DSG3-CAART Cell Therapy for Pemphigus Vulgaris

Recruiting at 9 trial locations

Overseen By Study Recruitment Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Cabaletta Bio

Must be taking: Immunosuppressive therapies

Must not be taking: Rituximab, Anti-CD20, Anti-CD19

Disqualifiers: Paraneoplastic pemphigus, Active malignancy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cell therapy called DSG3-CAART (Desmoglein 3 Chimeric Autoantibody Receptor T Cells) to determine its safety in treating pemphigus vulgaris, a condition where the immune system attacks the skin, causing painful blisters. Researchers aim to find the optimal dose and assess its effectiveness compared to standard treatments. Participants should have active pemphigus vulgaris not controlled by regular treatments and must test positive for specific antibodies related to the disease. 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.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it excludes those who have taken certain treatments like rituximab in the last 12 months or investigational treatments in the last 3 months. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that DSG3-CAART is being tested for pemphigus vulgaris, a rare skin condition. In earlier studies, higher doses of DSG3-CAART remained active in the body longer, which might be important for its effectiveness. The studies did not report any major side effects, suggesting it might be well-tolerated.

CABA-201 is another treatment under study, but specific safety details for CABA-201 are not available. As both treatments are in early testing stages, the main focus is on safety and determining the optimal dose. While early results appear promising, more research is needed to fully understand their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike traditional treatments for pemphigus vulgaris, which typically involve corticosteroids and immunosuppressants, DSG3-CAART offers a more targeted approach. This therapy uses chimeric autoantibody receptor T-cells specifically designed to seek out and eliminate the autoantibodies causing the disease. Researchers are excited about DSG3-CAART because it has the potential to provide a more precise treatment with fewer side effects than broad immunosuppression. Additionally, the possibility of a single infusion, as seen with the CABA-201 cohort, could simplify treatment regimens and improve patient compliance.

What evidence suggests that this trial's treatments could be effective for pemphigus vulgaris?

Research has shown that DSG3-CAART might help treat pemphigus vulgaris, a condition where the immune system mistakenly attacks the skin, causing painful blisters. DSG3-CAART is designed to find and remove the specific immune cells responsible for this issue. Early results suggest that DSG3-CAART can remain active in the body, potentially providing longer-lasting relief. This trial will evaluate DSG3-CAART in different dosing strategies and consider CABA-201 as another treatment option. Studies indicate that DSG3-CAART might lead to complete and lasting remission, potentially controlling the disease for an extended period. ^{1 2 3 6 7}

Who Is on the Research Team?

Cabaletta Bio

Principal Investigator

Cabaletta Bio

Are You a Good Fit for This Trial?

This trial is for patients with mucosal-dominant pemphigus vulgaris (mPV) who haven't responded well to standard treatments. They must have active mPV symptoms, a positive anti-DSG3 antibody test, and a confirmed diagnosis. People can't join if they've had certain other treatments recently or have another autoimmune disease needing treatment.

Inclusion Criteria

My mPV has not improved with standard immune treatments.

You have active myeloproliferative variant at the time of screening.

You test positive for anti-DSG3 antibodies.

Exclusion Criteria

I am on immunosuppressive drugs for an autoimmune disorder.

I am taking more than 0.25mg/kg/day of Prednisone.

I have skin lesions due to pemphigus vulgaris, showing more skin than mouth involvement.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive fractionated infusions of DSG3-CAART or a single infusion of CABA-201

3 months

Follow-up

Participants are monitored for safety, clinical remission, and serologic remission

36 months

Extension

Long-term monitoring of pharmacodynamics and pharmacokinetics for CABA-201 sub-study

156 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DSG3-CAART

Trial Overview The study is testing DSG3-CAART, an experimental cell therapy aimed at achieving long-lasting remission in mPV patients. The goal is to find the highest dose that's safe and work out the best schedule for giving it to patients.

How Is the Trial Designed?

