DSG3-CAART Cell Therapy for Pemphigus Vulgaris
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This trial is testing new cell therapies for patients with pemphigus vulgaris who don't respond to standard treatments. The therapies involve modifying the patient's own immune cells to better fight the disease and potentially provide long-term relief.
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.
What data supports the effectiveness of the treatment DSG3-CAART for pemphigus vulgaris?
Research shows that DSG3-CAART specifically targets and destroys harmful B cells in pemphigus vulgaris, reducing the disease-causing antibodies and leading to healing of blisters in preclinical models. This suggests it could be an effective treatment for this autoimmune condition.
12345What safety data exists for DSG3-CAART cell therapy in humans?
Preclinical studies of DSG3-CAART cell therapy showed that it specifically targets harmful B cells without causing off-target effects, suggesting it may be safe for human use. Toxicology tests did not find any unintended harmful interactions, which guided the design of the first human trial.
12467How is DSG3-CAART treatment different from other treatments for pemphigus vulgaris?
DSG3-CAART is a unique treatment because it uses specially engineered T cells to target and destroy the specific B cells that produce harmful antibodies in pemphigus vulgaris, offering a more precise approach compared to traditional immunosuppressive drugs.
158910Eligibility Criteria
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.
+1 more
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.
+3 more
Trial Timeline
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: DSG3-CAART or CABA-201Experimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Brigham and Women's HospitalBoston, MA
University of IowaIowa City, IA
Yale UniversityNew Haven, CT
Columbia UniversityNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Cabaletta BioLead Sponsor
References
Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris. [2021]Desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3ζ signaling domains, represent a precision cellular immunotherapy approach for antigen-specific B cell depletion. Here, we present definitive preclinical studies enabling a first-in-human trial of DSG3-CAART for mucosal PV. DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity consistent with a threshold dose in vivo, resulting in decreased target cell burden, decreased serum and tissue-bound autoantibodies, and increased DSG3-CAART engraftment. In a PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. DSG3 autoantibodies stimulated DSG3-CAART IFN-γ secretion and homotypic clustering, consistent with an activated phenotype. Toxicology screens using primary human cells and high-throughput membrane proteome arrays did not identify off-target cytotoxic interactions. These preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical development for other antibody-mediated diseases.
Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. [2021]Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. Here, we show that in the antibody-mediated autoimmune disease pemphigus vulgaris (PV), autoantigen-based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR). We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains. Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo. CAAR-T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody-mediated autoimmune disease.
Autoantibodies against Desmoglein 1 and 3 in South Tunisian pemphigus. [2022]Desmoglein (Dsg) 1 and 3 are the 2 major autoantigens in pemphigus foliaceus (PF) and pemphigus vulgaris (PV).
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. [2019]Pemphigus vulgaris (PV) is a life-threatening autoimmune bullous disease of the skin and mucous membranes which requires immunosuppressive therapy, most commonly a combination of glucocorticoids and additional immunosuppressive agents. Since the side effects of long-term immunosuppressive therapy contribute to the poor prognosis of this disorder, there is considerable interest in a more specific treatment of this severe skin disease. PV may serve as a model disease for the development of a specific immunotherapy, because its pathogenesis as well as involved immunogenetic factors are well-characterized. This review focuses on the characterization of autoreactive T cell responses to desmoglein 3 (Dsg3), the autoantigen of PV, that presumably regulate the production of autoantibodies by providing help to the autoreactive B cells. Current knowledge on T cell epitopes of Dsg3 and the HLA class II alleles that restrict Dsg3-specific autoreactive T cell responses, as well as potential applications for a specific immunotherapy of PV, are described.
Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice. [2021]Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4+ T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3-/- mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-γ- and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases.
Recognition of desmoglein 3 by autoreactive T cells in pemphigus vulgaris patients and normals. [2022]Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and is caused by autoantibodies against desmoglein 3 (Dsg3) on epidermal keratinocytes. Because the production of autoantibodies is presumably T cell dependent, Dsg3-specific T cell reactivity was investigated in 14 PV patients and 12 healthy donors. Peripheral blood mononuclear cells from seven PV patients with active disease showed a primary in vitro response to a recombinant protein containing the extracellular portion (EC1-5) of Dsg3, whereas two of seven PV patients in remission or under immunosuppressive treatment exhibited only secondary (2 degrees) or tertiary (3 degrees) T cell responses to Dsg3. T cell responses to Dsg3 were also observed in four of 12 healthy individuals upon 2 degrees or 3 degrees stimulation with Dsg3. Both PV patients and healthy responders were either positive for DRbeta1*0402 -- which is highly prevalent in PV -- or positive for DR11 alleles homologous to DRbeta1*0402. Two CD4+ Dsg3-specific T cell lines and 12 T cell clones from two PV patients and two CD4+ T cell lines and eight T cell clones from two normals were also stimulated by a Dsg3 protein devoid of the EC2-3 (deltaN1), suggesting that epitopes were located in the EC1, EC4, and/or EC5. Using Dsg3 peptides, one immunodominant peptide (residues 161-177) was also identified in the EC2. These observations demonstrate that T cell responses to Dsg3 can be detected in PV patients and in healthy donors carrying major histocompatibility class II alleles identical or similar to those highly prevalent in PV.
Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris. [2023]Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and/or mucous membranes caused by IgG autoantibodies that predominantly target two transmembrane desmosomal cadherins: desmoglein (DSG)1 and DSG3. DSG-specific T cells play a central role in PV pathogenesis because they provide help to autoreactive B cells for autoantibody production. In this study, we characterized DSG3-specific peripheral T cells in a cohort of 52 patients with PV and 41 healthy controls with regard to cytokine profile and epitope specificity. By ELISpot analysis, type 2 T cells reactive with the DSG3 ectodomain were significantly increased in patients with PV compared with those in healthy controls. By dextramer analysis, CD4+ T cells specific for an epitope within the extracellular domain of DSG3, DSG3(206-220), were found at significantly higher frequencies in patients with PV than in HLA-matched healthy controls. T-cell recognition of two distinct DSG3 epitopes, that is, DSG3(206-220) and DSG3(378-392), correlated significantly, suggesting a synergistic effect in B-cell help. Immunization of HLA-DRB1∗04:02-transgenic mice with PV with the same set of DSG3 peptides induced pathogenic DSG3-specific IgG antibodies, which induced loss of keratinocyte adhesion in vitro. Thus, DSG3 peptide-specific T cells are of particular interest as surrogate markers of disease activity and potential therapeutic targets in PV.
Immune dysregulation of pemphigus in humans and mice. [2017]Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes that is caused by immunoglobulin (Ig)G autoantibodies against the cadherin-type adhesion molecule desmoglein (Dsg)3 expressed on stratified epithelial cells. Interaction between antigen-specific T and B cells, which is selectively achieved through T-cell receptor/major histocompatibility complex-peptide complex association and subsequently corroborated by co-stimulatory molecules such as CD40/CD154, is required for production of pathological anti-desmoglein 3 antibody. Some genetically and environmentally susceptible individuals harbor desmoglein reactive B and T cells, and anti-desmoglein antibodies were detected in their serum. Analysis of the anti-desmoglein antibody clones derived from pemphigus patients or pemphigus model mice revealed that pathogenic antibodies mostly react with conformational epitopes on mature form desmogleins, whereas non-pathogenic ones tend to react with non-conformational epitopes. Surprisingly, antibodies to the Dsg1 precursor pro-protein are also cloned from individuals without pemphigus. These observations suggest that active suppression by regulatory cell subsets is dominant in these susceptible individuals. In fact, Dsg-reactive T-inducible regulatory type 1 (Tr1) cells are readily detected in healthy carriers of pemphigus-related human leukocyte antigen haplotypes, but rarely in pemphigus patients. These Tr1 cells can be functionally converted to T-helper 2-like cells which secrete interleukin-2 by inactivation of Foxp3 through antisense oligonucleotides. Thus, delicate balance between self-reactive lymphocytes and regulatory T cells may be a key element in determining whether individuals produce pathogenic antibodies and develop pemphigus phenotypes or not.
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. [2017]Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune disease of the skin and mucous membranes. Its pathogenesis is based on IgG autoantibodies that target the desmosomal cadherins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1) and induce intra-epidermal loss of adhesion. Although the PV pathogenesis is well-understood, therapeutic options are still limited to immunosuppressive drugs, particularly corticosteroids, which are associated with significant side effects. Dsg3-reactive T regulatory cells (Treg) have been previously identified in PV and healthy carriers of PV-associated HLA class II alleles. Ex vivo, Dsg3-specific Treg cells down-regulated the activation of pathogenic Dsg3-specific T-helper (Th) 2 cells. In this study, in a HLA-DRB1*04:02 transgenic mouse model of PV, peripheral Treg cells were modulated by the use of Treg-depleting or expanding monoclonal antibodies, respectively. Our findings show that, in vivo, although not statistically significant, Treg cells exert a clear down-regulatory effect on the Dsg3-driven T-cell response and, accordingly, the formation of Dsg3-specific IgG antibodies. These observations confirm the powerful immune regulatory functions of Treg cells and identify Treg cells as potential therapeutic modulators in PV.
Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. [2022]The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3(-/-) mice, but not Dsg3(+/-) littermates, produced anti-Dsg3 IgG that binds native Dsg3, when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3(-/-) mice were then adoptively transferred into Rag-2(-/-) immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for more than 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3(-/-) mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.