MuSK-CAART for Myasthenia Gravis

Recruiting at 5 trial locations

Overseen By Cabaletta Bio

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Cabaletta Bio

Must not be taking: Rituximab, Immunosuppressives, others

Disqualifiers: Other autoimmune disorders, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new cell therapy called MuSK-CAART for patients with a severe muscle disease known as MuSK myasthenia gravis. These patients have harmful antibodies that attack their muscles. The therapy uses special cells to find and stop these bad antibodies, potentially leading to long-term relief from the disease. Rituximab has been used to treat MuSK myasthenia gravis, showing some success in patients who are refractory to standard treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken rituximab in the last 12 months or investigational treatments for MG in the past 12 weeks. Also, prednisone use is limited in Part A of the trial.

What data supports the effectiveness of the treatment MuSK-CAART for Myasthenia Gravis?

MuSK-CAART has shown promise in targeting specific B cells that cause muscle weakness in myasthenia gravis, similar to how other T cell therapies work for different conditions. In animal studies, it reduced harmful antibodies without affecting overall immune function, suggesting it might be effective and safe for patients. ^{1 2 3 4 5}

Is MuSK-CAART safe for humans?

In studies, MuSK-CAART did not show specific off-target effects in tests with human cells, suggesting it may be safe, but more research is needed to confirm this in humans. ^{1 2 3 4 5}

How is the MuSK-CAART treatment different from other treatments for Myasthenia Gravis?

MuSK-CAART is unique because it uses genetically modified T cells to specifically target and neutralize harmful antibodies in Myasthenia Gravis, offering a more targeted approach compared to traditional treatments that generally suppress the immune system. ^{6 7 8 9 10}

Research Team

Medical Director

Principal Investigator

Cabaletta Bio

Eligibility Criteria

This trial is for people with MuSK myasthenia gravis, a muscle weakness disease. Participants must have tested positive for anti-MuSK antibodies and negative for anti-AChR antibodies, with an MG severity Class I to IVa. They can't join if they're on high-dose prednisone, had other autoimmune treatments recently, received investigational MG treatments in the last 12 weeks or rituximab in the past year.

Inclusion Criteria

You have previously tested negative for anti-AChR antibodies.

Your myasthenia gravis is classified as Class I to IVa according to the MGFA Clinical Classification.

I tested positive for anti-MuSK antibodies.

Exclusion Criteria

I have not received Rituximab in the last 12 months.

You have received an experimental treatment for myasthenia gravis in the last 12 weeks.

Your immune system's white blood cell count is very low.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive various dosing regimens of MuSK-CAART, alone or in combination with cyclophosphamide and fludarabine

3 months

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of clinical symptoms and quality of life

Up to 36 months

Treatment Details

Interventions

• MuSK-CAART (CAR T-cell Therapy)

Trial Overview The study tests different doses of MuSK-CAART alone or combined with cyclophosphamide (CY) and fludarabine (FLU). It's an open-label phase 1 trial aiming to see if this cell therapy can cause remission in patients with active MuSK myasthenia gravis.

Participant Groups

Group I: MuSK-CAART Experimental Treatment 1 Intervention

Cohort A: Infusion of MuSK-CAART at various dose levels with or without pre-treatment (6 groups planned). Cohort B: Infusion of MuSK-CAART at the dose regimen selected from Part A.

Who Is Running the Clinical Trial?

Cabaletta Bio

Lead Sponsor

Trials

6

Recruited

140+

Findings from Research

In a study of 18 patients with muscle-specific kinase antibody-associated myasthenia gravis (MuSK-MG), the most common symptoms were ocular manifestations, particularly mild symmetrical ptosis, and bulbar symptoms were prevalent in 88.89% of cases.

Treatment with tacrolimus (TAC) or low-dose rituximab (RTX) combined with prednisone (Pred) resulted in a more significant reduction of MuSK antibody titers and better clinical outcomes compared to azathioprine (AZA) plus Pred, with 94.44% of patients achieving favorable outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical features, treatment and prognosis of MuSK antibody-associated myasthenia gravis in Northwest China: a single-centre retrospective cohort study. Zhao, S., Zhang, K., Ren, K., et al.[2022]

The new 125I-MuSK immunoprecipitation assay successfully detected muscle-specific receptor tyrosine kinase antibodies (MuSKAbs) in 24% of patients with acetylcholine receptor antibody-negative myasthenia gravis, indicating its potential utility in diagnosing this condition.

The assay demonstrated high specificity, as no MuSKAbs were found in various control groups, including patients with other neuromuscular diseases and healthy individuals, suggesting it is a reliable tool for distinguishing between different types of myasthenia gravis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle-specific receptor tyrosine kinase autoantibodies--a new immunoprecipitation assay. Matthews, I., Chen, S., Hewer, R., et al.[2016]

MuSK antibodies are present in a subset of myasthenia gravis patients who do not have AChR antibodies, often affecting young adult females and leading to specific muscle weaknesses, but without significant changes in AChR numbers in muscle biopsies.

