Tumor Ablation Techniques Research Articles

Efficacy of Monopolar Radiofrequency or Microwave Ablation in Intrahepatic Cholangiocarcinoma: A Retrospective Multicenter Study from Association des Gastro-Entérologues Oncologues (AGEO).

Several locoregional treatments approaches, including thermoablation, have been tested for the treatment of intrahepatic cholangiocarcinoma (ICC) and have shown encouraging results. However, data are heterogeneous in terms of tumor number, size, and ablation technique. The aim of this study was to investigate the efficacy and prognostic factors in ICC treated by monopolar radiofrequency (RF) or microwave ablation (MW). This was a retrospective study including patients treated with RF or MW for ICC in six participating centers. DFS and OS were evaluated by the Kaplan-Meier method and prognostic factors by log-rank test and Cox modeling. From January 2015 to October 2023, 24 patients with 31 nodules were treated with RFA or MW. Overall, 70% had chronic liver disease, with 50% at cirrhosis stage. The median size of lesions was 17 mm (6-35 mm). After a median follow-up of 33 months (5-85), the median DFS was 10.5 months. The median OS was 40.8 months. On univariate and multivariate analysis, only lesion size > 17 mm was associated with a poor OS (HR 3.09; IC [1.02; 9.37] (p = 0.04). Monopolar radiofrequency or microwave ablation is an alternative to surgery for small ICCs. Tumors < 17 mm were associated with better OS.

SURG-48. LASER INTERSTITIAL THERMAL THERAPY REMODELS THE TUMOR IMMUNE LANDSCAPE IN A MOUSE GLIOMA MODEL

Abstract BACKGROUND Laser interstitial thermal therapy (LITT), a minimally invasive surgical technique for tumor ablation, is increasingly being used to treat primary and recurrent glioma. While the primary goal of using LITT has been to destroy tumor tissue, little is known about the impact of LITT on the overall immune response. To investigate changes in the tumor immune landscape, we utilized a mouse model of LITT and applied it to a poorly immunogenic mouse model of glioma. METHODS SB28 glioma cells were implanted in the right frontal lobe of C57BL/6 mice, and on day 7, an optical fiber is inserted into the tumor, paired with a thermocouple for real-time temperature monitoring. A 30W laser was activated in pulses to maintain a peri-lesional temperature of 44C for 150-180 seconds. The tumor and LITT-associated immune response was analyzed by multiparameter flow cytometry, single cell RNA-seq, and multiplex immunofluorescence. RESULTS LITT (versus sham control) triggered an increase in neutrophils in the tumor during the acute phase at day 3 following treatment. Total immune cell numbers increased over time in both sham- and LITT-treated mice, but there was a significant increase at post-LITT day 7 in select adaptive immune cell populations including type 1 conventional dendritic cells, NK cells, and gamma delta T cells. Monocytes/macrophages comprised the majority of the immune infiltrate, and multiplex immunofluorescence revealed these populations localized to the perimeter of the LITT lesion. scRNA-seq also revealed enrichment of a Fabp5- and Gpnmb-expressing macrophage subset following LITT. CONCLUSIONS LITT modifies the tumor immune infiltrate with increases in neutrophils as well as select adaptive cell and macrophage subsets. Future studies will explore adjunct therapies to further augment the immune response in the setting of LITT.

Ultrasound-guided percutaneous high-frequency irreversible electroporation in porcine livers using four electrode needles: A feasibility and safety study.

Malignant liver tumors seriously endanger human health. Among different therapeutic approaches, high-frequency irreversible electroporation (H-FIRE) is a recently emerging tumor ablation technique. The objective of this study was to evaluate the feasibility and safety of ultrasound-guided percutaneous H-FIRE using four electrode needles in porcine livers. Twelve experimental pigs underwent percutaneous H-FIRE ablation using a compound steep-pulse therapeutic device. Liver tissues adjacent to the gallbladder, blood vessels, and bile ducts were selected as the ablation targets. Pigs were randomly divided into three groups: (1) immediately after ablation (N = 4), (2) 2 days after ablation (N = 4), and (3) 7 days after ablation (N = 4). Blood routine, liver and kidney function, and myocardial enzyme levels were measured before and after ablation. Ultrasound, contrast-enhanced ultrasound (CEUS), contrast-enhanced magnetic resonance imaging (MRI), and hematoxylin-eosin staining were performed to evaluate the ablation performance. Ultrasound-guided percutaneous H-FIRE ablations using four electrode needles were successfully performed in all 12 experimental pigs. The general conditions of the pigs, including postoperative activities and feeding behaviors, were normal, with no significant changes compared with the preoperative conditions. The imaging features of ultrasound, CEUS, and MRI demonstrated no significant changes in the gallbladder walls, bile ducts, or blood vessels close to the ablation areas. Laboratory tests showed that liver function indices and myocardial enzymes increased temporarily after H-FIRE ablation, but decreased to normal levels at 7 days after ablation. Histopathological examinations of porcine liver specimens showed that this technique could effectively ablate the target areas without damaging the surrounding or internal vascular systems and gallbladder. This study demonstrated the feasibility and safety of ultrasound-guided percutaneous H-FIRE ablation in porcine livers invivo, and proposed a four-needle method to optimize its clinical application.

Scheduled dosage regimen by irreversible electroporation of loaded erythrocytes for cancer treatment.

Precise control of cargo release is essential but still a great challenge for any drug delivery system. Irreversible electroporation (IRE), utilizing short high-voltage pulsed electric fields to destabilize the biological membrane, has been recently approved as a non-thermal technique for tumor ablation without destroying the integrity of adjacent collagenous structures. Due to the electro-permeating membrane ability, IRE might also have great potential to realize the controlled drug release in response to various input IRE parameters, which were tested in a red blood cell (RBC) model in this work. According to the mathematical simulation model of a round biconcave disc-like cell based on RBC shape and dielectric characteristics, the permeability and the pore density of the RBC membrane were found to quantitatively depend on the pulse parameters. To further provide solid experimental evidence, indocyanine green (ICG) and doxorubicin (DOX) were both loaded inside RBCs (RBC@DOX&ICG) and the drug release rates were found to be tailorable by microsecond pulsed electric field (μsPEF). In addition, μsPEF could effectively modulate the tumor stroma to augment therapy efficacy by increasing micro-vessel density and permeability, softening extracellular matrix, and alleviating tumor hypoxia. Benefiting from these advantages, this IRE-responsive RBC@DOX&ICG achieved a remarkably synergistic anti-cancer effect by the combination of μsPEF and chemotherapy in the tumor-bearing mice model, with the survival time increasing above 90 days without tumor burden. Given that IRE is easily adaptable to different plasma membrane-based vehicles for delivering diverse drugs, this approach could offer a general applicability for cancer treatment.

New Developments in Image-Guided Percutaneous Irreversible Electroporation of Solid Tumors.

This review will describe the various applications, benefits, risks, and approaches of conventional irreversible electroporation (IRE), as well as highlight the new technological developments of this procedure along with their clinical applications. Minimally invasive image-guided percutaneous IRE ablation has emerged as a newer, non-thermal ablation technique for tumors in the solid organs, particularly within the liver, pancreas, kidney, and prostate. IRE allows for ablation near heat-sensitive structures, including major blood vessels and nerves, and is not susceptible to the heat sink effect. However, it is limited by certain requirements, such as the need for precise parallel placement of at least two probes with a maximum inter-probe distance of 2.5 cm to reduce the risk of arching phenomenon, the requirement for general anesthesia with muscle relaxant, and the need for cardiac synchronization. However, new technological advancements in the ablation system and image guidance tools have been introduced to improve the efficiency and efficacy of IRE. IRE is a safe and effective treatment option for solid tumor ablation within the liver, pancreas, kidney, and prostate. Compared with other ablation techniques, IRE has several advantages, such as the absence of heat sink effect and minimal injury to blood vessels and bile ducts while activating the immune system. Novel techniques such as H-FIRE, needle placement systems, and robotics have enhanced the accuracy and performance in placement of IRE probes. IRE can be especially beneficial when combined with chemotherapy, immunomodulation, and immunotherapy.

