CD19 CAR T-Cell Therapy for Scleroderma
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Kyverna Therapeutics
No Placebo Group
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?A Study of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Subjects with Systemic Sclerosis
Is the treatment KYV-101 a promising treatment for Scleroderma?Yes, KYV-101, which is a type of CAR T-cell therapy targeting CD19, shows promise as a treatment. It has been effective in treating autoimmune diseases like lupus by reducing harmful antibodies and improving symptoms. This suggests it could be beneficial for Scleroderma, another autoimmune condition.47101214
What data supports the idea that CD19 CAR T-Cell Therapy for Scleroderma is an effective treatment?The available research shows that CD19 CAR T-Cell Therapy has been effective in treating B-cell cancers, as it can lead to long-term remission in patients with advanced-stage B-cell malignancies. In studies, this treatment has shown the ability to eliminate cancerous cells and normal B cells for extended periods. Although the research primarily focuses on cancer, the success in targeting CD19-positive cells suggests potential effectiveness for other conditions like Scleroderma, which may involve similar cell types. However, there is no direct data on its effectiveness for Scleroderma specifically in the provided information.12456
What safety data is available for CD19 CAR T-Cell Therapy for Scleroderma?The provided research does not contain safety data for CD19 CAR T-Cell Therapy, KYV-101, or Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy. The studies focus on the safety of subcutaneous immunotherapy (SCIT) for allergies, not CAR T-Cell Therapy.3891113
Do I need to stop my current medications for this trial?The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators.
Eligibility Criteria
This trial is for people with a condition called systemic sclerosis, specifically the diffuse cutaneous type. They should be within 6 years of their first symptom that's not Raynaud's phenomenon and have active disease. Participants must also be current on vaccinations recommended for those with weakened immune systems.Inclusion Criteria
I have been diagnosed with systemic sclerosis.
Exclusion Criteria
I have a serious lung condition.
I have previously received CAR-T or gene therapy.
I have had a stem cell transplant.
I have had my spleen removed.
I have heart problems that affect my daily activities.
Treatment Details
The study is testing KYV-101, which is a type of CAR T-cell therapy targeting CD19, an antigen found on certain cells in the body. This therapy will be compared to or combined with standard treatments that reduce the number of lymphocytes (a type of white blood cell).
2Treatment groups
Experimental Treatment
Group I: KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 2)Experimental Treatment2 Interventions
Recommended Phase 2 Dose
Group II: KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 1)Experimental Treatment2 Interventions
Dosing with KYV-101 CAR T cells
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
Find a clinic near you
Research locations nearbySelect from list below to view details:
Northwell HealthGreat Neck, NY
Stanford University Medical CenterPalo Alto, CA
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Who is running the clinical trial?
Kyverna TherapeuticsLead Sponsor
References
Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. [2023]Adoptive T-cell therapy with anti-CD19 chimeric antigen receptor (CAR)-expressing T cells is a new approach for treating advanced B-cell malignancies. To evaluate anti-CD19-CAR-transduced T cells in a murine model of adoptive T-cell therapy, we developed a CAR that specifically recognized murine CD19. We used T cells that were retrovirally transduced with this CAR to treat mice bearing a syngeneic lymphoma that naturally expressed the self-antigen murine CD19. One infusion of anti-CD19-CAR-transduced T cells completely eliminated normal B cells from mice for at least 143 days. Anti-CD19-CAR-transduced T cells eradicated intraperitoneally injected lymphoma cells and large subcutaneous lymphoma masses. The antilymphoma efficacy of anti-CD19-CAR-transduced T cells was critically dependent on irradiation of mice before anti-CD19-CAR-transduced T-cell infusion. Anti-CD19-CAR-transduced T cells had superior antilymphoma efficacy compared with the anti-CD19 monoclonal antibody from which the anti-CD19 CAR was derived. Our results demonstrated impressive antilymphoma activity and profound destruction of normal B cells caused by anti-CD19-CAR-transduced T cells in a clinically relevant murine model.
