Evaluation of WT1 LAMP mRNA DC Vaccination Combined with Chemotherapy in First-Line Treatment of Malignant Pleural Mesothelioma

The primary objective of this study is to evaluate the **feasibility** and **safety** of Wilms' tumor 1 (WT1) mRNA-electroporated dendritic cell (DC) vaccinations in patients with **malignant pleural mesothelioma** (MPM) as a first-line treatment when combined with standard chemotherapy. This is clinically relevant as it aims to establish a novel therapeutic approach that could potentially improve patient outcomes in a disease with limited treatment options.

Secondary objectives include:

• Assessing the time to progression (TTP) and progression-free survival (PFS) after chemoimmunotherapy with or without pleurectomy/decortication (P/D), and evaluating overall survival (OS) from diagnosis and start of treatment.
• Determining the in vivo systemic and local immunogenicity of WT1-targeted DC vaccination when combined with chemotherapy as a treatment for MPM.

The clinical trial involves participants diagnosed with **Malignant Pleural Mesothelioma**. The study population includes both male and female subjects, aged 18 years and older, who are fit to undergo various medical procedures such as general anesthesia, thoracoscopy, leukapheresis, chemotherapy, and immunotherapy. Participants must have a WHO performance status of 0-1 at the time of enrollment. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include a histologically proven diagnosis of epithelial MPM and no history of intolerance to pemetrexed and/or cisplatin. Participants must not have received any investigational treatment within 28 days prior to study enrollment. The trial population includes vulnerable groups, and all participants are required to provide written informed consent in accordance with ICH/GCP and national/local regulations. Lifestyle considerations such as diet, physical activity, and habits are not detailed in the available data.

The clinical trial is designed to evaluate the **feasibility** and **safety** of Wilms' tumor 1 mRNA-electroporated dendritic cell (DC) vaccinations in patients with **malignant pleural mesothelioma** as a first-line treatment combined with standard chemotherapy. This is a Phase I/II trial, which is not categorized as low intervention. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from October 3, 2017, to March 30, 2025, with the primary endpoints focusing on safety and feasibility, and secondary endpoints assessing clinical and translational outcomes.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically proven diagnosis of epithelial malignant pleural mesothelioma, age of 18 years or older, and a WHO performance status of 0-1. The screening will also ensure participants have no history of intolerance to pemetrexed and/or cisplatin and have not received any investigational treatment within 28 days prior to enrollment. Following successful screening, participants will proceed to the treatment phase, which includes leukapheresis for DC vaccine preparation and administration of combined chemoimmunotherapy cycles.

Follow-up visits will be scheduled to monitor safety through clinical laboratory tests and adverse event reporting, including microbiological testing and assessment of local and systemic toxicity. Tumor assessments will be conducted according to the latest modified Response Evaluation Criteria In Solid Tumors (RECIST) and PET Response Criteria In Solid Tumors (PERCIST). The end-of-study visit will evaluate the overall survival, progression-free survival, and time to progression, alongside immunological response analysis to determine the in vivo immunogenicity of the DC vaccinations.

Participant involvement is expected to last up to 40 weeks, with conditions for early termination including the occurrence of unacceptable adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial aims to produce at least four DC vaccines per participant, with a maximum daily dose of 10,000,000 units administered via intradermal injection. The trial's success will be measured by the ability to adhere to the proposed treatment schedule and achieve the primary and secondary endpoints.

The clinical trial involves the administration of an **experimental medication** known as WT1 LAMP mRNA DC. This medication is formulated as a **suspension for injection** and is specifically designed for use in the treatment of malignant pleural mesothelioma. The active substance, WT1 LAMP mRNA DC, is a structurally diverse substance utilized in cell therapy. The medication is administered via **intradermal injection**. The dosing regimen includes a maximum daily dose of 10,000,000 units, with a total maximum dose of 10,000,000 units over a treatment period of up to 40 days. The treatment involves monocyte-derived dendritic cells that have been electroporated with Wilms' Tumor 1 LAMP mRNA, which is intended to target the WT1 protein.

In addition to the experimental treatment, participants in the study will receive standard chemotherapy as part of the first-line treatment regimen for malignant pleural mesothelioma. This standard-of-care therapy is administered in conjunction with the WT1 LAMP mRNA DC vaccinations to evaluate the feasibility and safety of the combined treatment approach. The study does not include a placebo or comparator treatment, as the focus is on the integration of the experimental therapy with existing standard treatments.

Participant compliance with the dosing schedule will be closely monitored throughout the trial to ensure adherence to the treatment protocol. The administration of the experimental medication and standard chemotherapy will be conducted under strict clinical supervision to maintain the safety and integrity of the trial. The trial aims to assess the potential benefits of the WT1-targeted dendritic cell vaccinations in enhancing the therapeutic outcomes for patients with malignant pleural mesothelioma.

Efficacy in this clinical trial will be assessed through both clinical and translational endpoints. The clinical endpoints include time to progression (TTP), progression-free survival (PFS), and overall survival (OS). Tumor assessments will be conducted according to the latest modified Response Evaluation Criteria In Solid Tumors (RECIST), PET Response Criteria In Solid Tumors (PERCIST), and endpoints for cancer immunotherapy trials. These criteria will provide a standardized method for evaluating tumor response and progression in patients with malignant pleural mesothelioma.

The translational endpoint focuses on immunological responses, specifically evaluating the systemic and local immunological response to the **WT1 mRNA-electroporated dendritic cell (DC) vaccinations**. This analysis aims to determine the in vivo immunogenicity of the vaccinations when combined with chemotherapy for the frontline treatment of malignant pleural mesothelioma. The development of effective anti-mesothelioma immunity will be assessed to understand the potential therapeutic impact of the treatment regimen.