Irreversible electroporation: Beyond the limits of tumor ablation

Irreversible Electroporation (IRE) is a non-thermal tumor ablation technique. High-voltage electrical pulses are applied between pairs of electrodes inserted around and/or inside a tumor. The generated electric current induces the creation of nanopores in the cell membrane, triggering apoptosis. As a result, IRE can be safely used in areas near delicate vascular structures where other thermal ablation methods are contraindicated.Currently, IRE has demonstrated to be a successful ablation technique for pancreatic, renal, and liver tumors and is widely used as a focal therapeutic option for prostate cancer.The need for specific anesthetic management and accurate parallel placement of multiple electrodes entails a high level of complexity and great expertise from the interventional team is required. Nevertheless, IRE is a very promising technique with a remarkable systemic immunological capability and may impact on distant metastases (abscopal effect).

Electroporación irreversible: ampliando las fronteras de la ablación

Irreversible electroporation (IRE) is a non-thermal tumor ablation technique. High-voltage electrical pulses are applied between pairs of electrodes inserted around and/or inside a tumor. The generated electric current induces the creation of nanopores in the cell membrane, triggering apoptosis. As a result, IRE can be safely used in areas near delicate vascular structures where other thermal ablation methods are contraindicated.Currently, IRE has demonstrated to be a successful ablation technique for pancreatic, renal, and liver tumors and is widely used as a focal therapeutic option for prostate cancer.The need for specific anesthetic management and accurate parallel placement of multiple electrodes entails a high level of complexity and great expertise from the interventional team is required. Nevertheless, IRE is a very promising technique with a remarkable systemic immunological capability and may impact on distant metastases (abscopal effect).

Enhanced Therapeutic Potential of Irreversible Electroporation under Combination with Gold-Doped Mesoporous Silica Nanoparticles against EMT-6 Breast Cancer Cells

Irreversible electroporation (IRE) is a non-thermal tumor ablation technique that delivers short pulses of strong electric fields to cancer tissues and induces cell death through the destruction of cell membranes. Here, we synthesized gold-doped mesoporous silica nanoparticles (Au-MSNs) via incipient wetness impregnation and evaluated the therapeutic potentials of combination therapy with IRE. The fabricated Au-MSNs had around 80-100 nm of particle size and were successfully end-doped with Au nanoparticles. Combination treatment of IRE (800 V/cm) and Au-MSNs (100 μg/mL) increased cell membrane permeability by 25-fold compared with single IRE treatment. Cellular reactive oxygen species (ROS) and lipid peroxidation of EMT-6 cells were significantly increased by 14- and 265-fold, respectively, under combination treatment of IRE (800 V/cm) and Au-MSNs (100 µg/mL). Cytotoxic cell death increased by 28% under a combination treatment of IRE (800 V/cm) and Au-MSNs (100 ug/mL) over single IRE. Our studies suggest that the combination treatment of IRE with Au-MSNs can enhance the therapeutic efficacy of IRE for breast cancer.

Liquid exfoliation of ultrasmall zirconium carbide nanodots as a noninflammatory photothermal agent in the treatment of glioma

Photothermal therapy (PTT), like other clinical translational tumor ablation techniques, requires a temperature increase above 50 °C to cause necrosis and death of tumor cells. Although the tumor can be eliminated rapidly by PTT, the inflammatory response is triggered by the large amounts of released reactive oxygen species (ROS). Therefore, liquid exfoliation was used to create ultrasmall zirconium carbide nanodots (NDs) with an average diameter of approximately 4.5 nm as noninflammatory/anti-inflammatory photosensitizers for PTT of glioma. Ultrasmall ZrC NDs showed excellent photothermal stability and biocompatibility but no obvious toxicity. Moreover, the ultrasmall ZrC NDs effectively ablated glioma at relatively low concentrations and inhibited tumor migration and proliferation in vitro and in vivo. Furthermore, the excellent ROS-scavenging ability of ultrasmall ZrC NDs suppressed the inflammatory response to PTT. Intriguingly, we found that ZrC had the capability of performing CT imaging. We demonstrated that the ultrasmall ZrC NDs created in this study could effectively and safely treat glioma without inflammation.

