Electrochemotherapy and Other Clinical Applications of Electroporation for the Targeted Therapy of Metastatic Melanoma.
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ABSTRACT:
SUBMITTER: Cucu CI
PROVIDER: S-EPMC8305146 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and study aims Electrochemotherapy is an anticancer treatment that uses electric pulses to facilitate uptake of chemotherapeutic drugs in tumor cells and has proven to have a high local cytotoxic effect with minimal adverse events. Electrochemotherapy has mostly been used in treatment of cutaneous metastases but development of a new endoscopic electrode device has made treatment of colorectal tumors possible. This first-in-man multicenter phase I study investigated safety and efficacy of electrochemotherapy using endoscopic electroporation in patients with colorectal tumors. Patients and methods Seven patients with colorectal tumors who were deemed ineligible for or had declined standard treatment were included. They were treated with bleomycin either intratumorally or intravenously and the electric pulses were delivered through the endoscopic electrode device. Safety and efficacy were assessed clinically and by scans immediately after treatment and adverse events were reported. Response was evaluated up to 6 months after treatment by scans (magnetic resonance imaging or computed tomography) and endoscopic examinations. Results Seven patients aged 62 to 88 years with multiple comorbidities were included and had one or two treatments each. Post-treatment scans showed tumor responses in the treated areas and no damage to surrounding tissues. Only a few grade one adverse events were reported. Three patients had preoperative rectal bleeding, of which two reported cessation of bleeding and one reported decreased bleeding. Conclusion This first-in-man study shows that electrochemotherapy for colorectal tumors using the endoscopic electrode device can induce local tumor response and is safe also for fragile elderly patients with comorbidities.
| S-EPMC6976320 | biostudies-literature
Project description:Electrochemotherapy is a local treatment combining chemotherapy and application of electric pulses to the tumour. Electrochemotherapy with bleomycin and cisplatin has already been found to be effective in controlling local tumour growth in the treatment of malignant melanoma. However, not much is known about the effect of electrochemotherapy on the metastatic potential of tumour cells. Prevention of metastasis is an important aspect of successful treatment. It is known that metastasis can be induced by different treatment modalities. Therefore, the aim of this study was to evaluate the effect of electrochemotherapy with cisplatin on the metastatic potential of human malignant melanoma cells. The cells treated by electrochemotherapy with cisplatin, were tested for their ability to migrate and invade through Matrigel coated porous membrane. There were no significant changes observed in cell migration and invasion after electrochemotherapy. Also, there were no changes observed in cell adhesion on Matrigel. Gene expression analysis demonstrated that very low number of genes was differentially expressed after electrochemotherapy with cisplatin. Two genes, LAMB3 and CD63 involved in cell migration, were both down-regulated after electrochemotherapy with cisplatin and the expression of metastasis promoting genes was not increased after electrochemotherapy. Our data suggest that electrochemotherapy does not increase metastatic behaviour of human melanoma cells.
2009-11-01 | GSE15138 | GEO
Project description:IntroductionTavokinogene Telseplasmid Electroporation Therapy (TAVO) and Pembrolizumab therapy is being studied in subjects with immune checkpoint inhibitor (ICI) resistant melanoma. TAVO is a novel office-based local therapy shown to be effective in patients with advanced melanoma. The technique involves the direct injection of a plasmid encoding IL-12 into an accessible tumor driven by electroporation. The tumor cells have then been shown to express high levels of IL-12 resulting in a local inflammatory response within the tumor microenvironment.Presentation of caseThe patient with stage IIB, pT3b melanoma was treated with primary tumor resection and found to have a negative sentinel node biopsy. She subsequently developed regional recurrence and was treated with inguinal lymphadenectomy and adjuvant Nivolumab. Despite therapy, she had progression of disease with skin and subcutaneous metastases (in-transit lesions), brain and liver lesions, hilar and iliac nodal disease. She was transitioned to nivolumab + ipilimumab, and Talimogene Laherparepvec (T-VEC) therapy for the in-transit lesions, without success. Stereotactic radiosurgery was used for the brain metastasis. Groin subcutaneous and in-transit lesions were treated with TAVO and intravenous pembrolizumab. Serial physical exams and CT scans were used to assess response.DiscussionAll lesions treated with TAVO resolved. An abscopal response was also noted: hilar and mediastinal lymphadenopathy resolved. The liver mass and pelvic lymphadenopathy decreased in size, and her brain metastasis remained stable after radiation.ConclusionThis case suggests that combination TAVO and Pembrolizumab is a safe and effective local treatment for ICI resistant metastatic melanoma in the setting of rheumatoid arthritis. An abscopal effect was also noted through control of systemic disease.
| S-EPMC7708754 | biostudies-literature
Project description:The combination of electrochemotherapy with immuno-modulatory treatments has already been explored and proven effective. However, the role of interferon alpha (IFN-?) adjuvant therapy of melanoma patients and implication on electrochemotherapy effectiveness has not been explored yet. Therefore, the aim of the study was to retrospectively evaluate the effectiveness and safety of electrochemotherapy after the previous adjuvant treatment with IFN-? in melanoma patients.The study was a retrospective single-center observational analysis of the patients with advanced melanoma, treated with electrochemotherapy after previous IFN-? adjuvant therapy. Five patients, treated between January 2008 and December 2014, were included into the study, regardless of the time point of IFN-? adjuvant therapy.Electrochemotherapy of recurrent melanoma after the IFN-? adjuvant therapy proved to be a safe and effective treatment. Patients with one or two metastases responded completely. Among patients with multiple metastases, there was a variable response rate. In one patient all 23 metastases responded completely, in second patient more than 85% of all together 80 metastases responded completely and in third patient all 5 metastases had partial response. Taking into account all metastases from all patients together there was an 85% complete response rate.The study showed that electrochemotherapy of recurrent melanoma after the IFN-? adjuvant therapy is a safe and effective treatment modality, which results in a high complete response rate, not only in single metastasis, but also in multiple metastases. The high complete response rate might be due to an IFN-? immune-editing effect, however, further studies with a larger number of patients are needed to support this presumption.
