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WO2023172773A1 - Systèmes et procédés d'utilisation de champs électriques pulsés pour commander spatialement des mécanismes de mort cellulaire - Google Patents

Systèmes et procédés d'utilisation de champs électriques pulsés pour commander spatialement des mécanismes de mort cellulaire Download PDF

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Publication number
WO2023172773A1
WO2023172773A1 PCT/US2023/015118 US2023015118W WO2023172773A1 WO 2023172773 A1 WO2023172773 A1 WO 2023172773A1 US 2023015118 W US2023015118 W US 2023015118W WO 2023172773 A1 WO2023172773 A1 WO 2023172773A1
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Prior art keywords
cell death
tissue
electroporation
electrical pulses
pulses
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Inventor
Rafael V. Davalos
Kenneth N. AYCOCK
Nastaran ALINEZHADBALALAMI
Irving Coy ALLEN
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Virginia Tech Intellectual Properties Inc
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Virginia Tech Intellectual Properties Inc
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Priority to US18/846,198 priority Critical patent/US20250205481A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B18/1477—Needle-like probes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00005—Cooling or heating of the probe or tissue immediately surrounding the probe
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00053—Mechanical features of the instrument of device
    • A61B2018/0016—Energy applicators arranged in a two- or three dimensional array
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00613—Irreversible electroporation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
    • A61B2018/00726—Duty cycle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
    • A61B2018/00732—Frequency
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
    • A61B2018/00761—Duration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
    • A61B2018/00767—Voltage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00773—Sensed parameters
    • A61B2018/00779—Power or energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00773—Sensed parameters
    • A61B2018/00791—Temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00773—Sensed parameters
    • A61B2018/00875—Resistance or impedance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/10—Computer-aided planning, simulation or modelling of surgical operations
    • A61B2034/101—Computer-aided simulation of surgical operations
    • A61B2034/102—Modelling of surgical devices, implants or prosthesis
    • A61B2034/104—Modelling the effect of the tool, e.g. the effect of an implanted prosthesis or for predicting the effect of ablation or burring

Definitions

  • Irreversible electroporation and high frequency irreversible electroporation (HFIRE) are tissue ablation strategies used in clinical and preclinical settings to treat aggressive tumors such as pancreatic, liver, and brain tumors with promising outcomes
  • IRE IRE
  • HFIRE high frequency irreversible electroporation
  • tissue ablation strategies used in clinical and preclinical settings to treat aggressive tumors such as pancreatic, liver, and brain tumors with promising outcomes
  • Talez Ud Din, A. et al . “Irreversible Electroporation for Liver Tumors: A Review of Literature”, Cureus 1 1, 2019; Martin, R. C. G., “Use of irreversible electroporation in unresectable pancreatic cancer”, Hepatobiliary Surg. Nutr. 4, 211-215, 2015; Garcia, P. A.
  • IRE and HFIRE have been shown to stimulate release of large quantities of antigens from treated cells, allowing for more potent antigen presentation and consequently activation of T cells in comparison to other focal ablation strategies (Shao, Q. et al., “Engineering T cell response to cancer antigens by choice of focal therapeutic conditions”, Tnt. J. Hyperth. 36, 130-138, 2019). These antigens may exhibit preserved integrity and orientation compared to those released by ablation with other modalities, enhancing their immunogenicity. It has also been demonstrated that manipulations to the voltage waveform can generate different outcomes in terms of cell death (Mercadal, B.
  • H-FIRE high-frequency bipolar pulses
  • IRE and HFIRE can generate either accidental cell death (ACD) or regulated cell death (RCD) - or even a distribution of both within the vicinity of the electrodes.
  • ACD accidental cell death
  • RCD regulated cell death
  • the most widely known form of ACD is necrosis - sometimes called immediate cell death - where affected cells lose membrane integrity, releasing large quantities of damage-associated molecular patterns (DAMPs) as they quickly lose viability.
  • DAMPs damage-associated molecular patterns
  • apoptosis - a “quiet” cell death mechanism - involves several highly programmed signaling cascades and is generally considered non-immunogenic. Cells undergo apoptosis as a part of general tissue maintenance, especially for tissues with high cellular turnover such as the intestinal epithelium.
  • Necroptosis is an inflammatory programed form of cell death that is morphologically similar to necrosis.
  • Pyroptosis is a form of RCD that is mediated by proinflammatory caspase activation pathways (CASP1) and is morphologically distinct from apoptosis (Tang, D et al., “The molecular machinery of regulated cell death”, Cell Res. 29, 347-364, 2019).
  • One or more types of cell death can occur especially in complex biological systems. Additionally, there are specific biochemical or biological processes associated with each type of cell death that can be evaluated to define the type of cell death. Due to the inflammatory nature of both cell death mechanisms, they are considered favorable forms of cell death when an immune response is advantageous.
  • IRE treatments induce an adaptive immune response that is hypothesized to be dependent on the cytotoxic T lymphocytes.
  • the immune response has been shown to be improved when used in combination with immune checkpoint blockades (Zhao, J. et al., “Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer”, Nat. Commun. 10, 899, 2019).
  • cytotoxic T cells can be activated with HFIRE treatments.
  • the extent of the T cell activation seemed to be dependent on the pulsing protocol (Alinezhadbalalami, 2021) alluding to the idea that the level of inflammation can vary changing the pulse parameters.
  • the type of cell death can vary based on the applied pulsing protocol, showing a shift in cell death mechanism with pulse widths that are 10 microseconds long in comparison to bursts with shorter pulse durations (Wasson, 2020).
  • IRE/HFIRE is effective in inducing systemic anti-tumor immune responses
  • Rhgel-Scaia 2019; Goswami, I. et al., “Irreversible electroporation inhibits pro-cancer inflammatory signaling in triple negative breast cancer cells”, Bioelectrochemistry, 2017; 113:42-50; Felsted, A. et al., “Histotripsy Ablation Stimulates Potentially Therapeutic Tumor-directed Systemic Immunity”, Society of Interventional Oncology; Boston MA, 2019; Hendricks, A.
  • a need remains for methods of selecting specific treatment parameters i.e. pulse duration, interphase delay, interpulse delay, polarity, delivery rate, energized time, number of bursts, etc.
  • electrode configurations i.e. monopolar probe(s) with or without a grounding pad, bipolar probe(s), flat plate electrodes, etc.
  • adjuvant molecules i.e. sucrose, calcium, saline, chemotherapeutics, etc.
  • probe designs i.e. internally cooled/heated, integrated phase change materials, etc.
  • This approach will govern the downstream innate and adaptive immune response.
  • the magnitude and temporal nature of the induced immune response is expected to play a critical role in the outcome of each patient.
  • Aspect 1 is a method of treating tissue with electrical pulses comprising administering a plurality of electrical pulses to a tissue according to a pulsing protocol expected to achieve a desired cell death gradient.
  • Aspect 2 is the method of Aspect 1, wherein the desired cell death gradient comprises multiple types of cell death mechanisms.
  • Aspect 3 is the method of Aspect 1 or 2, wherein the cell death gradient is capable of shifting a local tumor microenvironment from anti-inflammatory to pro-inflammatory, or from pro-inflammatory to anti-inflammatory, in response to the administering of the plurality of electrical pulses.
  • Aspect 4 is the method of any of Aspects 1-3, wherein the cell death gradient is capable of activating a local innate immune response and a systemic anti-tumor adaptive immune response, reducing metastatic lesions and/or preventing recurrence in tumors, such as mammary tumors, such as a predetermined immune response.
  • Aspect 5 is a method of treating tissue comprising: determining a desired gradient of cell death within a tissue; constructing a pulsing protocol capable of achieving the desired gradient; and applying a plurality of electrical pulses to tissue according to the pulsing protocol.
  • Aspect 6 is the method of any of Aspects 1 -5, wherein the plurality of electrical pulses is selected to elicit apoptosis, pyroptosis, necroptosis, necrosis, programmed necrosis, and/or coagulative necrosis according to the desired gradient of cell death.
  • Aspect 7 is the method of any of Aspects 1-6, further comprising monitoring: treatment progression; one or more effect of the plurality of electrical pulses on the tissue; the extent of one or more of the cell death(s) elicited; any change in tissue Joule heating; any change in temperature; any change in impedance (such as determined by FAST impedance measurements); cellular integrity or cellular recovery; the extent of non-thermal or thermal damage, if any; any thermal effects; and/or potential for Joule heating or thermal damage.
  • Aspect 8 is the method of any of Aspects 1-7, further comprising adjusting one or more parameter of the pulsing protocol to change the gradient and/or extent of cell death, such as in response to the monitoring.