Backflow modeling in nanofluid infusion and analysis of its effects on heat induced damage during magnetic hyperthermia

• Simulate the backflow behavior for nanofluid infusion inside bio-tissue under a geometric nonlinear model. • Investigate the bio-tissue deformation and its effect on the change of material property during nanofluid infusion. • Investigate the interstitial pressure and the local stress distribution inside bio-tissue due to the nanofluid infusion. • Effect of backflow on treatment temperature distribution and heat induced damage for malignant tissue. Although targeted magnetic hyperthermia has been proven to be an effective tumor ablation technique, its use in clinical applications is still scarce particularly due to the difficulty in imposing a desired nanofluid distribution in the therapeutic area. In addition to the inherent difficulty of imposing a distribution with few injection shots, during the nanofluid infusion, the tissue deformation can cause the nanofluid deviation from the targeted injection area and the backflow along the needle can deliver the injected nanofluid to the outer surface of the tissue. Both phenomena can result in an irregular distribution for nanofluid inside bio-tissue. This study develops a poroelastic model considering geometrically nonlinear behavior in order to evaluate the effect of syringe needle size and infusion rate on the backflow. A 26 gauge needle for syringe is used as a typical example to further investigate the nanofluid transport and the change of solid matrix material properties under different infusion rates after comparing the infusion results for several sizes of needle. Finally, the resulting nanofluid concentration distribution obtained with the proposed model is used to simulate the temperature distribution and the cancerous cell damage. The results demonstrate that the infusion pressure and its resulting tissue deformation are the fundamental reasons for obtaining an irregular solution distribution. Tissue deformation induces the increase of porosity and permeability for biomaterials around the tip, and enhances the fluidity of nanofluids inside the tissue. The results also indicate that the increase in backflow length can improve the uniformity of the nanofluid distribution after diffusion and, consequently, the treatment effect. However, it also increases the risk of MNP leakage from the targeted area to the tumor surface, so it is important to keep the backflow rate limited during the injection process.

Abstract A030: Investigating the feasibility of in-vivo histotripsy ablation for osteosarcoma using an orthotopic murine model and a canine model of spontaneous disease

Abstract Osteosarcoma (OS) is the most commonly occurring primary bone tumor in pediatric cancer patients and dogs, with estimated incidences of 3-4 cases per 1 million and 14 cases per 100,000, respectively. The biological similarities shared between human and canine OS and increased OS prevalence in dogs allows the dog to serve as an effective comparative oncology research model. Current standard of care treatment results in a 70% median 5-year survival for humans and a 10-12-month median survival for dogs, and these survival expectations have not improved in 30 years. There is a critical need for novel treatment options to improve the prognosis for OS patients. The objective of this study was to investigate the ablative (murine, canine) and immunological (canine) effects of histotripsy, a novel focused ultrasound tissue ablation technique, for OS. We utilized orthotopic xenograft murine models with induced canine (D17) or human (143B) OS tumors. Ablative outcomes were assessed grossly and microscopically via histopathological evaluation, and treatment effects on limb functionality were evaluated by monitoring lameness, grip capacity, nesting behavior, and body weight for the duration of the study. Fifteen client-owned dogs with suspected OS were enrolled into a clinical trial and underwent histotripsy treatment 24 hours prior to standard of care limb amputation surgery. Ablative outcomes were assessed grossly and microscopically via histopathological evaluation after surgical excision of treated tumors. Immunological outcomes were evaluated by peripheral blood samples collected pretreatment, 24 hours, and 2 weeks post treatment for immune cell phenotyping via flow cytometry to evaluate the systemic immune response. Locally, changes in the tumor immune microenvironment were assessed at both the cellular and molecular levels. Targeted ablation of the tumor tissue was achieved in both the murine models and the canine patients. Ablation was evident by gross and microscopic evaluation where loss of cellular architecture, lytic and coagulative necrosis and delineation of treated and untreated tumor regions were observed. In the mice, decreased limb function due to inflammation after histotripsy ablation resolved within 5-7 days post treatment. The dogs did not exhibit any increase in lameness after histotripsy ablation. The only clinical adverse event experienced by canine patients was mild transient dermal erythema at the treatment site. Our results suggest systemic immunomodulation evident by increases in CD4+ and CD8+ T lymphocyte populations post treatment and changes in monocyte expression of CD62L and CD80. Locally, we observed an upregulation in genes related to chemotaxis, regulation of inflammation, and immunogenic cell death in treated tumor samples compared to untreated samples. In conclusion our preliminary results suggest that histotripsy treatment has both immunotherapeutic and ablative potential and support the development of histotripsy as a tumor ablation technique and immunotherapeutic for OS. Citation Format: Alayna N. Hay, Lauren Ruger, Haleigh Hixson, Jessica Gannon, Alex Simon, Hannah Sheppard, Sheryl Coutermarsh-Ott, Elaina Davis, Katharine Kierski, Brittany Ciepluch, Nathan Neufeld, Eli Vlaisavljevich, Joanne Tuohy. Investigating the feasibility of in-vivo histotripsy ablation for osteosarcoma using an orthotopic murine model and a canine model of spontaneous disease [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A030.