A CD19/Fc fusion protein for detection of anti-CD19 chimeric antigen receptors. [2021]Chimeric Antigen Receptors (CARs) consist of the antigen-recognition portion of a monoclonal antibody fused to an intracellular signaling domain capable of activating T-cells. CARs displayed on the surface of transduced cells perform non-MHC-restricted antigen recognition and activating intracellular signaling pathways for induction of target cytolysis, cytokine secretion and proliferation. Clinical trials are in progress assessing the use of mature T-lymphocytes transduced with CARs targeting CD19 antigen to treat B-lineage malignancies. CD19 is an attractive target for immunotherapy because of its consistent and specific expression in most of the stages of maturation and malignancies of B-lymphocyte origin, but not on hematopoietic stem cells. Antibodies against the extracellular domain of the CAR molecule (anti-Fab, Fc or idiotype) have been used for detection of CAR expression in research and clinical samples by flow cytometry, but may need development for each construct and present significant background in samples from xenograft models.
AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions? [2022]To define the incidence of and clinical practices associated with subcutaneous immunotherapy (SCIT)-related systemic reactions (SRs).
Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. [2021]Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells. Additional patients have subsequently obtained long-term remissions of advanced-stage B-cell malignancies after infusions of anti-CD19 CAR T cells. Long-term eradication of normal CD19(+) B cells from patients receiving infusions of anti-CD19 CAR T cells demonstrates the potent antigen-specific activity of these T cells. Some patients treated with anti-CD19 CAR T cells have experienced acute adverse effects, which were associated with increased levels of serum inflammatory cytokines. Although anti-CD19 CAR T cells are at an early stage of development, the potent antigen-specific activity observed in patients suggests that infusions of anti-CD19 CAR T cells might become a standard therapy for some B-cell malignancies.
Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. [2023]Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies. However, the use of allogeneic CAR T cells poses a concern in that it may increase risk of the occurrence of GVHD, although this has not been reported in selected patients infused with donor-derived CD19 CAR T cells after allo-HSCT. To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice. We demonstrate that alloreactive T cells expressing CD28-costimulated CD19 CARs experience enhanced stimulation, resulting in the progressive loss of both their effector function and proliferative potential, clonal deletion, and significantly decreased occurrence of GVHD. Concurrently, the other CAR T cells that were present in bulk donor T cell populations retained their anti-lymphoma activity in accordance with the requirement that both the T cell receptor (TCR) and CAR be engaged to accelerate T cell exhaustion. In contrast, first-generation and 4-1BB-costimulated CAR T cells increased the occurrence of GVHD. These findings could explain the reduced risk of GVHD occurring with cumulative TCR and CAR signaling.
A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia. [2019]Label="PURPOSE">The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19+ B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.
Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art. [2021]Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%-40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.
Systemic reactions to subcutaneous immunotherapy: Effects of dosing and aeroallergen content. [2020]Systemic reactions are a known risk of subcutaneous immunotherapy (SCIT) for aeroallergens.
Safety of subcutaneous allergen immunotherapy in children: A retrospective review and bird eye to literature. [2019]Toprak-Kanık E, Yılmaz Ö, Yangın-Ergon E, Türkeli A, Yüksel H. Safety of subcutaneous allergen immunotherapy in children: A retrospective review and bird eye to literature. Turk J Pediatr 2018; 60: 684-690. Subcutaneous allergen immunotherapy (SCIT) has been shown to improve clinical course in children with asthma and allergic rhinitis (AR). Systemic and local side-effects may be seen during its administration. The purpose of this study was to evaluate risk factors associated with systemic and local side-effects in children receiving SCIT. We performed a retrospective chart review in the children who received allergen subcutaneous immunotherapy for asthma and/or allergen rhinitis. Demographic data, diagnosis, skin prick test results, presence of additional allergic diseases, the seasonal variation of adverse events in the first and third years of SCIT were recorded. A total of 508 eligible patients were included in the study. Mean age of the children was 10.9±3.2 years, and 65.4% were male. Asthma was present in 21.9% of the children, AR in 44.7%, 33.5% of them had both asthma and AR. According to the skin prick test results, sensitivity to more than one allergen was present in 45.1%, while the most common single-allergen sensitivities were to grass pollen and dermatophagoids (32.5% and 14.4%, respectively). Ratio of systemic and local side-effects was 4.7% and 9.3%, respectively. Local side-effects were more common than systemic reaction. SCIT is a safe treatment modality while using the appropriate dose and with the administration of dose-escalation protocol.
