Messenger Ribonucleic Acid (mRNA) Transfected Dendritic Cell Vaccination in High Risk Uveal Melanoma Patients

Study Overview
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Brief Summary
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Rationale Immunotherapy applying ex vivo generated and tumor antigen-loaded dendritic cells (DC) has now successfully been introduced in the clinic. A limited, but consistent, number of objective immunological and clinical responses have been observed. Most of the successful results have been observed in patients with minimal residual disease, rather than patients with advanced metastatic disease. Moreover, the investigators' preliminary results show that presence of tumor epitope specific T cells in biopsies taken from delayed type hypersensitivity (DTH) reaction sites highly correlates with prolonged progression free survival (PFS). Within uveal melanoma patients, a group with high risk of metastatic disease can be identified on basis of tumor specific genetic changes in loss of chromosome 3. At present no standard adjuvant or systemic treatment is available. Applying DC-based immunotherapy in this group of high risk patients might reduce the risk of recurrence without interference in the current treatment guidelines. Objectives In this joint clinical study of Radboud University Nijmegen Medical Centre (RUNMC) and Rotterdam Eye Hospital, the investigators aim to determine the in vivo immunological response induced in high risk uveal melanoma patients vaccinated with mRNA-transfected DC. Study design This study is an open label non-randomized phase II intervention study. Study population The investigators' study population consists of HLA-A2 positive patients with a high risk uveal melanoma with proven expression of melanoma associated antigens tyrosinase and/or gp100. Main study endpoints This is an exploratory study aiming to demonstrate proof of principle. The first study endpoints are in vivo immunological response induced in high risk uveal melanoma patients vaccinated with mRNA-transfected DC, administered i.v./i.d. and toxicity. Secondary study endpoints are progression free survival, overall survival, and toxicity.

Official Title
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mRNA Transfected Dendritic Cell Vaccination in High Risk Uveal Melanoma Patients

Conditions
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Uveal Melanoma

Intervention / Treatment
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* Biological: autologous dendritic cells electroporated with mRNA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histological documented uveal melanoma HLA-A2.1 phenotype (intervention arm) non-HLA-A2.1 phenotype (control arm) melanoma expressing gp100 and/or tyrosinase high risk genetic profile (loss of chromosome 3) determined by FISH interval since local treatment of uveal melanoma < 12 months no signs of liver metastasis determined by diagnostic CT-abdomen normal serum LDH no signs of cerebral metastases bilirubin < 25 micromol/l WHO performance scale 0-1 age 18-75 years written informed consent expected adequacy of followup no pregnant or lactating women Exclusion Criteria: history of second malignancy, except adequately treated basal cell carcinoma serious active infections autoimmune disease or organ allografts concomitant use of immunosuppressive drugs known allergy to shell-fish

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dendritic cell vaccination<br>HLA-A2.1 positive patient will receive 3 biweekly intradermal/intravenous vaccination with autologous mRNA transfected mature dendritic cells, followed by a DTH skin test for monitoring purposes. One such cycle is repeated every 6 months if no signs of progression, up to a total of 3 cycles. | Biological: autologous dendritic cells electroporated with mRNA<br>* Autologous mature monocyte-derived dendritic cells electroporated with mRNA encoding gp100 and tyrosinase are vaccinated intradermal/intravenously 3 times with biweekly intervals every 6 months, if no signs of progression, for a total of 9 vaccinations.<br>|
| No Intervention: control arm<br>For comparison, HLA-A2.1 negative patients will be monitored for clinical response (secondary endpoint). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| immunological response |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical response (progression free survival) |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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uveal melanoma, chromosome 3, high risk, immunotherapy, adjuvant, high risk genetic profile, loss of chromosome 3