Trial Summary
What is the purpose of this trial?The goal of this study is to test a drug called KYV-101 in people who have progressive multiple sclerosis (MS) and who have not responded to standard therapies to slow disease progression. The main questions it aims to answer are:
* What is the highest therapy dose that can be given without causing harm?
* Can this therapy enter the central nervous system?
Participants will be asked to:
* Attend 14 visits plus an 8-day inpatient hospital stay over the course of 58 weeks.
* Complete apheresis and chemotherapy treatments in preparation for KVY-101 therapy.
* Undergo medical and research testing such as physical and neurological exams, MRI, lumbar puncture, blood draws, questionnaires, and vision assessments.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you must stop taking your current medications. However, you must be able to interrupt autoimmune disease therapy prior to apheresis, and you cannot be on ongoing anticoagulation. It's best to discuss your specific medications with the study team.
What data supports the idea that CAR T Cell Therapy for Multiple Sclerosis is an effective treatment?
The available research shows that CAR T Cell Therapy, specifically engineered regulatory T cells, can suppress autoimmune activity in a model of multiple sclerosis. These engineered cells were able to reduce disease symptoms in experimental settings, suggesting potential effectiveness for MS patients. However, the research primarily focuses on preclinical models, and more studies are needed to confirm these results in humans. Compared to other treatments like interferon beta-1b, which is not suitable for all patients and is not a cure, CAR T Cell Therapy offers a promising alternative by directly targeting immune cells involved in MS.
12345What safety data exists for CAR T Cell Therapy in treating Multiple Sclerosis?
CAR T Cell Therapy, including treatments like KYV-101 and Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, has been associated with significant toxicities such as severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX). Studies have shown that these risks vary depending on the type of cancer treated, with acute lymphocytic leukemia patients experiencing higher risks compared to those with non-Hodgkin's lymphoma or multiple myeloma. The use of certain vector designs and cytokine-directed therapies can influence the rates of these toxicities. Additionally, cardiovascular events have been reported, with a notable association between neurotoxicity and cardiovascular events. Overall, while CAR T Cell Therapy shows promise, it is accompanied by serious safety concerns that require careful management and further research.
678910Is the treatment KYV-101 a promising treatment for Multiple Sclerosis?
Yes, KYV-101, a type of CAR T-cell therapy, shows promise for treating Multiple Sclerosis. It uses specially engineered cells to target and suppress harmful immune responses, potentially reducing disease symptoms and progression.
13111213Eligibility Criteria
This trial is for people with progressive multiple sclerosis who haven't improved with standard treatments. They must be able to attend numerous visits, including an 8-day hospital stay, and undergo procedures like apheresis (a blood filtering process), chemotherapy, MRI scans, lumbar punctures, and vision tests over approximately 58 weeks.Inclusion Criteria
I have been diagnosed with progressive MS.
Participant must sign a written informed consent form (ICF) prior to any screening procedures
My organs are functioning well.
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Exclusion Criteria
I have had cancer before, but it fits the trial's exceptions.
I have had my spleen removed.
I plan to get a live vaccine after joining the study.
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Participant Groups
The study is testing KYV-101, a type of CAR T cell therapy designed for MS. It includes preparatory chemotherapy with cyclophosphamide and fludarabine before administering KYV-101. The aim is to find the highest safe dose of KYV-101 and see if it can reach the central nervous system.
2Treatment groups
Experimental Treatment
Group I: Dosing Cohort #2: KYV-101 CAR+ T -- 1×10^8 cellsExperimental Treatment3 Interventions
An additional five participants are planned for enrollment at the higher dose level (1×10\^8 cells).
Group II: Dosing Cohort #1: KYV-101 CAR+ T -- 0.33 ×10^8 cellsExperimental Treatment3 Interventions
Five participants will be enrolled at the lower dose (0.33 ×10\^8 cells). Once safety and tolerability are adequately assessed, treatment will proceed to the higher dose level.
KYV-101 is already approved in United States for the following indications:
🇺🇸 Approved in United States as KYV-101 for:
- Refractory Lupus Nephritis
- Stiff-Person Syndrome
- Myasthenia Gravis
- Diffuse Cutaneous Systemic Sclerosis (Scleroderma)
- Primary and Secondary Progressive Multiple Sclerosis
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, San Francisco, Multiple Sclerosis CenterSan Francisco, CA
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Who Is Running the Clinical Trial?
