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

10 Participants Needed

Trial Summary

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.

What data supports the idea that CAR T Cell Therapy for Multiple Sclerosis is an effective treatment?

The available research shows that CAR T Cell Therapy, specifically engineered regulatory T cells, can suppress autoimmune activity in a model of multiple sclerosis. These engineered cells were able to reduce disease symptoms in experimental settings, suggesting potential effectiveness for MS patients. However, the research primarily focuses on preclinical models, and more studies are needed to confirm these results in humans. Compared to other treatments like interferon beta-1b, which is not suitable for all patients and is not a cure, CAR T Cell Therapy offers a promising alternative by directly targeting immune cells involved in MS. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment KYV-101, Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Multiple Sclerosis?

Research shows that similar CAR T-cell therapies targeting CD19 have been effective in treating B-cell lymphomas and have potential for treating autoimmune diseases by suppressing harmful immune responses. This suggests that KYV-101 might help manage multiple sclerosis by targeting specific immune cells. ^{1 2 3 4 5}

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 significant toxicities such as severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX). Studies have shown that these risks vary depending on the type of cancer treated, with acute lymphocytic leukemia patients experiencing higher risks compared to those with non-Hodgkin's lymphoma or multiple myeloma. The use of certain vector designs and cytokine-directed therapies can influence the rates of these toxicities. Additionally, cardiovascular events have been reported, with a notable association between neurotoxicity and cardiovascular events. Overall, while CAR T Cell Therapy shows promise, it is accompanied by serious safety concerns that require careful management and further research. ^{6 7 8 9 10}

What safety data exists for CAR T Cell Therapy in humans?

CAR T Cell Therapy has been associated with serious side effects like cytokine release syndrome (CRS), which is an intense immune reaction, and neurological issues. Some studies also report cardiovascular problems, such as irregular heartbeats and heart failure, especially when CRS or neurological issues are present. ^{6 7 8 9 10}

Is the treatment KYV-101 a promising treatment for Multiple Sclerosis?

Yes, KYV-101, a type of CAR T-cell therapy, shows promise for treating Multiple Sclerosis. It uses specially engineered cells to target and suppress harmful immune responses, potentially reducing disease symptoms and progression. ^{1 3 11 12 13}

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 may not be as targeted. ^{1 3 11 12 13}

What is the purpose of this trial?

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 to slow disease progression. The main questions it aims to answer are: * What is the highest therapy dose that can be given without causing harm? * Can this therapy enter the central nervous system? Participants will be asked to: * Attend 14 visits plus an 8-day inpatient hospital stay over the course of 58 weeks. * Complete apheresis and chemotherapy treatments in preparation for KVY-101 therapy. * Undergo medical and research testing such as physical and neurological exams, MRI, lumbar puncture, blood draws, questionnaires, and vision assessments.

Research Team

Bruce Cree, MD

Principal Investigator

University of California, San Francisco

Sasha Gupta, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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.

I plan to get a live vaccine after joining the study.

Timeline

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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 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-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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. [2021]

3. 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]

4. United States 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. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Investigational drug therapies of treatment of multiple sclerosis. [2017]

6. Japan pubmed.ncbi.nlm.nih.gov

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

7. 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]

8. England 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. [2023]

9. 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]

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

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

11. England pubmed.ncbi.nlm.nih.gov

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

12. England pubmed.ncbi.nlm.nih.gov

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

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

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