ZW171 for Mesothelioma
Recruiting in Palo Alto (17 mi)
+10 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Zymeworks BC Inc.
Must not be taking: High-dose corticosteroids
Disqualifiers: Additional malignancy, Transplant, Uncontrolled renal, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This study is being done to find out if ZW171 is safe and can treat participants with advanced (locally advanced \[inoperable\] and/or metastatic) mesothelin-expressing cancers.
Will I have to stop taking my current medications?
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 or your doctor.
What makes the treatment ZW171 unique for mesothelioma?
Research Team
PC
Pranshul Chauhan, MSc, MB, BCh, BAO
Principal Investigator
Zymeworks BC Inc.
Eligibility Criteria
This trial is for individuals with advanced or metastatic cancers that express mesothelin, meaning their cancer cells have a specific protein. Details on who can join are not fully provided, but typically participants need to meet certain health standards and may be required to have tried other treatments first.Inclusion Criteria
My organs are functioning well.
I am fully active or restricted in physically strenuous activity but can do light work.
My heart's left ventricle pumps well, with an efficiency of 50% or more.
See 1 more
Exclusion Criteria
I am on high-dose steroids or immunosuppressants for an autoimmune disease.
I do not have uncontrolled kidney, pancreas, or liver issues, except for allowed conditions.
I don't have major side effects from past cancer treatments, except for hair loss.
See 3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Part 1: Safety and Tolerability Evaluation
Evaluation of the safety and tolerability of ZW171
Up to 3 weeks
Part 2: Anti-tumor Activity Evaluation
Evaluation of the anti-tumor activity of ZW171 while continuing to evaluate safety and tolerability
Up to approximately 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- ZW171 (Monoclonal Antibodies)
Trial OverviewThe study is testing ZW171's safety and effectiveness in treating advanced or metastatic mesothelin-expressing cancers. It aims to determine the appropriate dosage and observe any potential benefits in shrinking or controlling the cancer.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: ZW171Experimental Treatment1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Norton Cancer InstituteLouisville, KY
Sarah Cannon Research InstituteNashville, TN
University of Southern California - Norris Comprehensive Cancer CenterLos Angeles, CA
University of Colorado Health Sciences CenterAurora, CO
More Trial Locations
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Who Is Running the Clinical Trial?
Zymeworks BC Inc.
Lead Sponsor
Trials
6
Patients Recruited
1,300+
References
The deubiquitinase ZRANB1 is an E3 ubiquitin ligase for SLC7A11 and regulates ferroptotic resistance. [2023]The dependency of cancer cells on iron increases their susceptibility to ferroptosis, thus providing new opportunities for patients with treatment-resistant tumors. However, we show that lipid peroxidation, a hallmark of ferroptosis, was found in various areas of patient samples, indicating the potential resistance of ferroptosis. Using whole deubiquitinases (DUBs) sgRNA screening, we found that loss of ZRANB1 confers cancer cell resistance to ferroptosis. Intriguingly, functional studies revealed that ZRANB1 ubiquitinates and represses SLC7A11 expression as an E3 ubiquitin ligase and that ZRANB1 inhibits glutathione (GSH) synthesis through SLC7A11 degradation, leading to elevated lipid peroxidation and ferroptosis. Deletion of the region (residues 463-584) abolishes the E3 activity of ZRANB1. Moreover, we show that ZRANB1 has lower expression in tumors, which is positively correlated with lipid peroxidation. Collectively, our results demonstrate the role of ZRANB1 in ferroptosis resistance and unveil mechanisms involving modulation of E3 ligase activity through an unconventional catalytic domain.
A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors. [2022]Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off-target cells. Herein, a Zn2+ doped layered double hydroxide (Zn-LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn-LDH sustainably neutralizes acidic TME and releases abundant Zn2+ , promoting a pro-inflammatory network composed of M1-tumor-associated macrophages, cytotoxic T cells, and natural-killer cells. Moreover, the Zn-LDH internalized by tumor cells effectively disrupts endo-/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas-STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor-associated antigens to induce antigen-specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn-LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom-up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors.
Zinc transporter ZIP7 is a novel determinant of ferroptosis. [2021]Ferroptosis is a newly described form of regulated cell death triggered by oxidative stresses and characterized by extensive lipid peroxidation and membrane damages. The name of ferroptosis indicates that the ferroptotic death process depends on iron, but not other metals, as one of its canonical features. Here, we reported that zinc is also essential for ferroptosis in breast and renal cancer cells. Zinc chelator suppressed ferroptosis, and zinc addition promoted ferroptosis, even during iron chelation. By interrogating zinc-related genes in a genome-wide RNAi screen of ferroptosis, we identified SLC39A7, encoding ZIP7 that controls zinc transport from endoplasmic reticulum (ER) to cytosol, as a novel genetic determinant of ferroptosis. Genetic and chemical inhibition of the ZIP7 protected cells against ferroptosis, and the ferroptosis protection upon ZIP7 knockdown can be abolished by zinc supplementation. We found that the genetic and chemical inhibition of ZIP7 triggered ER stresses, including the induction of the expression of HERPUD1 and ATF3. Importantly, the knockdown of HERPUD1 abolished the ferroptosis protection phenotypes of ZIP7 inhibition. Together, we have uncovered an unexpected role of ZIP7 in ferroptosis by maintaining ER homeostasis. These findings may have therapeutic implications for human diseases involving ferroptosis and zinc dysregulations.
HECW1 induces NCOA4-regulated ferroptosis in glioma through the ubiquitination and degradation of ZNF350. [2023]Tumor suppression by inducing NCOA4-mediated ferroptosis has been shown to be feasible in a variety of tumors, including gliomas. However, the regulatory mechanism of ferroptosis induced by NCOA4 in glioma has not been studied deeply. HECW1 and ZNF350 are involved in the biological processes of many tumors, but their specific effects and mechanisms on glioma are still unclear. In this study, we found that HECW1 decreased the survival rate of glioma cells and enhanced iron accumulation, lipid peroxidation, whereas ZNF350 showed the opposite effect. Mechanistically, HECW1 directly regulated the ubiquitination and degradation of ZNF350, eliminated the transcriptional inhibition of NCOA4 by ZNF350, and ultimately activated NCOA4-mediated iron accumulation, lipid peroxidation, and ferroptosis. We demonstrate that HECW1 induces ferroptosis and highlight the value of HECW1 and ZNF350 in the prognostic evaluation of patients with glioma. We also elucidate the mechanisms underlying the HECW1/ZNF350/NCOA4 axis and its regulation of ferroptosis. Our findings enrich the understanding of ferroptosis and provide potential treatment options for glioma patients.
Synthesis and application of zeolitic imidazolate frameworks-based nucleic acid delivery system in tumor diagnosis and therapy: a review. [2023]Cancer severely threatens human health, which makes it particularly urgent to develop effective strategies for cancer diagnosis and therapy. Gene therapy and nucleic acid-based cancer diagnosis play important roles in cancer theranostic, but their applicability is challenged by the low cellular uptake and enzymatic degradation. In response, safe and efficient carrier metal-organic frameworks (MOFs) have been proposed. Zeolite imidazole frameworks (ZIFs), a promising MOF type, can easily encapsulate negatively charged nucleic acid while offering a high loading efficiency, adjustable structure, and conditional responsiveness (pH, adenosine triphosphate (ATP), or glutathione (GSH)). In this review, we studied recent articles on nucleic acid-loading ZIFs-based nanoplatforms in tumor theranostics on the Pubmed database, with a focus on the synthesis and applications in tumor diagnosis and treatment. The relevant favorable aspects, potential challenges, and future opportunities are also discussed in this review.