RAY121 for Immune System Disorders
Recruiting in Palo Alto (17 mi)
+63 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Chugai Pharmaceutical
Must not be taking: Antivirals, Antibiotics, Antifungals, others
Disqualifiers: Cancer, Hepatitis, HIV, Tuberculosis, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This trial is testing a new drug called RAY121, which aims to help people with certain immune system diseases by blocking a part of the immune system that causes inflammation. The trial will check if the drug is safe and effective for patients with conditions like APS, BP, BS, DM, IMNM, and ITP.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications, but it mentions that certain treatments are prohibited. It's best to discuss your current medications with the trial team to see if they fall under the prohibited category.
What data supports the effectiveness of the drug RAY121 for immune system disorders?
What makes the drug RAY121 unique for treating immune system disorders?
RAY121 is unique because it involves the use of IL-12, a cytokine that can modulate the immune system by promoting T helper type 1 (Th1) cell responses, which are crucial for fighting infections and tumors. This mechanism of action is different from many existing treatments, as IL-12 can directly enhance the immune response and potentially overcome immune suppression seen in certain conditions.678910
Eligibility Criteria
This trial is for people with certain immune system disorders like low platelet count, antiphospholipid syndrome, dermatomyositis, Behcet's Disease, and bullous pemphigoid. Participants should have one of these conditions to join the study.Inclusion Criteria
Ability to comply with the study protocol
Signed informed consent form
APS cohort: Established primary APS defined by specific laboratory and clinical criteria
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Exclusion Criteria
I have an autoimmune disease that is not the disease this trial is targeting.
I have not received any treatments that are not allowed in this study.
My liver tests are high.
See 22 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive multiple doses of RAY121 to assess safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy
32 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- RAY121 (Complement Pathway Inhibitor)
Trial OverviewThe RAINBOW Trial is testing a new medication called RAY121 to see if it's safe and how well it works in treating various immunological diseases by inhibiting part of the body's immune response.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: RAY121Experimental Treatment1 Intervention
All enrolled patients will receive RAY121 multiple dose
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California-IrvineOrange, CA
Northwell Health, LLC PRIMELake Success, NY
Hospital for Special SurgeryNew York, NY
Ohio State UniversityColumbus, OH
More Trial Locations
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Who Is Running the Clinical Trial?
Chugai PharmaceuticalLead Sponsor
References
[Role of rituximab in the management of refractory autoimmune cytopenia]. [2015]This study examined the efficacy of rituximab in children with refractory autoimmune cytopenia.
Clinical effects and safety of rituximab for treatment of refractory pediatric autoimmune diseases. [2019]To evaluate the safety, tolerability, and clinical effects of rituximab, an anti-CD20 monoclonal antibody, in the treatment of severe pediatric autoimmune diseases.
A case report involving suppressed nuclear receptor transcription factors 4a1 and Stevens-Johnson syndrome induced by a single dose of pembrolizumab and successfully treated with early steroid administration, resulting in complete remission of stage III lung cancer. [2022]Immunotherapy with immune checkpoint inhibitors is associated with immune-related adverse events (irAEs). A positive correlation between treatment efficacy and irAEs has been reported. Clinical indicators are required for appropriate interventions, such as steroid administration, to prevent fatal outcomes. Nuclear receptor transcription factor 4a (Nr4a), which is involved in T-cell anergy, exhaustion, and regulatory T cells, were observed not only in thymocytes but in peripheral blood mononuclear cells. We describe a case of Stevens-Johnson syndrome (SJS) that was induced by a single dose of pembrolizumab and successfully treated with steroids, leading to complete remission of lung cancer during the monitoring of immune response indices, including Nr4a1 mRNA.
Durable Metastatic Melanoma Remission Following Pembrolizumab and Radiotherapy: A Case Report of Prophylactic Immunosuppression in a Patient with Myasthenia Gravis and Immune-Mediated Colitis. [2022]Immune checkpoint inhibitors (ICIs) and radiotherapy (RT) combinations for various metastatic cancers are increasingly utilized, yet the augmentation of anti-cancer immunity including distant tumor responses by RT remains ill-characterized. Immunosuppressive tumor microenvironments and defective anti-tumor immune activation including immune-related adverse events (irAEs) likely limit dramatic immuno-radiotherapy combinations, though it remains unclear which immune characteristics mediate dramatic systemic tumor regression in only a small subset of patients. Moreover, the efficacy of ICI treatment in patients receiving immunosuppressive therapies for autoimmune conditions or irAEs is convoluted, yet clinically valuable. Here, we report a case of a 75-year-old man with myasthenia gravis and metastatic melanoma who experienced complete and durable systemic regression after receiving pembrolizumab and single-lesion RT while on prednisone for myasthenia gravis prophylaxis and vedolizumab for immune-mediated colitis after previously experiencing mixed response on pembrolizumab monotherapy. We discuss the potential paradoxical effects and clinical considerations of immunosuppressive regimens in patients with underlying autoimmune disease or adverse immune reactions while receiving immuno-radiotherapy combinations.
Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients: A systematic review and meta-analysis of randomised trials. [2020]To assess the efficacy and safety of methotrexate (MTX) in combination with an approved biological agent compared to biological monotherapy, in the management of patients with rheumatoid arthritis (RA).