  • Aspect 9 is the method of any of Aspects 1-8, wherein the change in the gradient of cell death is a change in the extent or degree of apoptosis, pyroptosis, necroptosis, necrosis and/or coagulative necrosis.
  • Aspect 10 is the method of any of Aspects 1-9, wherein the constructing of the pulsing protocol is performed by reference to a model.
  • Aspect 11 is a method of treating tissue with electrical pulses comprising: administering a plurality of electrical pulses to a tissue; wherein the plurality of electrical pulses is capable of causing apoptosis, pyroptosis, necroptosis, necrosis and/or coagulative necrosis in selected zones of the tissue.
  • Aspect 12 is a method for treating tissue comprising: placing a probe in or near tissue within a body, such as a mammal or human, wherein the probe has at least a first electrode; applying a plurality of electrical pulses with the first electrode and optionally one or more additional electrodes, such as a second electrode; causing irreversible electroporation (IRE) of the tissue within a target ablation zone; wherein the electrical pulses are applied to the tissue such that a desired cell death mechanism occurs to stimulate or modulate an immune system response to the tissue, such as a predetermined immune response; optionally further administering one or more adjuvant, such as within the target ablation zone, to achieve a desired/predetermined cell death volume and/or immune system response.
  • IRE irreversible electroporation
  • Aspect 13 is the method of any of Aspects 1 -12, desired cell death mechanism is chosen from coagulative necrosis, programmed necrosis, necrosis, necroptosis, pyroptosis, and apoptosis.
  • Aspect 14 is a treatment planning method comprising: selecting one or more desired cell death mechanism; receiving and processing information from medical images of a target tissue and preparing a reconstruction model of the target tissue; using the model of the target tissue, one or more patient-specific characteristics, and one or more of the desired cell death mechanisms, constructing an electroporation protocol capable of achieving one or more of the desired cell death mechanisms in the target tissue and/or a desired gradient/pattern thereof.
  • Aspect 15 is a method of determining one or more cell death mechanism for an electroporation treatment protocol, comprising: receiving and processing information from medical images of a tissue and preparing a reconstruction model of the tissue; using the model of the tissue and one or more electroporation treatment pulse parameter, generating an image of one or more electroporation zones expected from applying one or more of the treatment pulse parameters to the tissue; and determining an expected cell death mechanism associated with one or more of the electroporation zones.
  • Aspect 16 is the method of any of Aspects 1-15, further comprising adjusting the electroporation protocol or one or more of the electroporation treatment pulse parameters to change the expected cell death mechanism to another cell death mechanism, such as coagulative necrosis, programmed necrosis, necrosis, necroptosis, pyroptosis, or apoptosis.
  • Aspect 17 is the method of any of Aspects 1 -16, further comprising applying a plurality of electrical pulses to the tissue to administer the electroporation protocol or the electroporation treatment pulse parameters and to elicit the expected cell death mechanism in one or more or each of the electroporation zones.
  • Aspect 18 is the method of any of Aspects 1-17, further comprising including in the determining of the expected cell death mechanism(s) an expected effect of administration of one or more type of adjuvants.
  • Aspect 19 is the method of any of Aspects 1-18, further comprising including in the determining of the expected cell death mechanism(s) an expected effect of electrode cooling.
  • Aspect 20 is the method of any of Aspects 1-19, wherein the electroporation protocol or the one or more electroporation treatment pulse parameter comprises a parameter chosen from pulse width, voltage, polarity, interpulse delay, interphase delay, frequency, number of pulses, and total energized time.
  • Aspect 21 is a method of activating an immune response to electroporation comprising: placing one or more electrode within a body, such as a mammal or human body; applying a plurality of electrical pulses through the one or more electrode; and causing electroporation of cells within a treatment area, such that the treatment area comprises one or more electroporation zones defined by a specific type of cell death capable of occurring in that electroporation zone; wherein the electroporation is capable of activating an immune response, such as a predetermined immune response; optionally wherein: cells in a first electroporation zone are killed via a first cell death mechanism; cells in a second electroporation zone are killed via a second cell death mechanism; cells in a third electroporation zone are killed via a third cell death mechanism; cells in a fourth electroporation zone are killed via a fourth cell death mechanism; and/or cells in a fifth electroporation zone are killed via a fifth cell death mechanism.