Patients with MuSK antibody-associated myasthenia gravis may not respond well to standard corticosteroid treatments, highlighting the need for alternative therapies and the potential for new clinical trials to improve treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. Vincent, A., Leite, MI.[2019]

Engineered T cells expressing a MuSK chimeric autoantibody receptor (MuSK-CAART) effectively targeted and depleted B cells producing harmful anti-MuSK autoantibodies, showing similar efficacy to existing therapies without the need for chronic immunosuppression.

In a mouse model of myasthenia gravis, MuSK-CAART specifically reduced anti-MuSK IgG levels while preserving overall B cell counts, indicating targeted action without significant off-target effects, paving the way for a phase 1 clinical study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells. Oh, S., Mao, X., Manfredo-Vieira, S., et al.[2023]

In a study of 21 patients with MuSK-MG, most were female (81%) with an average onset age of 51.9 years, and symptoms often progressed rapidly, particularly from ocular to generalized myasthenia gravis within about 4.4 months.

While conventional treatments like pyridostigmine and corticosteroids were used, only 4.8% achieved complete stable remission, indicating a need for more effective therapies as nearly 15% of patients had poor responses to current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on MuSK positive myasthenia gravis: clinical characteristics, treatment and outcomes. Huang, Q., Li, F., Zhao, S.[2022]

The study introduces a novel approach using a single ligand, CARL, to activate and expand CAR T cells of multiple specificities, simplifying the process of T cell therapy development.

By using CARL on artificial antigen presenting cells (aAPC), researchers can avoid the complexities and costs of creating separate aAPCs for each tumor-associated antigen, enhancing the efficiency of CAR T cell expansion for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity. Rushworth, D., Jena, B., Olivares, S., et al.[2021]

The study introduced 'CAR Pooling,' a method that allows for the rapid identification of effective CAR designs by evaluating 40 different CARs for their ability to stimulate T cell functions under conditions mimicking long-term tumor exposure.

Key findings showed that CARs utilizing signaling domains from the TNF receptor family, particularly BAFF-R, significantly enhanced T cell proliferation and cytotoxicity, leading to improved activity in a model of multiple myeloma, suggesting a promising avenue for enhancing CAR T cell therapy efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies. Goodman, DB., Azimi, CS., Kearns, K., et al.[2023]

The study developed an affinity-enhanced T cell receptor (TCR) targeting the MAGE A3 antigen for cancer therapy, which showed promising preclinical results with no off-target effects; however, it led to a serious adverse event in patients, indicating potential safety risks.

Post-adverse event investigations revealed that the TCR also recognized a peptide from the muscle protein Titin, suggesting that off-target recognition can occur in vivo, emphasizing the need for improved preclinical testing methods to prevent such toxicities in future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Cameron, BJ., Gerry, AB., Dukes, J., et al.[2023]

CAR T cells modified to target the erbB2 antigen can produce multiple cytokines and chemokines, indicating a robust immune response against tumor cells.

These CAR T cells show enhanced effectiveness upon repeated stimulation, with increased IFN-γ secretion and the ability to specifically kill erbB2-expressing tumor cells without harming non-target cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-redirected T cells display multifunctional capacity and enhanced tumor-specific cytokine secretion upon secondary ligation of chimeric receptor. Henderson, MA., Yong, CS., Duong, CP., et al.[2018]

The newly developed anti-CEA chimeric T cell receptor effectively targets tumor cells without being hindered by high levels of soluble CEA in the serum, maintaining its activation efficacy even at concentrations up to 25 micrograms/ml.

This chimeric receptor, composed of a humanized antibody fragment and a human signaling chain, successfully activates T cells to secrete IL-2 and kill CEA+ tumor cells, demonstrating its potential as a targeted therapy for cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA. Hombach, A., Koch, D., Sircar, R., et al.[2012]

References

1. England pubmed.ncbi.nlm.nih.gov

Clinical features, treatment and prognosis of MuSK antibody-associated myasthenia gravis in Northwest China: a single-centre retrospective cohort study. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Muscle-specific receptor tyrosine kinase autoantibodies--a new immunoprecipitation assay. [2016]

3. England pubmed.ncbi.nlm.nih.gov

Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. [2019]

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

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells. [2023]

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

Spotlight on MuSK positive myasthenia gravis: clinical characteristics, treatment and outcomes. [2022]

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

Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity. [2021]

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

Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies. [2023]

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

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-redirected T cells display multifunctional capacity and enhanced tumor-specific cytokine secretion upon secondary ligation of chimeric receptor. [2018]

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

A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA. [2012]