Immune Monitoring in Metastatic Melanoma

November 7, 2019 updated by: Edward Geissler, University of Regensburg

Immune Monitoring During Systemic Therapy of Metastatic Malignant Melanoma

The mean survival time in the advanced tumor stage in the presence of distant metastases in malignant melanoma was less than 9 months until a few years ago. Intensive research efforts have led to the development of promising new therapeutic strategies and their clinical application. These include on the one hand mutation-specific inhibitors of important for cell division serine-threonine kinase BRAF such as vemurafenib, dabrafenib and encorafenib and inhibitors of the downstream target protein, the mitogen-activated protein kinase kinase (MEK), such as trametinib, binimetinib and cobimetinib.

The group of immunotherapeutics is a second new class of drugs, in which great hope for the treatment of metastatic melanoma is placed. Antibody-mediated blockage of surface molecules expressed on immune cells, referred to as immune checkpoints, results in activation of the immune system. As a result, an anti-tumor immune response is triggered, which has led to considerable therapeutic success in metastatic melanoma. To date, three checkpoint inhibitors have been approved for the treatment of metastatic melanoma. Ipilimumab is an antibody that binds cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); Pembrolizumab and nivolumab cause immune stimulation by binding the Programmed Death Receptor (PD1).

However, the impact of the therapy on the immune system as a whole is largely unknown. A comprehensive understanding of these effects is crucial to be able to further develop the therapy and to evaluate useful combination therapies with other immunomodulatory agents.

Within the framework of this project changes of the immune response under a systemic therapy of the malignant melanoma are to be characterized. The material for the analysis comes from blood samples collected during routine patient check-ups.

The aim of the analyzes is to precisely characterize the effects of the different therapeutics on the function of the immune system. In particular, the study will investigate whether certain therapeutic agents can weaken or activate the immune system and thus, in addition to the direct effect on the tumor cells, mediate indirect therapeutic effects via immune modulation. In the long term, the investigators want to use the knowledge gained to further improve the already existing therapeutic strategies of malignant melanoma by additional modulation of the immune system.

Study Overview

Status

Unknown

Conditions

Detailed Description

Despite recent breakthroughs in the treatment of melanoma, the prognosis in the advanced stage of the disease continues to be very poor. 45-50% of all melanomas carry a point mutation in codon 600 of the BRAF gene encoding a serine-threonine kinase. The two most common BRAF mutations (V600E and V600K) constitutively activate the MAP kinase signaling pathway that drives the proliferation and survival of cancer cells. Specific BRAF V600 inhibitors such as vemurafenib, dabrafenib and encorafenib and inhibitors of the downstream target MEK such as trametinib, binimetinib and cobimetinib are very effective regimens in BRAF-positive metastatic melanoma.

Recent studies have shown that these inhibitors in addition to the effects on the tumor cells also have an influence on cells of the immune system. For example, vemurafenib leads to a loss of peripheral blood lymphocytes. Thus, the number of peripheral CD4 + positive cells decreases with vemurafenib therapy, while the number of natural killer cells (NK cells) increases. On the other hand, initial studies show that B cells and CD8 + positive cells are not affected numerically by vemurafenib. It has been demonstrated that vemurafenib but not dabrafenib reduces the number of peripheral lymphocytes in melanoma patients and changes the function and phenotype of CD4 + positive cells, although both drugs show comparable clinical efficacy. Selective inhibition of BRAF by inhibitors such as vemurafenib or dabrafenib thus has a significant influence on the peripheral lymphocyte populations of melanoma patients. Studies have been demonstrated that inhibition of BRAF can induce increased invasion of tumor-infiltrating lymphocytes into melanoma metastases. Tumor infiltration of CD4 + and CD8 + positive lymphocytes is surprisingly enhanced by therapy with a BRAF inhibitor. Furthermore, it could be shown in this study that the number of immunoreactive cells correlated with a reduction in tumor size and an increased necrosis in the tumor areas. The data obtained so far suggest that treatment with BRAF inhibitors increases melanoma antigen expression and thus facilitates T cell cytotoxicity. This results in a more favorable tumor microenvironment for a synergistic BRAF-targeted therapy and immunotherapy. This therapeutic strategy is currently being evaluated in clinical trials.