  • Aspect 22 is the method of any of Aspects 1-21, wherein at least 50% of the cells in the first electroporation zone are killed via the first cell death mechanism; and/or wherein at least 50% of the cells in the second electroporation zone are killed via the second cell death mechanism; and/or wherein at least 50% of the cells in the third electroporation zone are killed via the third cell death mechanism; and/or wherein at least 50% of the cells in the fourth electroporation zone are killed via the fourth cell death mechanism; and/or wherein at least 50% of the cells in the fifth electroporation zone are killed via the fifth cell death mechanism.
  • Aspect 23 is the method of any of Aspects 1-22, wherein the first, second, third, fourth and/or fifth cell death mechanism(s) is chosen from coagulative necrosis, programmed necrosis, necrosis, necroptosis, pyroptosis, and apoptosis.
  • Aspect 24 is the method of any of Aspects 1-23, further comprising a sixth electroporation zone, wherein cells are reversibly electroporated.
  • Aspect 25 is the method of any of Aspects 1-24, wherein the first electroporation zone is located closest to the one or more electrode and the sixth electroporation zone is located furthest from the one or more electrode.
  • Aspect 26 is the method of any of Aspects 1-25, wherein the plurality of electrical pulses is applied such that the volume of the first electroporation zone is smaller than any other zone.
  • Aspect 27 is the method of any of Aspects 1 -26, wherein the plurality of electrical pulses is applied such that the first cell death mechanism is coagulative necrosis or necrosis.
  • Aspect 28 is the method of any of Aspects 1-27, wherein the one or more electrode is cooled during the applying.
  • Aspect 29 is the method of any of Aspects 1-28, further comprising administering one or more adjuvant.
  • Aspect 30 is the method of any of Aspects 1-29, wherein one or more of the adjuvants is chosen from gymcitabine, calcium, bleomycin, and cisplatin.
  • Aspect 31 is the method of any of Aspects 1-30, wherein the adjuvant is capable of increasing or suppressing an immune system response, such as according to a predetermined immune response.
  • Aspect 32 is the method of any of Aspects 1-31, wherein the adjuvant is capable of increasing a volume of cells killed.
  • Aspect 33 is the method of any of Aspects 1-32, wherein the adjuvant is capable of changing the cell death mechanism.
  • Aspect 34 is a method of tissue ablation comprising: applying a series of electrical pulses to a tissue; wherein one or more pulse parameter (e.g., pulse width, repetition rate/frequency, etc.) is modified to manipulate volumes of tissue undergoing different types of cell death; optionally wherein the modifying of the pulse parameter(s) is performed before, during and/or after the applying of the electrical pulses and comprises selecting the pulse parameter(s) to achieve a desired, selected and/or predetermined gradient or pattern of cell death in the tissue.
  • pulse parameter e.g., pulse width, repetition rate/frequency, etc.
  • Aspect 35 is the method of any of Aspects 1-34, wherein one or more cell death mechanism attributable to one or more of the different types of cell death is controlled to elicit a specific, desired and/or predetermined patient-specific treatment outcome, such as by controlling the extent of one or more of the different types of cell death during the applying of the series of electrical pulses.
  • Aspect 36 is the method of any of Aspects 1-35, wherein: pulse width is reduced to increase the volume of tissue experiencing regulated cell death (RCD), such as apoptosis and/or pyroptosis; and/or pulse repetition rate is increased to elicit a larger volume of necrosis and/or necroptosis; wherein the pulse width reduction or the pulse repetition increase is performed before, during and/or after the applying of the electrical pulses; optionally wherein the pulse width reduction or the pulse repetition increase is measured relative to another pulsing protocol having a known outcome (such as a protocol resulting in less RCD) in order to achieve a different and/or modified outcome (such as more RCD) due to the difference(s).
  • RCD regulated cell death
  • Aspect 37 is the method of any of Aspects 1-36, wherein: pulse width, interphase delay and/or interpulse delay are modified in a manner capable of adjusting volumes of pyroptosis and/or necroptosis to achieve a desired immunological outcome, such as a predetermined immune response; wherein the pulse width, interphase delay and/or interpulse delay are modified before, during and/or after the applying of the electrical pulses; optionally wherein the pulse width, interphase delay and/or interpulse delay are modified relative to another pulsing protocol having a known outcome (such as a certain extent of pyroptosis and/or necroptosis) in order to achieve a different and/or modified outcome (such as an increase or decrease in the extent of tissue experiencing pyroptosis and/or necroptosis.
