Treating Malignant Melanoma – Research and Therapy Programs
Unique Decade-Long Trial at the Sharett Institute of Oncology Aims to Develop an Innovative Therapeutic Strategy for Malignant Melanoma, and to Elucidate the Basic Biology and Immunology of the Disease
Prophylactic Administration of an
Autologous Melanoma Tumor-Cell Vaccine
Who is eligible for the treatment?
The treatment program is intended for patients with stage IV melanoma who have undergone surgery to remove one or more metastases. A portion of the tissue removed is sent to the Sharett Institute’s Tumor Immunotherapy Laboratory.
Patients who show no evidence of additional tumor foci after surgery are eligible for the vaccine.
What is the purpose of the treatment?
To determine the therapeutic value of a melanoma vaccine derived from autologous tumor cells in preventing or delaying metastatic recurrence and prolonging overall survival.
How is the vaccine produced?
The vaccine is derived from tumor cells removed surgically from the patient. The cells are grown in culture in order to increase their number. Administration of the vaccine depends on our ability to produce a sufficient number of cells.
On the day of vaccination the melanoma cells are irradiated, coated in a substance called DNP (dinitrophenol) and mixed with BCG (weakened tuberculosis bacteria). The DNP improves the cells’ immunological capability and the BCG generates a local inflammatory response that is crucial to the immune process.
The vaccines are injected subcutaneously into the arm or thigh every 21 -28 days for a total of 8 doses. The first two vaccine doses are administered 4 days after intravenous administration of cyclophosphamide.
Cyclophosphamide is a chemotherapeutic agent which in this protocol is administered at a relatively low dosage for the purpose of eliminating T cells that suppress activation of the immune system (regulatory T cells).
What is the vaccine’s side effect/toxicity profile?
- The treatment has minimal adverse effects. Fever may result from the vaccination.
- A red node develops under the skin at the vaccination site and disappears weeks/months after vaccination, leaving a small indented scar.
- Cyclophosphamide is associated with decreased appetite and nausea that are effectively managed by antiemetic medications.
What is the alternative to this vaccine?
High-dose interferon alfa therapy for a period of one year.
Administration of an Autologous Melanoma Tumor-Cell Vaccine in Conjunction with Interleukin-2
Who is eligible for the treatment?
The treatment program is intended for patients with metastatic melanoma that has proved unresponsive to conventional chemotherapy, and from whom a metastatic focus may be surgically removed without significant risk.
What is the purpose of the treatment?
To determine the effectiveness of a melanoma vaccine derived from autologous tumor cells, in conjunction with interleukin-2, in shrinking melanoma metastases.
How is the vaccine produced?
In this program as well the vaccine is derived from surgically-removed tumor cells. The cells are grown in culture in order to increase their number. Administration of the vaccine depends on our ability to produce a sufficient number of cells. The vaccine is composed of melanoma cells that have been exposed to destructive radiation, coated in a substance called DNP (dinitrophenol) and mixed with BCG (weakened tuberculosis bacteria). The DNP improves the cells’ immunological capability and the BCG generates a local inflammatory response that is crucial to the immune process. The vaccines are injected subcutaneously into the arm or thigh every 21 -28 days for a total of 8 doses. The first two vaccine doses are administered 4 days after intravenous administration of cyclophosphamide. Interleukin-2 therapy begins with administration of the fourth vaccine dose.
What is interleukin-2?
Interleukin-2 (IL-2) is a biological substance derived from inflammatory cells that activates T-lymphocytes essential to the immune response. The substance can be administered via subcutaneous injection (low dose) or intravenously (high dose). Treatment with interleukin-2 is standard therapy for melanoma and covered by Israel’s “health basket.”
Low-dose injection of interleukin-2 is associated with fever, chills, weakness and fatigue. The side effects disappear within a few weeks after injection.
High-dose interleukin-2 is administered in a hospital setting, in a general or surgical intensive care unit. The drug may cause vascular leak syndrome, edema, breathing difficulties, renal impairment and sepsis. This drug regimen is suitable only for patients with normal heart function who are capable of tolerating physiological stress.
Why the combination of vaccine and interleukin-2?
We hypothesize that the vaccine generates an initial anti-tumor response and that the interleukin-2 augments this response.
The Role of Peptide-Pulsed Autologous Dendritic Cells in Augmenting the Response to Treatment with Interleukin-2
Who is eligible for the treatment?
Patients diagnosed with metastatic melanoma who are between the ages of 18 and 65 and whose overall status is compatible with high-dose interleukin-2 therapy are eligible for the treatment program. This immunological therapy is intended for patients who test positive for HLA-A2, an antigen that is present in 40-50% of the population. HLA-A2 is not itself a factor in determining the course of the disease; it is, however, essential to the efficacy of the particular vaccine being tested in this trial.
What is the purpose of the treatment?
The goal of this experimental therapy is to determine whether preliminary administration of a vaccine with dendritic cells affects the response to high-dose interleukin-2. Interleukin-2 is standard therapy for metastatic melanoma and does not in itself constitute a trial.