Group I: DSG3-CAART or CABA-201 Experimental Treatment 1 Intervention

Cohort A: Fractionated infusions of DSG3-CAART at increasing dose levels (6-9 groups) administered as a single cycle. Cohort B: Consolidation of infusion of DSG3-CAART to fewer fractionations than in Cohort A using the selected dose from Cohort A (1 group) administered as a single cycle. Cohort C: Infusion of final selected dose and fractionation of DSG3-CAART from Cohorts A and B (1 group) administered as a single cycle. OR CABA-201 Cohort: Single infusion of CABA-201.

DSG3-CAART is already approved in United States for the following indications:

Approved in United States as DSG3-CAART for:

• Orphan Drug Designation for Pemphigus Vulgaris

Who Is Running the Clinical Trial?

Cabaletta Bio

Lead Sponsor

Trials

6

Recruited

140+

Published Research Related to This Trial

In a study of 52 patients with pemphigus vulgaris (PV), researchers found that DSG3-specific T cells, particularly type 2 T cells, were significantly increased compared to healthy controls, indicating their role in the disease's autoimmune response.

The presence of DSG3 peptide-specific T cells correlates with the production of pathogenic IgG antibodies that disrupt skin cell adhesion, suggesting these T cells could serve as important markers for disease activity and potential targets for new therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris. Didona, D., Scarsella, L., Hudemann, C., et al.[2023]

Dsg3-specific CD4+ T helper cells play a crucial role in the development of pemphigus vulgaris (PV) by producing autoantibodies and causing tissue damage, as shown in a mouse model where these T cells induced a severe pemphigus-like phenotype.

The study revealed that T cell infiltration into Dsg3-expressing tissues leads to interface dermatitis, a form of T cell-mediated autoimmunity, highlighting the importance of TCR avidity and IFN-γ in this process, which could help in understanding other autoimmune skin diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice. Takahashi, H., Kouno, M., Nagao, K., et al.[2021]

In a study using a mouse model of pemphigus vulgaris (PV), T regulatory (Treg) cells were shown to down-regulate the immune response driven by Dsg3, which is crucial in the disease's pathogenesis.

The research suggests that modulating Treg cells could be a potential therapeutic strategy for PV, offering a promising alternative to traditional immunosuppressive treatments like corticosteroids, which have significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of T regulatory cells by the superagonistic anti-CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA-transgenic mouse model of pemphigus vulgaris. Schmidt, T., Willenborg, S., Hünig, T., et al.[2017]

Pemphigus vulgaris is caused by autoantibodies against desmoglein 3, and the disease develops when there is an imbalance between self-reactive T and B cells and regulatory T cells, particularly in genetically susceptible individuals.

Pathogenic antibodies primarily target conformational epitopes on desmogleins, while non-pathogenic antibodies target non-conformational epitopes, indicating that the type of immune response plays a crucial role in the disease's development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune dysregulation of pemphigus in humans and mice. Yokoyama, T., Amagai, M.[2017]

Pemphigus vulgaris (PV) is a serious autoimmune disease that typically requires long-term immunosuppressive therapy, which can lead to significant side effects and poor patient outcomes.

Research into the autoreactive T cell responses to desmoglein 3 (Dsg3), the autoantigen in PV, suggests that targeting these specific immune responses could lead to more effective and safer immunotherapies for treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA class II restriction of autoreactive T cell responses in pemphigus vulgaris: review of the literature and potential applications for the development of a specific immunotherapy. Riechers, R., Grötzinger, J., Hertl, M.[2019]

DSG3-CAART is a promising precision immunotherapy that specifically targets and depletes B cells producing the autoantigen associated with pemphigus vulgaris, showing effective reduction of autoantibodies and target cell burden in preclinical models.

Toxicology assessments indicated that DSG3-CAART does not cause off-target effects, supporting its safety for use in a first-in-human trial for treating mucosal pemphigus vulgaris.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris. Lee, J., Lundgren, DK., Mao, X., et al.[2021]

In a study of 14 pemphigus vulgaris (PV) patients and 12 healthy donors, T cell responses to the skin protein desmoglein 3 (Dsg3) were found to be active in patients with ongoing disease, indicating a direct link between T cell activity and the autoimmune response in PV.