  • a known outcome such as a certain extent of pyroptosis and/or necroptosis
  • Aspect 38 is the method of any of Aspects 1-37, wherein one or more adjuvant (such as adjuvant molecules including calcium) is used before, during and/or after the applying of the electrical pulses to increase necrosis/necroptosis and/or is otherwise introduced to manipulate volumes of tissue experiencing different mechanisms of cell death.
  • one or more adjuvant such as adjuvant molecules including calcium
  • Aspect 39 is the method of any of Aspects 1-38, wherein one or more adjuvant (such as adjuvant molecules including bleomycin and/or cisplatin) is introduced before, during and/or after the applying of the electrical pulses, such as to the tissue or a region of interest thereof) to increase overall volumes of cell death while maintaining and/or minimizing immunological effects.
  • one or more adjuvant such as adjuvant molecules including bleomycin and/or cisplatin
  • Aspect 40 is a method for tissue ablation comprising: applying a series of electrical pulses to a tissue using one or more electrode; modifying one or more electrode-based parameter to adjust volumes of cell death (such as increasing necrosis while limiting or reducing coagulative necrosis, or increasing apoptosis while limiting or reducing necrosis); wherein the electrode-based parameter(s) are modified before, during and/or after the applying of the electrical pulses; optionally wherein the electrode-based parameter(s) are modified relative to another pulsing protocol having a known outcome (such as having a certain extent of apoptosis, necrosis and/or coagulative necrosis) in order to achieve a different and/or modified outcome (such as an increase or decrease in the extent of tissue experiencing apoptosis, necrosis and/or coagulative necrosis).
  • a known outcome such as having a certain extent of apoptosis, necrosis and/or coagulative necrosis
  • Aspect 41 is the method of any of Aspects 1 -40, wherein the modifying comprises modifying one or more of: the number of electrodes, electrode shape and/or other electrode-based parameter; number of insertions, such as a number of necessary insertions; and/or thermalregulating technologies (e.g., active cooling, phase change materials, endothermic reactions, and/or exothermic reactions).
  • the modifying comprises modifying one or more of: the number of electrodes, electrode shape and/or other electrode-based parameter; number of insertions, such as a number of necessary insertions; and/or thermalregulating technologies (e.g., active cooling, phase change materials, endothermic reactions, and/or exothermic reactions).
  • Aspect 42 is the method of any of Aspects 1-41, wherein the electrical pulses, plurality of electrical pulses, electroporation protocol, pulsing protocol, or electroporation treatment parameter is/are applied with: a positive pulse width of above zero up to 1 ms, such as 100 ps; and/or a negative pulse width of above zero up to 1 ms, such as 100 ps; and/or; an interphase delay of above zero up to 1 s; and/or an interpulse delay of above zero up to 10 s; and/or an inter-burst delay of above zero up to 10 s; and/or no interphase, interpulse and/or inter-burst delay; and/or a number of pulses from 1-5,000; and/or a voltage of 1-10,000 V; and/or a frequency of from 1 Hz to 250 kHz; and/or a total energized time of from the smallest pulse width up to 1 s.
  • Aspect 43 is the method of any of Aspects 1-42, wherein the electrical pulses or plurality of electrical pulses is/are applied in a manner and/or in an amount sufficient to promote a local and/or systemic anti-tumor immune system response, such as a predetermined immune response.
  • Aspect 44 is the method of any of Aspects 1-43, wherein the tissue comprises cancer cells and/or non cancer cells.
  • Aspect 45 is the method of any of Aspects 1-44, wherein the cells are cancer cells.
  • Aspect 46 is the method of any of Aspects 1-45, wherein the cancer cells are breast, liver, pancreas, prostate, skin, and/or brain cancer cells
  • Aspect 47 is the method of any of Aspects 1-46, wherein the electrical pulses or plurality of electrical pulses are delivered in one or more burst(s) of electrical pulses, such as with an inter-burst delay of up to 10 s.
  • Aspect 48 is the method of any of Aspects 1-47, wherein the electrical pulses are monopolar pulses, bipolar pulses, or a combination thereof.
