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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

A Study of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Subjects with Non-relapsing and Progressive Forms of Multiple Sclerosis

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.

What safety data exists for CAR T-cell therapy in humans?

CAR T-cell therapy has been associated with serious side effects, including cytokine release syndrome (a severe immune reaction) and neurological issues. Cardiovascular problems like arrhythmias (irregular heartbeats) and heart failure have also been reported, with a higher risk of these events leading to increased mortality. ^{1 2 3 4 5}

How is the treatment KYV-101 different from other treatments for multiple sclerosis?

KYV-101 is a unique treatment for multiple sclerosis because it uses CAR T-cell therapy, which involves engineering the patient's own immune cells to specifically target and suppress harmful immune responses, unlike traditional treatments that generally suppress the immune system as a whole. ^{6 7 8 9 10}

Research Team

Jeffrey Dunn, MD

Principal Investigator

Stanford University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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-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]

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]

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]

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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. Japan pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular Events Associated with Chimeric Antigen Receptor T Cell Therapy: Cross-Sectional FDA Adverse Events Reporting System Analysis. [2021]

5. England 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. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Engineered regulatory T cells expressing myelin-specific chimeric antigen receptors suppress EAE progression. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Large-scale manufacturing and characterization of CMV-CD19CAR T cells. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. [2021]

9. England 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. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Application of CAR-T cell technology in autoimmune diseases and human immunodeficiency virus infection treatment. [2023]