CAR T Cell Therapy for Multiple Sclerosis

Overseen By Naomi Okinishi, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Bruce Cree

Must not be taking: Anticoagulants, Mitoxantrone, Cladribine, Alemtuzumab

Disqualifiers: HIV, Hepatitis B/C, Cardiac disease, 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: 18

Duration: 8 days (inpatient) + 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, KYV-101 (a type of CAR T cell therapy), for individuals with progressive multiple sclerosis (MS) who haven't responded to standard treatments. Researchers aim to determine the safest dose and assess whether the treatment can reach the central nervous system. Participants must have progressive MS that worsens despite other treatments. The trial includes several visits, a hospital stay, and various medical tests and procedures. As a Phase 1 trial, this research focuses on understanding how KYV-101 works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that you must be able to interrupt autoimmune disease therapy before apheresis. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that KYV-101 is likely to be safe for humans?

Research has shown that KYV-101, a type of CAR T-cell therapy, has been used in people with worsening multiple sclerosis (MS). Researchers are still studying this treatment to assess its safety. In earlier studies, patients generally tolerated KYV-101 well, though some side effects can occur, as with many new treatments.

In past treatments with similar CAR T-cell therapies, patients sometimes experienced mild to moderate side effects like tiredness or fever. So far, no major safety issues have been reported specifically for KYV-101. However, it is important to remember that this is a new treatment, and researchers are still learning about its safety.

This study is in the early stages, focusing primarily on determining its safety for people. Identifying the highest safe dose is a key focus. Participants in this study will help determine the best way to use KYV-101 safely in the future. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about KYV-101 for multiple sclerosis because it uses a novel approach called CAR T cell therapy, which is different from standard treatments like disease-modifying therapies and immunosuppressants. Unlike these traditional options that mainly target immune system activity to reduce inflammation, CAR T cell therapy involves engineering a patient's own T cells to specifically attack disease-causing cells. This personalized and targeted method holds the potential for more precise and effective treatment, possibly leading to better outcomes with fewer side effects.

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

Research suggests that KYV-101, a therapy using modified immune cells, may benefit people with progressive multiple sclerosis (MS) who haven't responded to standard treatments. Early studies have shown that KYV-101 targets and alters specific immune cells to reduce inflammation, a major issue in MS. Although still in the early stages, there is hope that it can reach the brain and spinal cord, which is crucial for treating MS. Initial treatments in a few patients showed positive signs, offering hope for those facing this challenging condition. Participants in this trial will receive KYV-101 at varying doses to assess its safety and effectiveness. ^{2 3 4 5 6}

Who Is on the Research Team?

Sasha Gupta, MD

Principal Investigator

University of California, San Francisco

Bruce Cree, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

Exclusion Criteria

I have had cancer before, but it fits the trial's exceptions.

I have had my spleen removed.

Positive serology for human immunodeficiency virus (HIV)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Apheresis and Chemotherapy Preparation

Participants undergo apheresis and chemotherapy treatments in preparation for KYV-101 therapy

2 weeks

1 visit (inpatient)

Treatment

Participants receive KYV-101 therapy and are monitored for safety and effectiveness

8 days (inpatient) + 48 weeks

14 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• KYV-101

Trial Overview 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.

How Is the Trial Designed?

Group I: Dosing Cohort #2: KYV-101 CAR+ T -- 1×10^8 cells Experimental Treatment 3 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 cells Experimental Treatment 3 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

Who Is Running the Clinical Trial?

Bruce Cree

Lead Sponsor

Trials

1

Recruited

10+

Kyverna Therapeutics

Industry Sponsor

Trials

11

Recruited

320+

Published Research Related to This Trial

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]

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]

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]

CD19-targeted CAR Tregs, generated from human peripheral blood mononuclear cells, can be expanded in the lab while retaining their regulatory properties, making them a promising option for therapy in autoimmune diseases.

These CAR Tregs effectively suppress antibody production and B cell differentiation through a TGF-β-dependent mechanism, potentially reducing the risk of graft-versus-host disease compared to conventional CAR T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. Imura, Y., Ando, M., Kondo, T., et al.[2021]

Interferon beta-1b was a groundbreaking treatment for multiple sclerosis (MS) in the U.S., but it is not suitable for all patients and does not cure the disease, highlighting the need for more effective therapies.

A variety of new treatments are being researched, including immunosuppressive drugs, monoclonal antibodies, and potassium channel blockers, but many are still in early development and may have significant side effects or limited effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigational drug therapies of treatment of multiple sclerosis. Panitch, HS.[2017]

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]

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 preclinical study using a mouse model, intra-cerebroventricular (i.c.v.) delivery of anti-CD19 CAR T cells effectively eliminated acute lymphoblastic leukemia (ALL) cells in the central nervous system (CNS), while intravenous (i.v.) delivery showed only partial effects.

The i.c.v. delivery method was found to be safe, as it did not result in fatal adverse events, although some mice experienced temporary clinical symptoms after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model. Tanaka, K., Kato, I., Tanaka, M., et al.[2020]

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]

Radiolabeling CAR-T cells with 89Zr-oxine is an effective method that allows for tracking their distribution in the body using PET imaging, while maintaining the cells' viability and functional characteristics for at least 8 days.

The study found that radiolabeled CAR-T cells retain their ability to target and kill IL-13Rα2 positive tumor cells without significant changes in activation or exhaustion markers, indicating that this labeling technique could enhance our understanding of CAR-T cell behavior in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging. Leland, P., Kumar, D., Nimmagadda, S., et al.[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]

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 ...