Electrochemotherapy Induces Changes in the Tumor Microenvironment of Cutaneous and Subcutaneous Metastases in Patients With Cutaneous Melanoma
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in Tumor-Infiltrating Lymphocytes (TIL) Score Assessed by MIA Scoring System (Azimi et al.)
研究概览
简要总结
In the last 10 years, the treatment of metastatic cutaneous melanoma has changed dramatically. The new systemic treatment with immunotherapy has led to a dramatic improvement in quality of life and overall survival. Systemic treatment means that the patient receives the drug as an infusion into a vein. Unfortunately, investigators know that immunotherapy is not equally successful in all patients. Recent studies have shown that the success of the treatment is not only influenced by the cellular composition of the metastasis, but also by its surroundings. This is called tumor microenvironment. Depending on the differences in the composition of this microenvironment, some metastases can be described as immunologically hot and others as immunologically cold. Immunologically hot metastases respond better to immunotherapy than immunologically cold metastases.
Studies have shown that with some interventions can change the tumor microenvironment from being immune-cold to being immune-hot. Electrochemotherapy is one of the interventions that might improve the efficacy of immunotherapy in cutaneous melanoma. Electrochemotherapy is an established method for the local treatment of tumors, in which only a certain tumor is treated with special electrodes, to which a weak electric current is applied. Investigators hypothesize that electrochemotherapy stimulates the body's own immune response and enables more effective treatment. Since immunotherapy also stimulates the body's own immune response to cutaneous melanoma cells, the interaction of the two drugs could be even more successful. Recent research results support this assumption.
The primary objective is to evaluate the changes in the tumor microenvironment of cutaneous and subcutaneous melanoma metastases induced by electrochemotherapy, based on the histologic analysis of treated and untreated metastases before and after treatment. The secondary aim is to determine whether the changes in the tumor microenvironment differ depending on the chemotherapeutic agent used.
The results will help Investigators better understand the synergistic effects of electrochemotherapy and immunotherapy on cutaneous melanoma metastases. The combination of systemic immunotherapy and electrochemotherapy could become an important treatment method for patients with metastatic melanoma.
详细描述
The study is prospective. The primary objective is to evaluate the changes in the tumor microenvironment of cutaneous and subcutaneous melanoma metastases induced by electrochemotherapy (ECT), based on the histologic analysis of treated and untreated metastases before and after treatment. The secondary aim is to determine whether the changes in the tumor microenvironment differ depending on the chemotherapeutic agent used.
In the study 10-15 patients will be enrolled and devided in two arms, ECT with bleomycin and ECT with cysplatin.
ECT will be offered to patients with cuteaneous melanoma and at least 5 in-transit or distant cutaneous and/or subcutaneous melanoma metastases regardless of previous treatments. The decision will be made in a multidisciplinary tumor board. The choice of chemotherapeuthic drug will depend on the size and number of lesions to be treated. Inclusion in the study has no influence on the decision regarding the timing of treatment with immunotherapy. Treatment with immunotherapy will later be included as a factor in the statistical analysis.
ECT will be performed according to the standard operating procedures for the treatment of cutaneous and subcutaneous tumors with ECT. ECT will be performed within 8 - 28 minutes after intravenous bolus administration of bleomycin (15.000 IU/m2 BSA) or directly after the intratumorally administration of cysplatin (0,5-2 mg/cm3 tumor). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.
One cutaneous/subcutaneous metastasis will be excised before ECT. One treated cutaneous/subcutaneous metastasis will be excised 2-4 and 9-13 days after the procedure. An untreated cutaneous/subcutaneous metastasis will be excised on day 9-13. The excisions will be performed under local anesthesia. All patients will be enrolled in the study after the procedures and the study have been explained to them in detail and they have signed an informed consent form. A venous blood sample will be taken at the same time points (before ECT, 2-4 days and 9-13 days after ECT).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Factorial
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •more than 4 cytologically and/or histologically confirmed intransit or distant cutaneous/subcutaneous cutaneous melanoma metastases
- •ECT should be proposed as a treatment in the multidisciplinary tumor board
- •cutaneous/subcutaneous melanoma metastases, that can be excised under local anesthesia with primary wound closure, minimal morbidity of the procedure (risk of complications < 5%) and nocosmetic or functional consequences of the procedure
- •stage IIIB, IIIC or IV of the disease
- •age over 18 years
- •performance status World Health Organization more than 2
- •patients must give informed consent
排除标准
- •age less than 18 years
- •polimorbidity
- •performance status World Health Organization more than 2
- •high risk for intervention under general anesthesia;
- •wound closure would require coverage with a skin graft or local flap;
- •undesirable cosmetic or functional consequences would be expected (face, extensor side of joints)
- •patients incapable of understanding the aim of the study or disagree with the entering into the clinical study
研究组 & 干预措施
Electrochemotherapy with Intratumoral Cysplatin
ECT will be performed directly after the intratumorally administration of cysplatin (0,5-2 mg/cm3 tumor). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.
干预措施: Electrochemotherapy with Intratumoral Cysplatin (Procedure)
Electrochemotherapy with Intravenous Bleomycin
ECT will be performed within 8 - 28 minutes after intravenous bolus administration of bleomycin (15.000 IU/m2 BSA). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.
干预措施: Electrochemotherapy with Intravenous Bleomycin (Procedure)
结局指标
主要结局
Change in Tumor-Infiltrating Lymphocytes (TIL) Score Assessed by MIA Scoring System (Azimi et al.)
时间窗: Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy
Tumor-infiltrating lymphocytes (TILs) will be evaluated semi-quantitatively using the MIA scoring system (Azimi et al.) in tissue samples from treated and untreated cutaneous/subcutaneous melanoma metastases. Assessment will be performed independently by two experienced pathologists.
Lymphocyte and Macrophage Distribution Density in Tumor Microenvironment Assessed by Park CH Method
时间窗: Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy
Distribution densities of lymphocytes and macrophages in the tumor microenvironment will be estimated according to Park CH et al. in biopsies of treated and untreated melanoma metastases. Assessment will be performed independently by two experienced pathologists.
Number of Immune Marker-Positive Cells per mm² in Tumor Tissue Assessed by Immunohistochemistry (IHC)
时间窗: Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy
The number of CD3+, CD4+, CD8+, CD56+, CD163+, FoxP3+, PGM1+, and PD-L1 (CD274)+ cells per mm² will be quantified by immunohistochemistry (IHC) in tissue samples from treated and untreated melanoma metastases. Results will be evaluated independently by two experienced pathologists.
次要结局
- Difference in Change of Tumor-Infiltrating Lymphocytes (TIL) Score (MIA Scoring) Between Bleomycin and Cisplatin Electrochemotherapy(Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy)
- Difference in Immune Cell Density and Immune Marker-Positive Cells per mm² Between Bleomycin and Cisplatin Electrochemotherapy(Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy)