YTB323 for Lupus
Recruiting in Palo Alto (17 mi)
+14 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Novartis Pharmaceuticals
Disqualifiers: Infections, Uncontrolled diabetes, Malignancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
The study is intended to assess safety, efficacy and cellular kinetics of YTB323 treatment in participants with severe refractory systemic lupus erythematosus.
Do I need to stop my current medications for the YTB323 trial?
The trial protocol does not specify if you need to stop your current medications, but it mentions an 'immunosuppressive washout' period, which suggests you might need to stop certain medications. It's best to discuss this with the trial team.
What data supports the effectiveness of the treatment YTB323 for Lupus?
What safety data exists for YTB323 (Rapcabtagene autoleucel) in humans?
The safety of CAR T-cell therapies, like YTB323, often involves risks such as cytokine release syndrome (a severe immune reaction), neurological side effects, infections, fever, diarrhea, nausea, low blood pressure, and fatigue. These side effects have been observed in similar therapies, such as Yescarta and Kymriah, which are also anti-CD19 CAR T-cell treatments.678910
How is the YTB323 treatment different from other lupus treatments?
YTB323 is a unique treatment for lupus because it uses CAR T-cell therapy, which involves modifying a patient's own immune cells to target and destroy specific B cells that contribute to the disease. This approach is different from traditional lupus treatments, which often involve general immunosuppressive drugs, as it offers a more targeted and potentially long-lasting effect.25111213
Eligibility Criteria
This trial is for adults aged 18-65 with severe, treatment-resistant systemic lupus erythematosus (SLE). Participants must meet specific SLE criteria and have certain autoantibodies. They should have tried at least two immunosuppressive therapies without success and may also have kidney, heart, lung or blood vessel involvement. Major organ functions need to be adequate.Inclusion Criteria
Signed informed consent
My kidney, liver, heart, blood, and lung functions are all within normal ranges.
I am between 18 and 65 years old and have been diagnosed with SLE according to the 2019 EULAR/ACR criteria.
See 3 more
Exclusion Criteria
Any psychiatric condition or disability making compliance with treatment or informed consent impossible
My condition is B cell aplasia.
I do not have any serious or recurring infections.
See 10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single infusion of YTB323
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 2 years
Regular visits (in-person and virtual) for monitoring
Long-term safety follow-up
Long term safety follow-up to monitor adverse events and efficacy
Up to 2 years
Treatment Details
Interventions
- YTB323 (Other)
Trial OverviewThe study tests YTB323's safety, effectiveness, and how it affects immune cells in patients with severe refractory SLE. It aims to see if this new treatment can help where others failed.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: YTB323Experimental Treatment1 Intervention
Single infusion of YTB323
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
WA Uni School Of Med WUSCMSaint Louis, MO
Division of Rheumatology ImmunologyBirmingham, AL
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Who Is Running the Clinical Trial?
Novartis PharmaceuticalsLead Sponsor
References
Journal Club: Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Refractory Systemic Lupus Erythematosus. [2023]Despite substantial advances in the treatment of systemic lupus erythematosus (SLE), some patients do not respond to the current state-of-the art therapies. This study assessed the tolerability and efficacy of CD19 chimeric antigen receptor (CAR) T cells in a small series of seriously ill and treatment-resistant patients with SLE.
CAR T therapy extends its reach to autoimmune diseases. [2023]CAR T therapy has revolutionized the treatment of hematologic cancers. In their recent Nature Medicine paper, Mackensen et al. report the use of CAR T cells to treat systemic lupus erythematosus in five patients. This provides enthusiasm to further explore CAR T therapy beyond oncology.
Slamming the brakes on lupus with CAR T cells. [2019]Sustained depletion of B cells with CAR T cells induces disease remission in lupus-prone mice.
Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. [2021]The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F1 and MRL fas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44+CD62L+ T cell subset. Adoptively transferred splenic T cells from CAR T cell-treated mice depleted CD19+ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.
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.
CAR T Cell Toxicity: Current Management and Future Directions. [2020]By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, or adult patients with large B-cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite) is indicated for the treatment of adult patients with large B-cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA-1 trial). This review will offer a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlight strategies to diminish these side effects in the future.
Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. [2023]Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care.
EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma. [2022]On June 28, 2018, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yescarta for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy. Yescarta, which was designated as an orphan medicinal product and included in the European Medicines Agency's Priority Medicines scheme, was granted an accelerated review timetable. The active substance of Yescarta is axicabtagene ciloleucel, an engineered autologous T-cell immunotherapy product whereby a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction using a retroviral vector to express a chimeric antigen receptor (CAR) comprising an anti-CD19 single chain variable fragment linked to CD28 costimulatory domain and CD3-zeta signaling domain. The transduced anti-CD19 CAR T cells are expanded ex vivo and infused back into the patient, where they can recognize and eliminate CD19-expressing cells. The benefits of Yescarta as studied in ZUMA-1 phase II (NCT02348216) were an overall response rate per central review of 66% (95% confidence interval, 56%-75%) at a median follow-up of 15.1 months in the intention to treat population and a complete response rate of 47% with a significant duration. The most common adverse events were cytokine release syndrome, neurological adverse events, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. IMPLICATIONS FOR PRACTICE: Yescarta (axicabtagene ciloleucel) was the first chimeric antigen receptor T-cell therapy to be submitted for evaluation to the European Medicines Agency and admitted into the "priority medicine" scheme; it was granted accelerated assessment on the basis of anticipated clinical benefit in relapsed/refractory diffuse large B-cell lymphoma, a condition of unmet medical need. Indeed, Yescarta showed an overall response rate of 66% and a complete response rate of 47% with a significant duration and a manageable toxicity that compared very favorably with historical controls. Here the analysis of benefits and risks is presented, and specific challenges with this important novel product are highlighted, providing further insights and reflections for future medical research.
[CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm]. [2021]Following the first demonstration of efficacy of anti-CD19-directed chimeric antigen receptor (CAR) T cells in a patient with relapsed chronic lymphocytic leukemia (CLL) in 2011, pivotal studies for this innovative therapy were initially conducted in multiple relapsed or refractory (r/r) childhood and young adult acute B‑cell leukemia and in aggressive adult B‑cell lymphoma. The studies demonstrated efficacy even in chemotherapy-refractory disease, resulting in the first approval of autologous and genetically engineered T cells for the treatment of r/r B‑cell acute lymphoblastic leukemia (B-ALL) in the US for the product tisagenlecleucel (Kymriah®, Novartis) back in 2018. Approval for the treatment of r/r aggressive B‑cell lymphoma followed shortly thereafter for tisagenlecleucel and axicabtagene ciloleucel (Yescarta, Kite/Gilead). This review focuses on the treatment of aggressive B‑cell lymphoma and other CD19 positive B‑cell lymphomas by summarizing the study results of clinically tested CAR T cells, discussing possible resistance mechanisms, and providing an outlook on ongoing studies with new target antigens for the treatment of B‑cell lymphomas.
The promise of CAR T-cell therapy in aggressive B-cell lymphoma. [2021]Relapsed or refractory aggressive B-cell lymphoma has an extremely poor prognosis and efforts to develop novel therapies for these patients have failed for almost four decades until the advent of chimeric antigen receptor (CAR) T-cell therapy. Within the last one year, two anti-CD19 CAR T-cell therapy products, axicabtagene ciloleucel and tisagenlecleucel, were approved by the United States Food and Drug Administration for the treatment of relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy based on multicenter single-arm phase two clinical trials. Here, we will discuss the different components of the CAR construct and their mechanisms of action, the role of conditioning chemotherapy, the efficacy and toxicity observed with anti-CD19 CAR T-cell therapies in aggressive B-cell lymphomas, and emerging strategies to further improve the safety and efficacy of these highly promising approaches.
Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus. [2023]Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell-targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell-suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.
Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. [2022]Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.
[The variation of T-cell clonal repertoire in patients with systemic lupus erythematosus (SLE) following autologous peripheral blood hematopoietic stem cell transplantation]. [2006]Analyze the variation of T cell receptor(beta) (TCRbeta) CDR3 gene expressing repertoire in systemic lupus erythematosus (SLE) patients before and after autologous peripheral blood hematopoietic stem cell transplantation (APBSCT), to search the pathogenesis of SLE and characteristics of T cell reconstitute immune after APBSCT.