The group of immunotherapeutics is a second new class of drugs, in which great hope for the treatment of metastatic melanoma is placed. Ipilimumab is an antibody that binds the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), thereby stimulating T-cell activation and proliferation. The drug has been approved for the treatment of metastatic melanoma since July 2011 and significantly increases survival in some patients. In addition, at the end of 2015, a monoclonal antibody directed against the Programmed Death Receptor (PD1) was approved by the European Medicines Commission for the treatment of unresectable or metastatic melanoma. PD1 is a receptor that is expressed on T cells and inhibits T cell activation upon binding of a ligand. Study results have shown that blocking this T-cell inhibition with PD1 or PD-L1 antagonists is a very effective therapeutic strategy for melanoma and other tumor entities.

Current data show that targeted therapy has a major impact on the tumor microenvironment and on the regulatory and effector cells of the immune system. However, the impact of the therapy on the immune system as a whole is largely unknown. A comprehensive understanding of these effects is crucial to be able to further develop the therapy and to evaluate useful combination therapies with other immunomodulatory agents.

In the context of this study, the immune status, e.g. the number and the activation state of different immune cells at the beginning and in the course of a systemic therapy for metastatic melanoma should be determined. For this purpose, 10 ml of EDTA blood is taken as part of the guideline-compliant routine care (The blood samples taken in the study are given every 4 weeks for therapy with kinase inhibitors and every 2 weeks for therapy with checkpoint inhibitors). The blood samples taken before and during therapy will be analyzed by flow cytometry and the changes in the immunophenotype will be correlated with the response to therapy. In this way, the investigator want to identify both predictive and prognostic markers. The assessment of the immune status should help to optimize the effectiveness of melanoma therapy. Therefore, it would be important to identify suitable markers and to characterize subgroups of immune cells that have an impact on the tumor microenvironment.

The evaluation of the immune status in melanoma patients could thus be incorporated into the treatment strategies in the future in order to combine a targeted therapy with immunomodulating substances or also from enriched sub-populations of immune cells in order to increase the effectiveness of the treatment.

Study Type

Observational

Enrollment (Anticipated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with metastatic melanoma of all ages and both sexes will be screened for inclusion if they qualify for systemic therapy.

Description

Inclusion Criteria:

  • Presence of metastatic melanoma expecting treatment with immune or targeted therapy

Exclusion Criteria:

  • <18 years

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Checkpoint Inhibitors
Patients with metastatic melanoma receiving systemic therapy with checkpoint inhibitors
Kinase Inhibitors
Patients with metastatic melanoma receiving systemic therapy with kinase inhibitors

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in frequency of peripheral immune cell populations assessed by immune monitoring through flow cytometry (ONE study FACS panel)
Time Frame: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year
As part of the course of therapy during routine check-up, blood samples are collected and then analyzed by flow cytometry (ONE study panel). Frequency of surface antigens of PBMC are analyzed and the characterized sub-populations are monitored during the follow-up. Thereby, changes in frequency of surface antigens will be assessed compared to baseline (before start of treatment). This allows to determine the individual immunophenotype of a patient.
Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year
Change in activation status of peripheral immune cell populations assessed by immune monitoring through flow cytometry (ONE study FACS panel)
Time Frame: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year
As part of the course of therapy during routine check-up, blood samples are collected and then analyzed by flow cytometry (ONE study panel). Expression level of surface antigens of PBMC are analyzed and the characterized sub-populations are monitored during the follow-up. Thereby, changes in expression level of surface antigens will be assessed compared to baseline (before start of treatment). This allows to determine the individual immunophenotype of a patient.
Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Liver inflammation (ALT)
Time Frame: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year
Screening for liver inflammation (serum ALT U/l)
Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year
Liver inflammation (AST)
Time Frame: Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year
Screening for liver inflammation (serum AST U/l)
Before start of treatment, 3 and 6 weeks after start of treatment as well as through study completion, an average of 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Regensburg

Investigators

  • Principal Investigator: Edward K Geissler, Phd, Dept. of Exp. Surgery, University Hospital Regensburg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

August 1, 2016

Primary Completion (ANTICIPATED)

July 31, 2020

Study Completion (ANTICIPATED)

July 31, 2021

Study Registration Dates

First Submitted

October 23, 2019

First Submitted That Met QC Criteria

November 7, 2019

First Posted (ACTUAL)

November 8, 2019

Study Record Updates

Last Update Posted (ACTUAL)

November 8, 2019

Last Update Submitted That Met QC Criteria

November 7, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16-101-0125

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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