Uveal melanoma (Ocular melanoma, choroid melanoma): Help by way of an activated immune system
In approximately half of patients diagnosed with uveal melanoma, there remains a risk of life-threatening metastases (in particular in the liver), despite removal or destruction of the original tumor. These high risk patients can now be identified using molecular biological tests. In a new clinical study, the only one of its kind, sponsored by the German Cancer Association, the goal is to evaluate whether a personalized Dendritic Cell (DC) vaccination against the tumor antigens, can stop or at least slow down the occurrence of these metastases. This form of vaccination has already proved to be effective in treating other types of tumors.
The Dermatology Clinic at the University of Erlangen has initiated a Phase III study for treating patients diagnosed with monosomy 3-uveal melanoma. Eight university eye clinics in Germany (Erlangen, Essen, Hamburg-Eppendorf, Homburg/Saar, Köln, Lübeck, Tübingen and Würzburg) are participating in this multi-center trial. If uveal melanoma is suspected, it is imperative that the study center be contacted before therapeutic measures are undertaken, since in order to make the vaccine, the tumor must be handled in a special manner.
Ocular melanoma, also known as uveal melanoma, is the most common malignant ocular tumor known in man. Currently, adjuvant treatment for this tumor is available in the 8 German University Clinics mentioned above. This treatment offers patients the opportunity to actively fight against the progression of the disease. By using a vaccination aimed at this cancer, the immune system can be activated to combat the tumor.
Normally, once uveal melanoma has been diagnosed, therapy is often carried out as soon as possible and includes either immediate radiotherapy or surgical removal of the tumor, in order to minimize the risk of metastases and related tumors. The larger the tumor is at the time of diagnosis, the higher the risk is that metastases will occur, for example in the liver.
Genetic alterations are just as important as tumor size for determining the prognosis of uveal melanoma. In approximately a half of the patients with uveal melanoma, the tumor cells exhibit a loss of chromosome 3, also known as Monosomy 3. Monosomy 3 correlates strongly with metastatic spread and therefore, a poor prognosis. Almost all tumors with this genetic change result in a 50% decrease in the 2 year survival of the patient, due to rapid metastasis, in particular to the liver.
It is of the essence for patients with uveal melanoma that the spread of the tumor be stopped. Unfortunately, there are currently no medications that can hinder the spread of the disease. It is for this reason that clinical studies, using highly specialized immune-activation against patient specific tumor antigens are being carried out, in an effort to stop or at least slow down, disease progression.
In 2013, cancer immunotherapy was celebrated worldwide, as a scientific breakthrough. Over the last 2 years, the knowledge that cancer is under the influence of the immune system has become clearer. The discovery of dendritic cells, their role in the immune system and most importantly, the ability to manipulate these cells for the treatment of cancer has played a major role in current immunotherapy.
Dendritic cells are immune-regulating cells that influence the activity of so-called killer cells. Dendritic cells either activate or prevent activation of killer cells. Dendritic cells determine the target of the killer cells, be it a virus or tumor substance. In the case of cancer, it is possible to use matured and thus activated dendritic cells to mobilize the patients’ immune system to actively attack the tumor cells. This method has been proven effective in thousands of patients in many world-wide clinical trials, which have used dendritic cell therapy to treat skin melanoma, kidney cell carcinoma, and prostate cancer as well as brain cancer. In few cases, the vaccination has led to tumor regression, in many cases to a clear slowing of and in some cases vaccination has led to a halt in disease progression. In particular in early stages of cancer diagnosis, when no large tumor masses have been formed, immunotherapy has been successful as a targeted immune-response against tumor antigens and can prevent metastases.
The Dermatology Clinic at the University of Erlangen has initiated the trial in 8 participating ophthalmology clinics for the treatment of large, newly diagnosed uveal melanoma tumors. In order to give patients the opportunity to activate their immune system and to prevent metastases of their tumor, a personal tumor specific, customized vaccination will be manufactured in the sterile labs at the Dermatology Clinic –Experimental Immunotherapy. Manufacture of the vaccination requires surgical removal of the tumor and preparation of an autologous dendritic cell vaccination loaded with patient specific tumor RNA.
In order to participate in the study, patients suspected of having uveal melanoma must be presented at any of the participating centers listed above BEFORE any therapy (surgery or radiation) is undertaken. If primary therapy is undertaken outside the participating study centers, patients are no longer eligible for inclusion into the study. The reason for this is that the tumor material must be surgically removed, stored and transported to the manufacturing lab (Experimentelle Immuntherapie, Hautklinik, Universitätsklinikum Erlangen) under specific standardized and controlled conditions. The tumor material is used to extract RNA, which provides the tumor specific genetic information.
Once the patient has been initiated into a study center, the tumor has been removed and delivered to the manufacturing lab according to study criteria, the patient is required to give blood, which will be used to grow the dendritic cells. These dendritic cells are able to perform 2 tasks.
The first task that dendritic cells perform is turning the immune system ‘on’ or ‘off’. Similar to a General in an army, the dendritic cells order the killer cells to turn on or off. The second task that the dendritic cells are responsible for is coordination of the ‘target’. This means giving the killer cells directions as to what exactly they are expected to kill. In this study, the attack will be against the surface antigens of the patient tumor. In this way, tumor cells that remain in the patient will be attacked by these programmed killer cells, and in doing so, they will hopefully prevent metastases.
As soon as the patients’ dendritic cells (immune activating cells) are turned ‘on’ and loaded with the patients’ tumor RNA (coordination against target), the vaccination will be divided into in 8 portions, each containing 30 million cells, frozen and ready for use as per vaccination protocol. Intensive quality assurance is performed on the product before it is released to the center that performed the initial surgery. The 8 vaccinations will be administered intravenously over a period of 2 years at increasing interval (2, 4, 6 weeks, 3 months and then half-yearly). Through the loaded dendritic –cell vaccination, the killer cells are activated and triggered into attacking the remaining uveal melanoma tumor cells that may be circulating in the patient’s body.
The vaccination has minimal consequences on the patient’s quality of life. Some minor side effects may occur, including short fever episodes with flu-like symptoms, rashes and vitiligo (white patches of skin).