The research identified specific T cell reactivity to Dsg3 in both PV patients and some healthy individuals, suggesting that certain genetic factors (like specific HLA alleles) may influence susceptibility to PV and the immune response to Dsg3.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recognition of desmoglein 3 by autoreactive T cells in pemphigus vulgaris patients and normals. Hertl, M., Amagai, M., Sundaram, H., et al.[2022]

In pemphigus vulgaris, a type of autoimmune disease, engineered T cells expressing chimeric autoantibody receptors (CAAR) can specifically target and kill autoreactive B cells, showing promise for treating autoimmune conditions.

The CAAR-T cells demonstrated effective cytotoxicity against B cells with specific receptors for the autoantigen desmoglein 3, indicating a potential strategy for selectively eliminating harmful immune cells while preserving protective immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Ellebrecht, CT., Bhoj, VG., Nace, A., et al.[2021]

In a study of 82 patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV), anti-Dsg1 antibodies were found to correlate significantly with skin lesions and disease activity in PF, indicating their usefulness in monitoring this condition.

The study established specific cut-off values for anti-Dsg1 (161.5 U/mL) and anti-Dsg3 (30.7 U/mL) antibodies, which provided high sensitivity and specificity for assessing disease activity in PF and PV, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autoantibodies against Desmoglein 1 and 3 in South Tunisian pemphigus. Jerbi, A., Hachicha, H., Feki, S., et al.[2022]

Knockout mice lacking desmoglein 3 (Dsg3) successfully developed an active model of pemphigus vulgaris (PV), producing anti-Dsg3 antibodies that led to disease symptoms, demonstrating the model's efficacy in studying autoimmune diseases.

The study showed that these antibodies could be transferred to immunodeficient mice, resulting in long-term production of anti-Dsg3 IgG and the development of PV-like symptoms, indicating the model's potential for testing new treatments for autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. Amagai, M., Tsunoda, K., Suzuki, H., et al.[2022]

Citations

1. cabalettabio.com cabalettabio.com/news-media/press-releases/detail/52/cabaletta-bio-reports-clinical-data-from-the-third-dose

Cabaletta Bio Reports Clinical Data from the Third Dose ... Dose dependent increase in DSG3-CAART persistence observed in the third dose cohort relative to the first two low dose cohorts throughout ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04422912

Study Details | NCT04422912 | A Phase 1/2, Open-label, ... DSG3-CAART or CABA-201 may potentially lead to complete and durable remission of disease. Official Title. A Phase 1/2, Open-label, Safety and Dosing Study of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7685721/

Antigen-specific B cell depletion for precision therapy of ... In the autoimmune disease mucosal pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (DSG3) cause painful mucosal blisters. Rituximab is effective as ...

4. reporter.nih.gov reporter.nih.gov/search/14E9CE024F8FC5D27598B8961CAA4A01A2FFCEB861BF/project-details/11013344

Project Details - NIH RePORTER Immunomodulatory effects of desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) in mucosal pemphigus vulgaris. Project Number5R01AR082675-04.

5. pemphigus.org pemphigus.org/wp-content/uploads/DC1.pdf

A Phase 1 trial of desmoglein 3 chimeric autoantibody ... DSG3-CAART cells express all the relevant DSG3 domains. • Since all pathogenic autoantibodies in mPV are directed against EC1, EC2, EC3, or EC4 of the DSG3 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04422912?term=AREA%5BBasicSearch%5D(CABA-201)&rank=4

A Phase 1/2, Open-label, Safety and Dosing Study ... DSG3-CAART or CABA-201 may potentially lead to complete and durable remission of disease. Official Title. A Phase 1/2, Open-label, Safety and Dosing Study of ...

7. reporter.nih.gov reporter.nih.gov/project-details/11013344

Immunomodulatory effects of desmoglein 3 chimeric autoantibody ... We established proof-of-concept for CAAR safety and efficacy in experimental models of pemphigus vulgaris (PV), a potentially fatal blistering disease caused by ...