CD19-targeted CAR regulatory T cells suppress B cell pathology without GvHD. [2021]Regulatory T cells (Tregs) play essential roles in maintaining immunological self-tolerance and preventing autoimmunity. The adoptive transfer of antigen-specific Tregs has been expected to be a potent therapeutic method for autoimmune diseases, severe allergy, and rejection in organ transplantation. However, effective Treg therapy has not yet been established because of the difficulty in preparing a limited number of antigen-specific Tregs. Chimeric antigen receptor (CAR) T cells have been shown to be a powerful therapeutic method for treating B cell lymphomas, but application of CAR to Treg-mediated therapy has not yet been established. Here, we generated CD19-targeted CAR (CD19-CAR) Tregs from human PBMCs (hPBMCs) and optimized the fraction of the Treg source as CD4+CD25+CD127loCD45RA+CD45RO-. CD19-CAR Tregs could be expanded in vitro while maintaining Treg properties, including high expression of the latent form of TGF-β. CD19-CAR Tregs suppressed IgG antibody production and differentiation of B cells via a TGF-β-dependent mechanism. Unlike conventional CD19-CAR CD8+ T cells, CD19-CAR Tregs suppressed antibody production in immunodeficient mice that were reconstituted with hPBMCs, reducing the risk of graft-versus-host disease. Therefore, the adoptive transfer of CD19-CAR Tregs may provide a novel therapeutic method for treating autoantibody-mediated autoimmune diseases.
Subcutaneous immunotherapy with aeroallergens: safety profile assessment. [2022]Label="SUMMARY" NlmCategory="CONCLUSIONS"> Introduction. Severe systemic reactions (SR) to allergen subcutaneous immunotherapy (SCIT) are rare but local reactions (LR) are common. We aimed to characterize the type of reactions and safety profile. Methods. Retrospective analysis of medical record from patients under SCIT between 2013-2016. Results. Total of 7372 SCIT injections in 323 patients: 52% female; mean age 30 years (SD 13); mean treatment time 19 months (SD 13). There were 57 patients (17.6% of population, 70% female) with at least one adverse reaction, for 93 reactions described (1.3% injections). There were 79 LR (1.1% injections) in 46(14.2%) patients: 36 in build-up, 43 in maintenance. There were 14 SR (0.19% injections) in 12(3.7%) patients: 12 in build-up, 2 in maintenance. All SR were grade 1. The majority of reactions were caused by mite SCIT (69.9%). Conclusions. SCIT is safe and well tolerated, with no report of SR grade > 1.
Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. [2023]Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE.
A single center retrospective study of systemic reactions' distribution and risk factors to subcutaneous immunotherapy with dust mite extract in patients with allergic rhinitis and/ or asthma. [2023]To analyze various risk factors including causes that may lead to adverse reactions, especially systemic adverse reactions（SRs）, before and after mite allergen subcutaneous immunotherapy (SCIT), so as to provide real-world reference data for further improving the safety of mite allergen SCIT. Methods: The local adverse reactions（LRs）and SRs of 230 patients with allergic rhinitis and/or asthma who received SCIT in Weifang people's hospital were analyzed retrospectively. The data of patient characteristics, drug factors and environmental elements of adverse reactions were collected and statistically analyzed. Results: There were 28 cases (12.2%) of SRs in 230 patients. All the patients received a total of 7515 injections and 37 SRs (0.49%) were observed. 32.4% (12/37) of SRs could identify their external and subjective triggers. SRs patients had higher 2-year SCIT compliance than no-SRs patients (p = 0.026). The prevalence of SRs in SCIT patients with atopic dermatitis or simple allergic asthma are no statistical significance (P = 0.111). Conclusion: the incidence of SRs in this study is within an ideal range. Through professional patient education and pre injection risk factor assessment, Compliance is still well-controlled and guaranteed although SRs occurred.
Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy. [2023]Chimeric antigen receptor (CAR) T cells targeting CD19+ B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR T cell therapy is well tolerated and highly effective, the immunologic consequences of CAR T cell therapy in SLE patients remain unclear. We profiled serum in six refractory SLE patients prior to and 3 months following CAR T cell infusion. Three months post T cell infusion, the inflammatory cytokines IL-6 and TNFα decreased in patient sera. This was accompanied by elevations in serum IL-7 and BAFF. Furthermore, SLE-associated antibodies dropped profoundly in five of six patients. Last, consistent with other reports of CD19 CAR T therapy in B cell malignancies, we were able to show marginal impact of anti-CD19 CART therapy on pre-existing humoral immune responses in SLE patients. Together, these results provide insights into the mechanisms of efficacy of anti-CD19 CAR T cell therapy in SLE.