Percutaneous Ablation of Metastatic Lymph Nodes: An Insight from the Comparison of Efficacy and Safety Between Cryoablation and Radiofrequency Ablation.

To retrospectively compare efficacy and safety of computed tomography (CT)-guided percutaneous ablation of metastatic lymph nodes (LN) between cryoablation (CA) and radiofrequency ablation (RFA). A bi-central institutional database research identified 28 patients (42 metastatic LNs) who underwent percutaneous CT-guided ablation. RFA group included 18 patients/26 tumors;CA group included 10 patients/16 tumors. Contrast-enhanced CT or MRI was used for post-ablation follow-up. Patient and tumor characteristics, technical and clinical success on a per tumor and a per patient basis and complication rates were recorded, evaluated and compared between the 2 groups. Both RFA and CA groups had the same median tumor size (2.00 vs. 2.20cm, p = 0.257), the same median follow-up time (20.50 vs. 20.00months, p = 0.923) and the same median lengthof hospitalstay(1.00 vs. 1.00days, p = 0.283). CA group had a higher median procedure time (110.50 vs. 52.00min, p = 0.001). On a per lesion basis, the overall complete response post-ablation was88.46% (23/26 lesions) in the RFA and 93.75% (15/16 lesions) in the CA group; no association was revealed between local tumor control and ablation technique (p = 0.709). No complications were recorded in both Groups. On a per patient basis, CA had a longer disease-free interval (24.00 vs. 14.50, p = 0.012) which, however, did not affect the overall survival between the two techniques (26.0 vs. 22.0, p = 0.099 for CA and RFA respectively). Our limited data suggest that CT-guided RFA and CA are equally effective on terms of efficacy and safety for the treatment of metastatic lymph nodes.

Exploration of Novel Pathways Underlying Irreversible Electroporation Induced Anti-Tumor Immunity in Pancreatic Cancer.

Advancements in medical sciences and technologies have significantly improved the survival of many cancers; however, pancreatic cancer remains a deadly diagnosis. This malignancy is often diagnosed late in the disease when metastases have already occurred. Additionally, the location of the pancreas near vital organs limits surgical candidacy, the tumor’s immunosuppressive environment limits immunotherapy success, and it is highly resistant to radiation and chemotherapy. Hence, clinicians and patients alike need a treatment paradigm that reduces primary tumor burden, activates systemic anti-tumor immunity, and reverses the local immunosuppressive microenvironment to eventually clear distant metastases. Irreversible electroporation (IRE), a novel non-thermal tumor ablation technique, applies high‐voltage ultra-short pulses to permeabilize targeted cell membranes and induce cell death. Progression with IRE technology and an array of research studies have shown that beyond tumor debulking, IRE can induce anti-tumor immune responses possibly through tumor neo-antigen release. However, the success of IRE treatment (i.e. full ablation and tumor recurrence) is variable. We believe that IRE treatment induces IFNγ expression, which then modulates immune checkpoint molecules and thus leads to tumor recurrence. This indicates a co-therapeutic use of IRE and immune checkpoint inhibitors as a promising treatment for pancreatic cancer patients. Here, we review the well-defined and speculated pathways involved in the immunostimulatory effects of IRE treatment for pancreatic cancer, as well as the regulatory pathways that may negate these anti-tumor responses. By defining these underlying mechanisms, future studies may identify improvements to systemic immune system engagement following local tumor ablation with IRE and beyond.

Sublethal heat treatment promotes breast cancer metastasis and its molecular mechanism revealed by quantitative proteomic analysis.

