CAR T-Cell Therapy for Multiple Sclerosis
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: Kyverna Therapeutics
No Placebo Group
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?
A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects with Refractory Primary and Secondary Progressive Multiple Sclerosis
Do I have to stop taking my current medications for this trial?
The trial protocol does not specify if you need to stop taking your current medications. However, since it involves CAR T-Cell therapy, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.
What data supports the idea that CAR T-Cell Therapy for Multiple Sclerosis is an effective treatment?
The available research does not provide specific data on CAR T-Cell Therapy for Multiple Sclerosis. Instead, it discusses other treatments like autologous hematopoietic stem cell transplantation (HSCT) and cell-based therapies. These treatments have shown some promise in managing multiple sclerosis by resetting the immune system and potentially offering neuroprotection. However, they also come with safety concerns and unresolved questions. Without specific data on CAR T-Cell Therapy, it's difficult to compare its effectiveness to these other treatments.12345
What 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 several safety concerns. Key adverse events include severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX), as identified in a cross-study safety analysis involving 1,926 subjects from various trials. The use of gammaretrovirus vectors with CD28 sequences was linked to higher rates of sNTX. Management strategies, such as cytokine-directed therapies and corticosteroids, have been associated with reduced sCRS rates. Cardiovascular events, including arrhythmias and heart failure, have also been reported, with a higher mortality rate observed in patients experiencing these events. Overall, while CAR T-Cell Therapy shows promise, it carries significant risks that require careful management.678910
Is the treatment KYV-101 a promising treatment for Multiple Sclerosis?
Research Team
M
MD
Principal Investigator
Kyverna Therapeutics, Inc.
Eligibility Criteria
This trial is for people with a tough form of multiple sclerosis (MS) that hasn't improved after other treatments. Participants must have been diagnosed with primary or secondary progressive MS and shown worsening disability despite previous anti-CD20 mAB therapy.Inclusion Criteria
I have been diagnosed with progressive MS.
My condition worsened despite anti-CD20 treatment over the last 6 months.
Key
Treatment Details
Interventions
- KYV-101 (CAR T-cell Therapy)
Trial OverviewThe study tests a new therapy using modified T-cells, called Anti-CD19 CAR T-cell therapy (KYV-101), to see if it can help manage severe MS. It's given after a standard treatment that reduces the number of immune cells in the body.
Participant Groups
2Treatment groups
Experimental Treatment
Active Control
Group I: KYV-101 CAR-T cells with lymphodepletion conditioningExperimental Treatment2 Interventions
Dosing with KYV-101 CAR T cells
Group II: Anti- CD20 mAbActive Control1 Intervention
Dosing with anti-CD20 mAb
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:
Stanford University Medical CenterPalo Alto, CA
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Who Is Running the Clinical Trial?
Kyverna Therapeutics
Lead Sponsor
Trials
11
Patients Recruited
320+
References
Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. [2013]Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P=0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for all patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P=0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens.
Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS. [2020]Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire.
Cell-based therapeutic strategies for multiple sclerosis. [2023]The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.
Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. [2020]To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).
RETRACTED: Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity [2023]Treatment of chronic neurodegenerative diseases such as multiple sclerosis (MS) remains a major challenge. Here we genetically engineer neural stem cells (NSCs) to produce a triply therapeutic cocktail comprising IL-10, NT-3, and LINGO-1-Fc, thus simultaneously targeting all mechanisms underlie chronicity of MS in the central nervous system (CNS): persistent inflammation, loss of trophic support for oligodendrocytes and neurons, and accumulation of neuroregeneration inhibitors. After transplantation, NSCs migrated into the CNS inflamed foci and delivered these therapeutic molecules in situ. NSCs transduced with one, two, or none of these molecules had no or limited effect when injected at the chronic stage of experimental autoimmune encephalomyelitis; cocktail-producing NSCs, in contrast, mediated the most effective recovery through inducing M2 macrophages/microglia, reducing astrogliosis, and promoting axonal integrity and endogenous oligodendrocyte/neuron differentiation. These engineered NSCs simultaneously target major mechanisms underlying chronicity of multiple sclerosis (MS) and encephalomyelitis (EAE), thus representing a novel and potentially effective therapy for the chronic stage of MS, for which there is currently no treatment available.
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.
[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.
Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies. [2023]Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia.
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.
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.
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.
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.