CAR T-Cell Therapy for Multiple Sclerosis

Overseen By Kyverna Therapeutics, Inc.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Kyverna Therapeutics

Must be taking: Anti-CD20 mAb

Must not be taking: CAR-T, Gene therapy

Disqualifiers: HIV, Hepatitis B/C, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KYV-101, a type of CAR T-cell therapy, to determine its effectiveness for people with multiple sclerosis (MS) that worsens despite other treatments. The study compares KYV-101 with an existing drug to identify which works better for progressive forms of MS. Suitable participants have primary or secondary progressive MS and have experienced worsening disability despite past treatments. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that KYV-101, a therapy using modified immune cells, is being tested for safety in treating multiple sclerosis (MS). In earlier studies, patients who received KYV-101 had promising outcomes. Some reports indicate it is generally well-tolerated, with no major safety issues so far. For instance, a study involving two patients with progressive MS found KYV-101 to be mostly safe.

These results are hopeful, but more research is needed to fully understand the treatment's safety. KYV-101 is currently in a Phase 2 study, meaning researchers are still collecting information on its effectiveness and safety. This phase indicates that while there is some evidence of safety, more data is needed to confirm how well the treatment is tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple sclerosis?

Researchers are excited about KYV-101 CAR T-cell therapy for multiple sclerosis because it offers a cutting-edge approach by using the body's own immune cells to fight the disease. Unlike standard treatments like interferons or monoclonal antibodies that mainly aim to reduce inflammation, KYV-101 involves reprogramming the patient’s T-cells to specifically target and eliminate problematic immune cells causing the damage. This novel mechanism could potentially provide longer-lasting relief and address the disease more precisely. Additionally, the use of lymphodepletion conditioning enhances the effectiveness of the CAR T-cells, which could result in more significant and sustained improvements for patients.

What evidence suggests that this trial's treatments could be effective for multiple sclerosis?

Research has shown that KYV-101, a type of treatment known as CD19 CAR T-cell therapy, may help treat progressive multiple sclerosis (MS). In this trial, some participants will receive KYV-101 CAR T cells with lymphodepletion conditioning. Early tests administered KYV-101 to a small group of patients who did not improve with other treatments. These patients showed promising results, indicating that the therapy can reach the central nervous system (CNS) to target MS. The treatment uses specially modified immune cells to attack certain cells in the body that might be involved in MS. While more research is needed to confirm its effectiveness, these early findings offer hope for people with progressive forms of MS. ^{2 3 4 5 6}

Who Is on the Research Team?

MD

Principal Investigator

Kyverna Therapeutics, Inc.

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive KYV-101 CAR T cells with lymphodepletion conditioning or anti-CD20 mAb

12 weeks

Multiple visits for dosing and monitoring

Follow-up

Participants are monitored for safety, efficacy, and pharmacokinetics of KYV-101

Up to 2 years

Regular visits for safety and efficacy assessments

What Are the Treatments Tested in This Trial?

Interventions

• KYV-101

Trial Overview The 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.

How Is the Trial Designed?

Group I: KYV-101 CAR-T cells with lymphodepletion conditioning Experimental Treatment 2 Interventions

Dosing with KYV-101 CAR T cells

Group II: Anti- CD20 mAb Active Control 1 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

Who Is Running the Clinical Trial?

Kyverna Therapeutics

Lead Sponsor

Trials

11

Recruited

320+

Published Research Related to This Trial

In a review of 996 adverse events related to CAR T cell therapy from 2017 to 2019, 19.7% were cardiovascular events (CVEs), with arrhythmias being the most common, indicating a significant risk associated with this treatment.

Patients experiencing CVEs had a higher mortality rate of 30.1%, highlighting the need for careful monitoring for cardiovascular issues, especially in those also presenting with neurotoxicity or cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Events Associated with Chimeric Antigen Receptor T Cell Therapy: Cross-Sectional FDA Adverse Events Reporting System Analysis. Guha, A., Addison, D., Jain, P., et al.[2021]

Current disease-modifying medications for multiple sclerosis are only partially effective and do not promote repair of the central nervous system, highlighting the need for new treatment strategies.

Cell-based therapies, such as stem cell transplantation and pharmacologic manipulation of endogenous stem cells, show promise for immune modulation and neuroprotection, but they also come with safety concerns and require further research to address methodological and ethical issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell-based therapeutic strategies for multiple sclerosis. Scolding, NJ., Pasquini, M., Reingold, SC., et al.[2023]

Engineered T regulatory cells (Tregs) expressing chimeric antigen receptors (CARs) targeting myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG) effectively suppressed autoimmune responses in a model of multiple sclerosis, indicating their potential as a targeted therapy.

These CAR-Tregs maintained key Treg characteristics after long-term expansion in the lab and successfully reduced autoimmune pathology in experimental autoimmune encephalomyelitis (EAE), suggesting a promising approach for treating immune-mediated diseases like multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered regulatory T cells expressing myelin-specific chimeric antigen receptors suppress EAE progression. De Paula Pohl, A., Schmidt, A., Zhang, AH., et al.[2022]

The study developed a method to enhance the effectiveness of CD4+CD25+ regulatory T-cells by genetically modifying them to specifically target and suppress harmful T lymphocytes, showing significant potential for treating autoimmune diseases.

In an experimental model of allergic encephalomyelitis, these modified T-cells not only prevented disease onset but also achieved complete remission and reduced mortality from over 50% to 0%, demonstrating their powerful therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Mekala, DJ., Geiger, TL.[2021]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

In a study of 45 patients with active CNS lymphoma receiving CAR T-cell therapy, 68.9% showed a CNS response, with 40% achieving a complete response lasting an average of 11.4 months, indicating the therapy's efficacy in this challenging population.