Radiofrequency ablation (RFA) is a frequently used thermal ablation technique for breast tumors. The study aimed to identify the effect of sublethal heat treatment on biological function of breast cancer cells and reveal its potential molecular mechanism. The expression profile of dysregulated proteins in sublethal heat treated breast cancer cells was analyzed by quantitative proteomic analysis. The differentially expressed proteins in the sublethal heat treated breast cancer were identified. The potential biological functions of these proteins were evaluated. The proliferation and invasion ability of breast cancer cells were enhanced after sublethal heat treatment. The expression profile of proteins in sublethal heat treated breast cancer cells was abundant, and most of which were newly discovered. A total of 206 differentially expressed proteins were identified. Among them, 101 proteins were downregulated while 105 proteins were upregulated. GO and KEGG analysis indicated that various systems were involved in the process of sublethal heat treatment including cancer, immune system, et al. Immunohistochemistry staining showed that the expression of Heat shock protein 1B, NOB1 and CRIP1 was highly expressed while the expression of BCLAF1 was lower in sublethal heat treated group. The proliferation and invasion ability of breast cancer cells were enhanced after sublethal heat treatment. Sublethal heat treatment caused gene alterations in cancer and immune system. Heat shock protein 1B, NOB1 and CRIP1 were upregulated while BCLAF1 was downregulated in breast cancer after sublethal heat treatment.

Minimally-invasive pain management techniques in palliative care.

Pain is a common source of suffering for seriously ill patients. Typical first-line treatments consist of lifestyle modifications and medication therapy, including opioids. However, medical treatments often fail or are associated with limiting systemic toxicities, and more targeted interventional approaches are necessary. Herein, we present options for minimally invasive techniques for the alleviation of pain in palliative patients from a head-to-toe approach, with a focus on emerging therapies and advanced techniques. Head and neck: image-guided interventions targeted to sympathetic ganglia of the head and neck, such as sphenopalatine ganglion (SPG) and stellate ganglion, have been shown to be effective for some forms of sympathetically-maintained and visceral pain. Interventions targeting branches of cranial nerves and upper cervical nerves, such as the glossopharyngeal nerve (GPN), are options in treating somatic head and face pain. Abdominal and pelvic: sympathetic blocks, including celiac plexus, inferior hypogastric, and ganglion impar can relieve visceral abdominal and pelvic pain. Spine and somatic pain: fascial plane blocks of the chest and abdominal wall and myofascial trigger point injections can be used for somatic pain indications. Cementoplasties, such as kyphoplasty and vertebroplasty, are used for pain related to bony metastases and compression fractures. Tumor ablative techniques can also be used for lytic lesions of the bone. Spinal cord stimulation (SCS), intrathecal drug delivery systems (IDDS), and cordotomy have also been used successfully in patients requiring advanced options, such as those with significant spinal, ischemic, or visceral pain.

Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol.

Simple SummaryMetastatic pancreatic ductal adenocarcinoma has a dismal prognosis, and to date no curative treatment options exist. The image guided tumor ablation technique irreversible electroporation (IRE) employs high-voltage electrical pulses through the application of several needle electrodes in and around the tumor in order to induce cell death. IRE ablation of the primary tumor has the ability to reduce pancreatic tumor induced immune suppression while allowing the expansion of tumor specific effector T cells, hereby possibly shifting the pancreatic tumor microenvironment into a more immune permissive state. The addition of immune enhancing therapies to IRE might work synergistically and could potentially induce a clinically significant treatment effect. This study protocol describes the rationale and design of the PANFIRE-III trial that aims to assess the safety of the combination of IRE with IMO-2125 (toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma.Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor’s immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC’s dismal prognosis.

Immune Modulation Plus Tumor Ablation: Adjuvants and Antibodies to Prime and Boost Anti-Tumor Immunity In Situ.

