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New blood test for response monitoring of malignant melanoma patients with immune checkpoint inhibitors

Liquid biopsy could complement radiological diagnostics

Treatment with immune checkpoint inhibitors has significantly improved survival of patients with advanced-stage malignant melanoma. However, whether patients respond to the therapy can only be checked around three months after the start of therapy for example by radiological imaging. A relatively new blood test - the liquid biopsy - can provide information on whether the tumor is progressing earlier. In a study, researchers from Tübingen were able to show that liquid biopsy can complement response assessment for melanoma patients.

Immune checkpoint inhibitors (ICI) are antibodies that strengthen the body's own immune system in the fight against cancer. Since the approval of ICI for the treatment of advanced malignant melanoma, the ten-year survival rate of patients has more than doubled. For a few years now, ICIs have also been approved after surgical removal of high-risk melanoma or metastases and help to minimize the risk of recurrence (relapse).

However, ICIs can cause serious immune-related ad erse events. This is because the natural brake on the immune system is released, allowing immune cells to attack the body's own tissue or healthy organs. As only around one in two patients responds to ICI, it is important to recognize as early as possible who is benefitting from the therapy and who is not. In order to determine whether and how the cancer is developing, staging diagnostics are carried out using whole-body computed tomography (CT) or PET-CT. In contrast to conventional whole-body CT, PET-CT can provide additional information on the metabolic activity of the tumor tissue. Currently, response evaluation by radiological imaging precedures is recommended after three months of treatment.

Liquid biopsy shows amount of tumor DNA in the blood

In parallel to staging diagnostics, researchers from Tübingen have carried out a study to monitor tumor response by using a new procedure known as liquid biopsy - a blood test that enables the detection of tumor DNA circulating in the blood. Liquid biopsy is already routinely performed for breast and lung cancer. In melanoma patients it is currently only used in individual cases. In skin cancer, liquid biopsy is not reimbursed by health insurance companies in routine care. Nonetheless, liquid biopsy is becoming increasingly relevant for cancer therapy monitoring. “In contrast to PET-CT, it is significantly cheaper and can be repeated several times in a short time frame, for example every month. 

Just a few weeks after starting treatment with ICI, the test shows whether the amount of tumor DNA in the blood is decreasing or increasing,” explains Prof. Dr. Andrea Forschner, Head of the Melanoma Outpatient Department at the University Dermatology Clinic in Tübingen. Together with Dr. Christopher Schroeder from the Institute of Medical Genetics and Applied Genomics, Forschner conducted a study to investigate whether liquid biopsy indicates that patients are responding to ICI. “We wanted to know how reliably the liquid biopsy indicates that the therapy is working - or that recurrences can be detected,” explains Forschner. New bioinformatic analysis methods, developed in the group of Prof. Dr. Stephan Ossowski from the Institute of Medical Genetics and Applied Genomics, make it possible to identify even very small amounts of tumor DNA in blood plasma.

Blood test could complement PET-CT for melanoma

Today, half of advanced metastatic melanoma patients with inoperable metastases and first-line ICI live longer than ten years. There are now also patients in whom all metastases have even disappeared completely. “The radiation exposure from radiological diagnostics should therefore be kept as low as possible in order to minimize the risk of long-term toxicities,” emphasizes melanoma researcher Forschner. The results of the study have now been published in the journal Nature Communications. 

In the study, the research team used a new liquid biopsy procedure, which was carried out on 87 melanoma patients every few weeks. They examined not just a single genetic tumor variant, but up to 30. “With the new method, it was possible to detect even very small amounts of tumor DNA in the blood, which is particularly important for monitoring of possible recurrences in tumor-free melanoma patients,” explains Schroeder. The results of the liquid biopsies were compared with those of the PET-CT.

Liquid biopsy to be financed by health insurance companies

“We were able to show that the results of liquid biopsies can indicate earlier than regularly scheduled PET-CT whether a patient is responding to ICI or not,” explains Forschner. In particular, patients who do not respond to ICI therapy but develop side effects could be switched to other therapies earlier. All tumor-free patients in whom the development of a recurrence was monitored remained negative in both, the liquid biopsy and PET-CT during the study period, which indicates the high reliability of the liquid biopsy. In the future, frequent radiological diagnostics could be replaced by liquid biopsies. Furthermore, the exact timing of radiological diagnostics could thus be better adapted to the clinical situation.

The study team is currently working on testing treatment monitoring using liquid biopsy in further studies to confirm the current results. The researchers are positive that these studies will be the next step on the way to offer liquid biopsies to all melanoma patients in the future. The study was financed by funding from the Immuno-Oncology Foundation.

Further information: 

Titel: Tumour-informed liquid biopsies to monitor advanced melanoma patients under immune checkpoint inhibition

Authos: Schroeder C., Gatidis S., Kelemen O., Schütz L., Bonzheim I., Muyas F., Martus P., Admard j., Armeanu-Ebinger S., Gückel B., Küstner T., Garbe C., Flatz L., Pfannenberg C., Ossowski S., Forschner A.

Link: www.nature.com/articles/s41467-024-52923-0

DOI: 10.1038/s41467-024-52923-0 

Experts: 

Prof. Dr. Andrea Forschner

Head of the Melanoma Outpatient Department

University Dermatology Clinic

Dr. Christopher Schroeder

Specialist in human genetics

Institute of Medical Genetics and Applied Genomics 

Prof. Dr. Stephan Ossowski

Head of the Clinical Genome Data Analysis Section

Institute of Medical Genetics and Applied Genomics