What does the treatment program consist of?
The treatment consists of injecting dendritic cells into regional lymph nodes, along with two hospitalizations for intravenous administration of high-dose interleukin-2.
Dendritic cells are white blood cells that specialize in presenting foreign proteins to the immune system. Their role is to elicit specific responses to proteins and to the cells that contain them, as in infection and cancer. Dendritic cells are produced from the patient’s blood by a process known as cytapharesis. In this process two needles are inserted into the patient, one for collecting blood and one for returning it.
The blood passes through a centrifuge apparatus to separate the white blood cells before its return to the patient. This process takes about two hours and involves no significant discomfort beyond confinement to the treatment chair. It does not compromise the immune system in any way. After the white blood cells are separated from the blood they used to produce the desired dendritic cells. The process takes place under sterile laboratory conditions.
A day or two before the treatment the dendritic cells are thawed and cultivated in the laboratory together with inflammatory agents. The purpose of this addition is to improve the dendritic cells’ ability to induce an immunological response. Prior to administration the cells are loaded with short protein segments called peptides. For purposes of this therapy 4 peptides were chosen that are highly prevalent on, and typical of, malignant melanomas.
The dendritic cells are injected into the patient’s lymph nodes. The injection takes place at the Department of Medical Imaging and entails lymph node detection via ultrasound. It is not always possible to find and identify the lymph nodes. In such instances the cells are injected into an approximate site.
High-dose interleukin-2 is a patented and standard treatment for metastatic melanoma, but it is a demanding regimen associated with numerous adverse effects. Prior to therapy the patient is subjected to stress and pulmonary function tests to determine his/her suitability for the treatment. High-dose interleukin-2 is administered intravenously in a hospital intensive care unit, 3 doses a day for 5 days, patient tolerance permitting.
The treatment regimen includes 3 doses of dendritic cell vaccine administered at two-week intervals. The first interleukin-2 treatment is administered one week after the third vaccine dose. Four weeks later another therapeutic cycle of 3 vaccine doses followed by interleukin-2 is initiated.
Who is not eligible for the treatment?
§ Patients who lack the appropriate histocompatibility profile.
§ Patients suffering from heart or lung disease, or with stress test abnormalities.
§ Patients with vascular insufficiency.
§ Patients suffering from chronic inflammatory disease.
Intradermal Injection of Immature Dendritic Cells and Maturation of the Cells via Short-Term Systemic Administration of Interferon Alfa – Therapy for Metastatic Malignant Melanoma
Who is eligible for the treatment?
The treatment program is intended for metastatic melanoma patients who have undergone one course of conventional therapy and who have a tumor focus that is accessible for injection and irradiation.
What is the purpose of the treatment?
The goal of the trial is to determine the therapeutic value of immature dendritic cells injected into a previously irradiated metastatic tumor site.
What are dendritic cells?
Dendritic cells are white blood cells that specialize in presenting foreign proteins to the immune system. Their role is to elicit specific responses to proteins and to the cells that contain them, as in infection and cancer. Dendritic cells are produced from the patient’s blood by a process known as cytapharesis.
In this process two needles are inserted into the patient, one for collecting blood and one for returning it. The blood passes through a centrifuge apparatus that separates the white blood cells before its return to the patient. This process takes about two hours and involves no significant discomfort beyond confinement to the treatment chair. It does not compromise the immune system in any way. After the white blood cells are separated from the blood they used to produce the desired dendritic cells. The process takes place under sterile laboratory conditions.
What does the treatment program consist of?
Prior to the start of therapy, the tumor focus selected for injection is subjected to a brief (3-day) course of radiation. The dendritic cells are administered via injection into the irradiated tumor focus. We anticipate that the therapeutic effect will be perceptible not only at the injection site but at other, more distant disease sites that have not been directly treated.
The injections will be carried out at an ambulatory oncology unit, at 14-day intervals, for a total of 6 injections. Starting with the second injection interferon alfa will be administered as well. The first interferon dose will be administered 12 hours after injection of the dendritic cells. The substance will be injected into the subcutaneous layer over the course of 3 days. Each additional injection will be accompanied by a dose of interferon alfa.
What are the treatment’s side effects?
Anticipated side effects include sensitivity and redness of the irradiated tumor site. Injection of the dendritic cells may intensify the localized redness and sensitivity. Interferon alfa may cause fever, muscle and joint pain and flu-like symptoms. Regular interferon alfa therapy may lead to a reduction in white blood cell counts or impaired liver or thyroid function. In your treatment regimen the drug will be given intermittently, not regularly. Side effects may be eased by taking Acamol or Optalgin.
The first two dendritic cell injections will be accompanied by an indium isotope test. The injected cells will be radioactively tagged. The radiation dose is negligible and not dangerous. After the injection full-body mappings will be carried at the following intervals: 4 hours, 8 hours, 16 hours and 48 hours. The mappings will be carried out at Hadassah’s Department of Medical Biophysics and Nuclear Medicine.
Who is not eligible for the treatment?
Patients with rapidly-progressing disease whose prognosis is short (weeks).