The regulation and activity of interleukin-12. [2022]Interleukin-12 (IL-12) is a key cytokine in the development of T helper type 1 (Th1) cell polarization, and its production of IL-12 is redundantly regulated. An important pro-inflammatory cytokine, IL-12 has been shown to have potent immunomodulatory, antitumor, and anti-infection activity in vitro and in vivo. Therefore, following a series of promising results from preclinical animal models experiments, researchers have begun to explore the clinical use of recombinant human IL-12 (rhIL-12) for treating a variety of diseases. In a series of phase I and phase II clinical trials related to cancer, viral infections, and hematopoietic stem cell transplants (HSCT), various strategies of rhIL-12 administration have been used with promising preliminary clinical results associated with tolerable toxicities.
Interleukin-12, a key cytokine in Th1-mediated autoimmune diseases. [2005]Interleukin 12 (IL-12) is a heterodimeric cytokine produced primarily by antigen-presenting cells (APCs) which plays a key role in promoting type 1 T helper cell (Th1) responses. The powerful activity of IL-12 requires tight control, which is exerted at various levels. Primary control is exerted on IL-12 production by APCs, a major factor driving the response towards the Th1 or Th2 phenotype. Another level of control regulates expression of the IL-12 receptor (IL-12R), which is composed of two subunits, beta 1 and beta 2. The IL-12R beta 2 subunit has signal-transducing capacity and modulation of its expression is central to the regulation of IL-12 responsiveness. Endogenous IL-12 plays an important role in host defense against infection by a variety of intracellular pathogens. Its Th1-promoting activity, however, also favors Th1-mediated immunopathology and, in particular, the induction of Th1-mediated autoimmune diseases.
Endogenous IL-12 triggers an antiangiogenic program in melanoma cells. [2022]The IL12RB2 gene acts as a tumor suppressor in human B cell malignancies. Indeed, Il12rb2 knockout (KO) mice develop spontaneously B cell tumors, but also lung epithelial tumors. This latter phenotype may be related to (i) impairment of host IL-12-mediated immunosurveillance and/or (ii) IL-12 inability to inhibit directly the growth of IL-12 unresponsive malignant cells. To address this issue, we transplanted IL-12R(+) B16 melanoma cells into syngeneic Il12rb2 KO mice with the following rationale: (i) these mice have severe defects in IFN-gamma production, as well as in cytotoxic T lymphocyte and natural killer cell cytotoxicity, and (ii) they produce but do not use IL-12 that can potentially bind to and target tumor cells only. Il12rb2 KO mice displayed higher endogenous serum levels of IL-12 and developed smaller B16 tumors than WT animals. These tumors showed reduced proliferation, increased apoptosis, and defective microvessel formation related to down-regulated expression of a set of proangiogenic genes previously unrelated to IL-12. Such effects depended on direct activity of endogenous IL-12 on tumor cells in KO mice, and hydrodynamic delivered IL-12 caused further reduced tumorigenicity of B16 cells in these mice. A previously undescribed mechanism of the IL-12 antitumor activity has been here identified and characterized.
Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. [2021]The interleukin-12 receptor beta2 (Il12rb2) gene is silenced in tumor cells from different human B-cell malignancies as opposed to their normal counterparts. It was hypothesized that this silencing allows neoplastic B cells to escape the control exerted by IL-12 on their growth. The aim of this study was to investigate whether targeted inactivation of the Il12rb2 gene in mice resulted into increased susceptibility to spontaneous tumor formation and immunopathology. Il12rb2 gene-deficient animals developed in the first year of life immune-complex mesangial glomerulonephritis with serum antinuclear antibodies. In older animals, multiorgan lymphoid infiltrates with features of vasculitis and Sjögren syndrome were detected in association with systemic B- and T-cell activation. In half of aged animals, lymph node plasmacytoma or lung carcinoma was observed. A mechanism for spontaneous development of autoimmune pathology and B-cell tumors is suggested by a strong IL-6 up-regulation detected in splenocytes and lymphoid infiltrates associated with oligoclonal B-cell expansion. The emergence of lung tumors may likely be attributed to an interferon-gamma (IFN-gamma) deficiency secondary to lack of IL-12 signaling. The development of autoimmunity, lymphoproliferation, and B-cell tumors in Il12rb2 knockout (KO) mice suggests that IL-12 functions physiologically to restrain aberrant B-cell activation.
B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12. [2022]Immunotherapies have revolutionized the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but the duration of responses is still sub-optimal. We sought to identify mechanisms of immune suppression in B-ALL and strategies to overcome them. Plasma collected from children with B-ALL with measurable residual disease after induction chemotherapy showed differential cytokine expression, particularly IL-7, while single-cell RNA-sequencing revealed the expression of genes associated with immune exhaustion in immune cell subsets. We also found that the supernatant of leukemia cells suppressed T-cell function ex vivo. Modeling B-ALL in mice, we observed an altered tumor immune microenvironment, including compromised activation of T-cells and dendritic cells (DC). However, recombinant IL-12 (rIL-12) treatment of mice with B-ALL restored the levels of several pro-inflammatory cytokines and chemokines in the bone marrow and increased the number of splenic and bone marrow resident T-cells and DCs. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in genes associated with exhaustion, including Lag3, Tigit, and Il10, was abrogated with rIL-12 treatment. In addition, the cytolytic capacity of T-cells co-cultured with B-ALL cells was enhanced when IL-12 and blinatumomab treatments were combined. Overall, these results demonstrate that the leukemia immune suppressive microenvironment can be restored with rIL-12 treatment which has direct therapeutic implications.