| S-EPMC4825333 | biostudies-other
Project description:Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma? In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy.
| S-EPMC5650456 | biostudies-literature
Project description:New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The 225Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient mice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of 225Ac-DOTA-MC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of 225Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
| S-EPMC6681690 | biostudies-literature
Project description:Metastatic melanoma is the most aggressive and obstinate skin cancer with poor prognosis. Variant novel applicable regimens have emerged during the past decades intensively, while the most profound approaches are oncogene-targeted therapy and T-lymphocyte mediated immunotherapy. Although targeted therapies generated remarkable and rapid clinical responses in the majority of patients, acquired resistance was developed promptly within months leading to tumor relapse. By contrast, immunotherapies elicited long-term tumor regression. However, the overall response rate was limited. In view of the above, either targeted therapy or immunotherapy cannot elicit durable clinical responses in large range of patients. Interestingly, the advantages and limitations of these regimens happened to be complementary. An increasing number of preclinical studies and clinical trials proved a synergistic antitumor effect with the combination of targeted therapy and immunotherapy, implying a promising prospect for the treatment of metastatic melanoma. In order to achieve a better therapeutic effectiveness and reduce toxicity in patients, great efforts need to be made to illuminate multifaceted interplay between targeted therapy and immunotherapy.
| S-EPMC6513976 | biostudies-literature
Project description:Electrochemotherapy, a combination of high voltage electric pulses and of an anticancer drug, has been demonstrated to be highly effective in treatment of cutaneous and subcutaneous tumors. Unique properties of electrochemotherapy (e.g., high specificity for targeting cancer cells, high degree of localization of treatment effect, capacity for preserving the innate immune response and the structure of the extracellular matrix) are facilitating its wide spread in the clinics. Due to high effectiveness of electrochemotherapy in treatment of cutaneous and subcutaneous tumors regardless of histological origin, there are now attempts to extend its use to treatment of internal tumors. To advance the applicability of electrochemotherapy to treatment of internal solid tumors, new technological developments are needed that will enable treatment of these tumors in daily clinical practice. New electrodes through which electric pulses are delivered to target tissue need to be designed with the aim to access target tissue anywhere in the body. To increase the probability of complete tumor eradication, the electrodes have to be accurately positioned, first to provide an adequate extent of electroporation of all tumor cells and second not to damage critical healthy tissue or organs in its vicinity. This can be achieved by image guided insertion of electrodes that will enable accurate positioning of the electrodes in combination with patient-specific numerical treatment planning or using a predefined geometry of electrodes. In order to be able to use electrochemotherapy safely for treatment of internal tumors located in relative proximity of the heart (e.g., in case of liver metastases), the treatment must be performed without interfering with the heart's electrical activity. We describe recent technological advances, which allow treatment of liver and bone metastases, soft tissue sarcomas, brain tumors, and colorectal and esophageal tumors. The first clinical experiences in these novel application areas of electrochemotherapy are also described.
| S-EPMC3514699 | biostudies-literature
Project description:Targeted therapies (TT) and immune checkpoint inhibitors (ICI) have become increasingly important in the treatment of metastatic malignant melanoma in recent years. We examined implementation and effectiveness of these new therapies over time in Germany with a focus on regional differences. We analyzed data from 12 clinical cancer registries in 8 federal states in Germany over the period 2000-2016. A total of 3871 patients with malignant melanoma in Union internationale contre le cancer (UICC) stage IV at primary diagnosis (synchronous metastases) or with metachronous metastases were included. We investigated differences in survival of patients treated with new and conventional therapies by log-rank tests for Kaplan-Meier curves. Cox regression models were estimated to adjust therapy effects for demographic, regional, and prognostic factors. New systemic therapies were increasingly applied throughout Germany. TT were most frequently documented in Eastern Germany (East: 11.2%; West: 6.3%), whereas ICI therapies were more frequently used in Western Germany (East: 1.7%; West: 3.9%). TT had a relevant influence on patient survival (hazard ratio (HR) = 0.831; 95%-CI = (0.729; 0.948)). Survival was worse in Eastern Germany (HR = 1.470; 95%-CI = (1.347; 1.604)) relative to Western Germany. Treatment and survival prospects of patients with melanoma differed considerably between Western and Eastern Germany. The differences in regional medication behavior and survival require further exploration.
| S-EPMC7565277 | biostudies-literature
Project description:Melanoma is the deadliest form of skin cancer and one of the few malignancies whose incidence is on the rise. The treatment of metastatic melanoma continues to be quite challenging, although in recent years, there has been significant progress. Current National Comprehensive Cancer Network guidelines list immunotherapy, chemotherapy, surgery and clinical trials as potential options for patients with metastatic disease but do not clearly recommend which is superior. Additionally, when utilizing combined modality treatment there are no clear guidelines for the optimal timing of surgery in the treatment of metastatic melanoma. In this paper we sought to compile the current evidence and on-going trials in order to provide a comprehensive review of the different options available and underway in regards to the treatment of metastatic melanoma. It is clear that with the responses now seen with systemic immunotherapies and targeted therapies, an expanded role for surgery is the logical next step.
| S-EPMC6094597 | biostudies-literature