Bruce CreeLead Sponsor
Kyverna TherapeuticsIndustry Sponsor
References
Engineered regulatory T cells expressing myelin-specific chimeric antigen receptors suppress EAE progression. [2022]The expansion of polyclonal T regulatory cells (Tregs) offers great promise for the treatment of immune-mediated diseases, such as multiple sclerosis (MS). However, polyclonal Tregs can be non-specifically immunosuppressive. Based on the advancements with chimeric antigen receptor (CAR) therapy in leukemia, we previously engineered Tregs to express a T-cell receptor (TCR) specific for a myelin basic protein (MBP) peptide. These TCR-engineered specific Tregs suppressed the proliferation of MBP-reactive T effector cells and ameliorated myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). Herein, we extend this approach by creating human regulatory T cells expressing functional single-chain chimeric antigen receptors (scFv CAR), targeting either MBP or MOG. These scFv CAR-transduced Tregs retained FoxP3 and Helios, characteristic of Treg cells, after long-term expansion in vitro. Importantly, these engineered CNS targeting CAR-Tregs were able to suppress autoimmune pathology in EAE, demonstrating that these Tregs have the potential to be used as a cellular therapy for MS patients.
CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. [2021]Regulatory T cells (Tregs) play essential roles in maintaining immunological self-tolerance and preventing autoimmunity. The adoptive transfer of antigen-specific Tregs has been expected to be a potent therapeutic method for autoimmune diseases, severe allergy, and rejection in organ transplantation. However, effective Treg therapy has not yet been established because of the difficulty in preparing a limited number of antigen-specific Tregs. Chimeric antigen receptor (CAR) T cells have been shown to be a powerful therapeutic method for treating B cell lymphomas, but application of CAR to Treg-mediated therapy has not yet been established. Here, we generated CD19-targeted CAR (CD19-CAR) Tregs from human PBMCs (hPBMCs) and optimized the fraction of the Treg source as CD4+CD25+CD127loCD45RA+CD45RO-. CD19-CAR Tregs could be expanded in vitro while maintaining Treg properties, including high expression of the latent form of TGF-β. CD19-CAR Tregs suppressed IgG antibody production and differentiation of B cells via a TGF-β-dependent mechanism. Unlike conventional CD19-CAR CD8+ T cells, CD19-CAR Tregs suppressed antibody production in immunodeficient mice that were reconstituted with hPBMCs, reducing the risk of graft-versus-host disease. Therefore, the adoptive transfer of CD19-CAR Tregs may provide a novel therapeutic method for treating autoantibody-mediated autoimmune diseases.
Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells. [2023]Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited.
Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model. [2020]The anti-CD19 chimeric antigen receptor (CAR) T cells showed excellent effect against acute lymphoblastic leukemia (ALL) in bone marrow (BM) in clinical trials. However, it remains to be elucidated whether the CD19 CAR T cell therapy is effective for ALL cells in central nervous system (CNS) because the patients with isolated or advanced CNS disease were excluded from clinical trials of systemic intravenous (i.v.) delivery of CAR T cells. Therefore, the preclinical evaluation for the efficacy of CAR T cell therapy against ALL cells in CNS is essential for clinical application. We evaluated the effect and adverse reaction of CD19 CAR T cells against ALL in CNS using a xenograft mouse model by i.v. or intra-cerebroventricular (i.c.v.) delivery of CAR T cells. Injection of piggyBac CD19 CAR T cells by i.v. had partial effects, whereas all CAR T i.c.v.-delivered mice had eliminated ALL in CNS. Although some CAR T i.c.v.-delivered mice showed transient changes of clinical symptoms during the first few days after treatment, none of CAR T i.c.v.-delivered mice displayed fatal adverse events. In this study, we demonstrated that direct delivery into CNS of CAR T cells is a possible therapeutic approach with the xenograft mouse model.
Investigational drug therapies of treatment of multiple sclerosis. [2017]The licensing of interferon beta-1b dramatically changed the treatment of multiple sclerosis (MS) in the United States. Although it was the first therapeutic agent shown to affect the natural course of the disease, interferon beta-1b is not appropriate for all patients and is far from being a cure. Several other promising therapies now under study include immunosuppressive and immunomodulatory drugs to limit inflammation; oral administration of myelin to induce tolerance; monoclonal antibodies designed to deliver targeted immunotherapy; potassium channel blockers to facilitate conduction along demyelinated axons; and glial growth factors to promote remyelination. Clinical trials of potential therapeutic agents have proliferated in the past decade in conjunction with rapid advances in our understanding of the immunologic basis of MS. Some investigational therapies are associated with problematic toxicities, others benefit only a minority of patients, and many are still in the early stages of development. Nevertheless, because current therapeutic options are limited, and because the history of MS therapy is one of disappointment and frustration, it is essential that legitimate, scientifically based advances be widely disseminated to the neurologic community. This article reviews some of the most promising current and investigational therapies for MS.
[Management of adverse events of CAR-T therapy]. [2023]Chimeric antigen receptor T cell (CAR-T) therapy has strong efficacy as well as characteristic complications. Although overshadowed by the glaring clinical picture of cytokine releasing syndrome and immune effector cell-associated neurotoxicity syndrome, there are many other side effects that are important to manage. In this article, CAR-T-specific adverse events will be reviewed based on the actual clinical experience.
Cardiovascular Events Associated with Chimeric Antigen Receptor T Cell Therapy: Cross-Sectional FDA Adverse Events Reporting System Analysis. [2021]Chimeric antigen receptor (CAR) T cell therapy is approved in the United States for the treatment of acute lymphocytic leukemia and aggressive B cell lymphomas. Multiple cardiovascular adverse events (CVEs) associated with CAR-Ts have been observed in small studies, but no large-scale studies exist. Leveraging the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), we identified all reported adverse events (AEs) associated with CAR-T therapy (tisagenlecleucel and axicabtagene ciloleucel) from 2017 to 2019. Reports with missing age and sex were excluded. CVEs were classified into arrhythmias, heart failure (HF), myocardial infarction (MI), and other CVEs. Logistic regression and hierarchical clustering were used to identify factors associated with CVEs. A total of 996 reported AEs were observed (39.1% associated with tisagenlecleucel and 60% with axicabtagene ciloleucel). Of all patients experiencing AEs, the median age was 54 (interquartile range, 21 to 65) years; 38.9% were females. In total, 19.7% (196) of all AEs reported to the FDA were CVEs. The most common CVEs were arrhythmia (77.6%), followed by HF (14.3%) and MI (0.5%). In adjusted analysis a positive association was observed between those presenting with CVE with neurotoxicity (odds ratio, 1.76; 95% confidence interval, 1.20 to 2.60; P = .004). Additionally, when both CVE and cytokine release syndrome (CRS) are present, neurotoxicity is the most common noncardiac AE, which clusters with them (Jaccard similarity: 73.1). The mortality rate was 21.1% overall but 30.1% for those reporting CVEs. In FAERS, reported CVEs with CAR-T are associated with high reported mortality. The development of either CRS or neurotoxicity should prompt vigilance for cardiovascular events.
Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging. [2023]Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Enabling in vitro methods to allow meaningful, sensitive in vivo biodistribution studies is needed to better understand CAR-T cell disposition and its relationship to both effectiveness and safety of these products.
Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. Although this exploratory study was limited by unadjusted cross-study comparisons, it independently reproduced known risk factors for CAR T cell toxicity. Findings provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.
Associated Toxicities: Assessment and Management Related to CAR T-Cell Therapy. [2020]The impressive disease response observed with chimeric antigen receptor (CAR) T-cell therapy is accompanied by the potential for unique and severe toxicities. Cytokine release syndrome (CRS) and neurologic toxicities have emerged as prominent toxicities associated with this treatment modality.
Application of CAR-T cell technology in autoimmune diseases and human immunodeficiency virus infection treatment. [2023]Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy approach that has played a tremendous role in the battle against cancer for years. Since the CAR T lymphocytes are unrestricted-major histocompatibility complex T lymphocytes, they could identify more targets than natural T cells, resulting in practical and widespread functions. The good prospects of CAR T-cell therapy in oncology can be additionally applied to treat other diseases such as autoimmune and infectious diseases. CAR-T cell-derived immunotherapy for autoimmune disorders can be allocated to CAR-Tregs and chimeric autoantibody receptor T cells. Other generations of CARs target human immunodeficiency virus (HIV) proteins. In this review, we summarize CAR-T cell therapies in autoimmune disorders and HIV infection.
Large-scale manufacturing and characterization of CMV-CD19CAR T cells. [2022]Adoptive transfer of CD19-specific chimeric antigen receptor (CD19CAR) T cells can induce dramatic disease regression in patients with B cell malignancies. CD19CAR T cell therapy may be limited by insufficient engraftment and persistence, resulting in tumor relapse. We previously demonstrated a proof of principle that cytomegalovirus (CMV)-specific T cells can be isolated and enriched prior to CD19CAR transduction to produce CMV-CD19CAR T cells, and that these CMV-CD19CAR T cells can be expanded in vivo through CMV vaccination, resulting in better tumor control in a murine model. Here we developed a clinical platform for generating CMV-CD19CAR T cells.
Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. [2021]We developed an approach that increases CD4+CD25+ regulatory T-cell potency by antigen-specifically redirecting them against pathologic T lymphocytes. The regulatory cells are transgenically modified with chimeric receptors that link antigen-major histocompatibility complex (MHC) extracellular and transmembrane domains with the cytoplasmic signaling tail of T-cell receptor zeta (TCR-zeta). The receptors' antigen-MHC recognizes the TCR of cognate T lymphocytes. Receptor engagement stimulates the receptor-modified T cell (RMTC) through the linked zeta chain. CD4+CD25+ RMTCs expressing a myelin basic protein (MBP) 89-101-IAs-zeta receptor, unlike unmodified CD4+CD25+ T cells or CD4+CD25- RMTCs, prevented and treated experimental allergic encephalomyelitis (EAE) induced with MBP89-101. The RMTCs were effective even after the autoreactive T-cell repertoire had diversified to include specificities not directly targeted by the chimeric receptor. Remissions were sustained and mortality was decreased from more than 50% to 0%. These results provide proof of principal for a novel approach to enforce the interaction of regulatory and pathologic T lymphocytes, thereby facilitating the treatment of autoimmune disease.