In situ tumor ablation techniques, like radiotherapy, cryo- and heat-based thermal ablation are successfully applied in oncology for local destruction of tumor masses. Although diverse in technology and mechanism of inducing cell death, ablative techniques share one key feature: they generate tumor debris which remains in situ. This tumor debris functions as an unbiased source of tumor antigens available to the immune system and has led to the concept of in situ cancer vaccination. Most studies, however, report generally modest tumor-directed immune responses following local tumor ablation as stand-alone treatment. Tumors have evolved mechanisms to create an immunosuppressive tumor microenvironment (TME), parts of which may admix with the antigen depot. Provision of immune stimuli, as well as approaches that counteract the immunosuppressive TME, have shown to be key to boost ablation-induced anti-tumor immunity. Recent advances in protein engineering have yielded novel multifunctional antibody formats. These multifunctional antibodies can provide a combination of distinct effector functions or allow for delivery of immunomodulators specifically to the relevant locations, thereby mitigating potential toxic side effects. This review provides an update on immune activation strategies that have been tested to act in concert with tumor debris to achieve in situ cancer vaccination. We further provide a rationale for multifunctional antibody formats to be applied together with in situ ablation to boost anti-tumor immunity for local and systemic tumor control.

Nanomaterial-Based Tumor Photothermal Immunotherapy.

In recent years, photothermal therapy (PTT) particularly nanomaterial-based PTT is a promising therapeutic modality and technique for cancer tumor ablation. In addition to killing tumor cells directly through heat, PTT also can induce immunogenic cell death (ICD) to activate the whole-body anti-tumor immune response, including the redistribution and activation of immune effector cells, the expression and secretion of cytokines and the transformation of memory T lymphocytes. When used in combination with immunotherapy, the efficacy of nanomaterial-based PTT can be improved. This article summarized the mechanism of nanomaterial-based PTT against cancer and how nanomaterial-based PTT impacts the tumor microenvironment and induces an immune response. Moreover, we reviewed recent advances of nanomaterial-based photothermal immunotherapy and discussed challenges and future outlook.

Kinetics of irreversible pore formation under constant electrical tension in giant unilamellar vesicles.

Stretching in the plasma membranes of cells and lipid membranes of vesicles plays important roles in various physiological and physicochemical phenomena. Irreversible electroporation (IRE) is a minimally invasive non-thermal tumor ablation technique where a series of short electrical energy pulses with high frequency is applied to destabilize the cell membranes. IRE also induces lateral tension due to stretching in the membranes of giant unilamellar vesicles (GUVs). Here, the kinetics of irreversible pore formation under constant electrical tension in GUVs has been investigated. The GUVs are prepared by a mixture of dioleoylphosphatidylglycerol and dioleoylphosphatidylcholine using the natural swelling method. An IRE signal of frequency 1.1kHz is applied to the GUVs through a gold-coated electrode system. Stochastic pore formation is observed for several 'single GUVs' at a particular constant tension. The time course of the fraction of intact GUVs among all the examined GUVs is fitted with a single-exponential decay function from which the rate constant of pore formation in the vesicle, kp, is calculated. The value of kp increases with an increase of membrane tension. An increase in the proportion of negatively charged lipids in a membrane gives a higher kp. Theoretical equations are fitted to the tension-dependent kp and to the probability of pore formation, which allows us to obtain the line tension of the membranes. The decrease in the energy barrier for formation of the nano-size nascent or prepore state, due to the increase in electrical tension, is the main factor explaining the increase of kp.

Irreversible Electroporation for Locally Advanced Pancreatic Cancer

Several minimally invasive image guided tumor ablation techniques have been added to the treatment spectrum for locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) might have a significant additive value in the management of this difficult-to-treat disease. As opposed to thermal ablative techniques, IRE induces cell death by the delivery of high-voltage electrical pulses. The electrical energy disrupts the cellular membrane integrity, causes loss of cellular homeostasis and ultimately results in cell death. The extracellular matrix of connective tissue in surrounding delicate structures such as bile ducts, bowel wall, and larger blood vessels is spared. The preservation of these structures makes IRE attractive for the treatment of pancreatic cancers that are unresectable due to their anatomical location (ie, LAPC and local recurrence after surgical resection). In addition to its cytoreductive abilities, evidence is emerging on IRE's capability to induce systemic immunomodulation through active in vivo vaccination against pancreatic cancer cells. These effects in combination with immunotherapy may offer a new treatment paradigm for tumors with low immunogenic potential like pancreatic ductal adenocarcinoma (PDAC). This review discusses several practical and technical issues of IRE for LAPC: clinical evaluation, indications, patient preparations, procedural steps, imaging characteristics, clinical results, and "tricks of the trade" used to improve the safety and efficacy of the treatment. Future directions such as the combination of IRE with immunotherapy will be shortly addressed.