While CAR T-cell therapy demonstrated a favorable safety profile, mild to severe neurotoxicity (ICANS) occurred in 42.2% and 15.6% of transfusions, respectively, with higher risks associated with secondary CNS lymphoma and certain pre-treatment factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells. Karschnia, P., Arrillaga-Romany, IC., Eichler, A., et al.[2023]

CAR T-cell therapy is a powerful immunotherapy that not only shows promise in treating various cancers but can also be adapted to target autoimmune diseases and infections like HIV.

The therapy utilizes engineered T cells that can recognize a wider range of targets compared to natural T cells, enhancing its potential effectiveness in diverse medical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of CAR-T cell technology in autoimmune diseases and human immunodeficiency virus infection treatment. Adabi, N., Pordel, S., Rezaee, MA., et al.[2023]

CAR T-cell therapy can lead to significant toxicities, particularly cytokine release syndrome (CRS) and neurologic toxicities, which require careful monitoring and management.

Recent guidelines and evidence-based practices are evolving to help healthcare professionals, especially nurses, effectively assess and manage these toxicities to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associated Toxicities: Assessment and Management Related to CAR T-Cell Therapy. Anderson, K., Latchford, T.[2020]

CAR-T therapy is highly effective in treating certain cancers, but it is associated with significant complications, particularly cytokine release syndrome and neurotoxicity.

In addition to the well-known side effects, there are various other CAR-T-specific adverse events that require careful management based on clinical experiences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of adverse events of CAR-T therapy]. Arai, Y.[2023]

A new clinical platform successfully generates CMV-CD19CAR T cells from healthy donors, achieving a high enrichment of CMV-specific T cells and a transduction efficiency of 27%, which is crucial for effective cancer treatment.

These CMV-CD19CAR T cells showed strong anti-tumor activity and maintained memory characteristics, indicating their potential for improved persistence and efficacy in treating B cell malignancies, with plans for a clinical trial in patients with non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large-scale manufacturing and characterization of CMV-CD19CAR T cells. Wang, X., Urak, R., Walter, M., et al.[2022]

CAR-T therapies show a higher rate of complete response and improved progression-free survival in patients with recurrent/relapsed B-cell lymphoma, but do not demonstrate a significant difference in overall survival compared to standard of care treatments.

The evidence for the efficacy and safety of CAR-T therapies is limited and heterogeneous, indicating a need for more robust comparative studies to fully understand their benefits and risks in treating hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies. Saiz, LC., Leache, L., Gutiérrez-Valencia, M., et al.[2023]

In a study of 41 patients with refractory multiple sclerosis, the conditioning regimen CY/rabbit ATG showed lower complication rates (40%) compared to BEAM/horse ATG (71.4%), indicating it may be a safer option for patients undergoing autologous hematopoietic stem cell transplantation.

Both regimens had similar event-free survival rates (EFS), with 58.54% overall, suggesting that while CY/rATG is less toxic, further long-term studies are needed to determine if it is equally effective in preventing disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. Hamerschlak, N., Rodrigues, M., Moraes, DA., et al.[2013]

Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) leads to significant changes in lymphocyte subsets, with CD4+ T-cells and T-regulatory cells not returning to baseline levels, suggesting a reset of the immune system.

After ASCT, neurological function remained stable for most patients, with a progression-free survival rate of 69% at three years, indicating that ASCT may be an effective treatment option for managing progressive MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS. Cull, G., Hall, D., Fabis-Pedrini, MJ., et al.[2020]

In a case series of 10 patients with relapsing-remitting multiple sclerosis (MS) treated with autologous hematopoietic stem cell transplantation (HSCT), 5 patients achieved sustained complete remission after 10 years, indicating the potential long-term benefits of this treatment.

Among those in remission, 3 patients showed signs of MS resolution, as evidenced by normalized intrathecal IgG production and cerebrospinal fluid neurofilament light levels, suggesting that HSCT may effectively halt disease progression in some individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Tolf, A., Fagius, J., Carlson, K., et al.[2020]

The article has been retracted due to significant concerns about image reuse and misrepresentation of data, which undermines the integrity of the research.

Despite the authors' disagreement with the retraction, the editorial office confirmed that the issues found in the article represent a serious violation of scientific publishing standards.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RETRACTED: Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity Li, X., Zhang, Y., Yan, Y., et al.[2023]

Citations

1. ir.kyvernatx.com ir.kyvernatx.com/node/7596/pdf

Kyverna Therapeutics Highlights Potential of KYV-101 in ... UCSF is conducting an open-label, Phase 1, single-center study of KYV-101 in patients with treatment refractory progressive multiple sclerosis.

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3469.1/529281/A-Study-of-Kyv-101-a-CD19-CAR-T-Cell-Therapy-in

A Study of Kyv-101, a CD19 CAR T Cell Therapy, in ... We hypothesize that KYV-101, a fully human autologous CD19 CAR T-cell, will achieve CNS penetration in patients with progressive forms of MS.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06451159

NCT06451159 | A Study of KYV-101, a CD19 CAR T Cell ... 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 ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666634024001144

CD19-targeted chimeric antigen receptor T cell therapy in ... We report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS.

5. neurology.org neurology.org/doi/10.1212/WNL.0000000000211457

An Investigator Initiated Study of KYV-101, a CD19 CAR T ... Conclusions: The present trial will provide preliminary data which we expect will support the use of CD19 CAR T-cell therapy for this disease.

6. neurology.org neurology.org/doi/10.1212/WNL.0000000000212317

A Phase 1, Open-label, Single Center Study of KYV-101 ... We are conducting a Phase 1 prospective clinical trial assessing the feasibility and safety of treating subjects with progressive Multiple Sclerosis with ...