assess CAR T-cell presence, IgG index, OCB, and biomarkers as above; MRI brain at baseline, and at 8 weeks and 48 weeks after KYV-101 infusion; and monitoring of standard laboratory parameters, neurologic status, PROs, and EDSS regularly through the follow up period. Key endpoints will be summarized using descriptive statistics as appropriate. For this phase 1b study, sample size was determined based on feasibility. Conclusion Improving treatments for patients with progressive MS is a major unmet need. The present trial will provide preliminary data which we expect will support the use of CD19 CAR T-cell therapy for this disease. As of July 2024, one patient has been enrolled and has undergone apheresis. Available data may be presented at the time of the conference. The study is expected to complete in 2026. MRS and SG contributed equally to the work