CAR T-cell Therapy for Multiple Sclerosis

Overseen By Esther Nie, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Must not be taking: Anticoagulants, Antiplatelets, Anti-CD20

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KYV-101, which uses CAR T-cell therapy to help people with progressive forms of multiple sclerosis (MS). The goal is to determine if this treatment can reduce symptoms and slow MS progression. Participants must have a confirmed diagnosis of progressive MS and meet specific health criteria, such as having antibodies to certain viruses and adequate organ function. The study seeks individuals who have not recently received treatments that could interfere with the trial results. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop my current medications for the trial?

The trial requires a washout period for certain medications: a 30-day washout for glatiramer acetate, interferon-beta, and fumarates, and a 60-day washout for sphingosine-i-phosphate modulators and natalizumab. If you are on these medications, you will need to stop them before participating.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that KYV-101, a type of CAR T-cell therapy, is being tested for safety in treating multiple sclerosis (MS). In earlier studies with patients who have progressive MS, researchers assessed how well patients could tolerate KYV-101. Although detailed safety information remains limited, the therapy is in the early stages of testing, focusing primarily on ensuring it does not cause harmful effects.

So far, reports have not indicated major safety issues. However, it is important to remember that this type of study is just beginning to evaluate the safety of KYV-101 in humans. While no major problems have been identified yet, further research is necessary to fully understand the safety of this treatment. ^{1 2 3 4 5}

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

Most treatments for multiple sclerosis (MS), like disease-modifying therapies, aim to slow the disease's progression and manage symptoms by modulating or suppressing the immune system. But KYV-101 offers a unique approach by using CAR T-cell therapy, which involves engineering a patient's own immune cells to specifically target and eliminate problematic cells causing the disease. This method not only provides a targeted attack but also has the potential to offer long-lasting effects, reducing the need for continuous treatment. Researchers are excited because this could transform how MS is treated, offering more precise and potentially more effective management of the disease.

What evidence suggests that KYV-101 might be an effective treatment for multiple sclerosis?

Research has shown that KYV-101, a type of CAR T-cell therapy, may help treat progressive forms of multiple sclerosis (MS). This trial will investigate KYV-101, which targets a protein called CD19 on certain immune cells that might contribute to the disease. Early reports on KYV-101 in people with progressive MS suggest it could help by altering immune system function. Although information on its effectiveness in humans remains limited, the therapy is designed to reach the central nervous system (CNS), where MS causes damage. Initial results from CAR T-cell therapies in other conditions have been promising, offering hope that KYV-101 could benefit MS patients. ^{2 3 4 5 6}

Who Is on the Research Team?

Jeffrey Dunn, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-55 with progressive forms of Multiple Sclerosis, as per the McDonald and Lublin criteria. Participants must have certain antibody levels, normal organ function, no recent investigational drugs or specific treatments, and agree to contraception if applicable.

Inclusion Criteria

You have been diagnosed with multiple sclerosis using the 2017 McDonald Criteria.

My kidney, liver, lung, and heart functions are all within normal ranges.

You need to be tested to make sure you don't have certain infections or diseases.

Exclusion Criteria

I have a heart valve condition.

My kidneys do not work well.

I have a history of NMOSD or MOGAD.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Conditioning

Participants undergo lymphodepletion conditioning prior to receiving KYV-101 CAR T cells

1 week

Treatment

Participants receive KYV-101 CAR T cells

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and clinical response

12 months

What Are the Treatments Tested in This Trial?

Interventions

• KYV-101

Trial Overview The study tests KYV-101 anti-CD19 CAR-T cell therapy following a standard lymphodepletion regimen in patients with non-relapsing and progressive MS. It aims to evaluate the safety and effectiveness of this innovative treatment approach.

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

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Kyverna Therapeutics

Industry Sponsor

Trials

11

Recruited

320+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 ...