  • Aspect 49 is the method of any of Aspects 1-48, wherein the electrical pulses or plurality of electrical pulses is/are capable of one or more of electroporation-based therapy, electroporation, irreversible electroporation, reversible electroporation, electrochemotherapy, electrogenetherapy, supraporation, and/or high frequency irreversible electroporation, or combinations thereof, such as by way of a DC current.
  • Aspect 50 is the method of any of Aspects 1-49, wherein the electrical pulses are administered from two or more electrodes, and from any number of electrodes, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 electrodes, and in any configuration relative to one another, such as being delivered by way of one or more pairs of electrodes.
  • Aspect 51 is the method of any of Aspects 1-50, wherein the electrical pulses or plurality of electrical pulses are delivered at a voltage of 0 V to 10,000 V, such as above 0 V or 1 V up to 10,000 V, and/or from 500 V up to 3,000 V, and/or from 1,000 V up to 2,000 V, such as up to 250 V, up to 300 V, up to 350 V, up to 600 V, up to 650 V, up to 800 V, up to 1,200 V, up to 1,500 V, up to 5,000 V, up to 7,500 V, or any range in between any of these ranges or endpoints, including as endpoints any number encompassed thereby.
  • Aspect 52 is the method of any of Aspects 1-51, wherein one or more pulses of the electrical pulses or plurality of electrical pulses have a pulse length in the ns to second range, such as in the nanosecond to ms range, such as from 1 picosecond to 1 ms, or from 1 picosecond to 100 microseconds, or from 1 picosecond to 10 microseconds, or from 1 picosecond to 1 microsecond, or from at least 0.1 microsecond up to 1 second, or from 0.5 microseconds up to 10 microseconds, or up to 20 microseconds, or up to 50 microseconds, such as 15, 25, 30, 35, 40, 55, 60, 75, 80, 90, 100, 110, or 200 microseconds, or any range in between any of these ranges or endpoints, including as endpoints any number encompassed thereby.
  • a pulse length in the ns to second range such as in the nanosecond to ms range, such as from 1 picosecond to 1 ms, or from 1 picosecond to
  • Aspect 53 is the method of any of Aspects 1-52, wherein the plurality of electrical pulses has a frequency in the range of 0 Hz to 100 MHz, such as from above 0 Hz or 1 Hz up to 100 MHz, such as from 2 Hz to 100 Hz, or from 3 Hz to 80 Hz, or from 4 Hz to 75 Hz, or from 15 Hz to 80 Hz, or from 20 Hz up to 60 Hz, or from 25 Hz to 33 Hz, or from 30 Hz to 55 Hz, or from 35 Hz to 40 Hz, or from 28 Hz to 52 Hz, or any range in between any of these ranges or endpoints, including as endpoints any number encompassed thereby.
  • Aspect 54 is the method of any of Aspects 1-53, wherein the electrical pulses have a waveform that is square, triangular, trapezoidal, exponential decay, sawtooth, sinusoidal, and/or alternating polarity.
  • Aspect 55 is the method of any of Aspects 1-54, wherein a total number of electrical pulses delivered, and/or a total number of pulses delivered per burst, ranges from 1 to 5,000 pulses, such as from at least 1 up to 3,000 pulses, or at least 2 up to 2,000 pulses, or at least 5 up to 1,000 pulses, or at least 10 up to 500 pulses, or from 10 to 100 pulses, such as from 20 to 75 pulses, or from 30 to 50 pulses, such as 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, or 90 pulses, or any range in between any of these ranges or endpoints, including as endpoints any number encompassed thereby.
  • Aspect 56 is the method of any of Aspects 1-55, further comprising measuring temperature with one or more thermal sensor, such as measuring temperature of the tissue and/or electrodes.
  • Aspect 57 is the method of any of Aspects 1-56, further comprising measuring impedance and/or conductivity and/or capacitance, such as tissue, intra- or extra-cellular impedance, conductivity and/or capacitance.
  • Aspect 58 is a system capable of performing any one or more of the methods of Aspects 1-57.
  • Aspect 59 is a treatment planning system for determining a patient-specific electroporation-based treatment protocol comprising: a processing module operably configured for performing the following stages: receiving and processing information from medical images of a target tissue and preparing a reconstruction model of the target tissue; and using the model of the target tissue and one or more desired cell death mechanism as inputs, constructing one or more protocols each providing a treatment region with parameters for electroporating the target tissue and the volume of the treatment region expected to undergo the desired cell death mechanism(s); and a processor for executing the stages of the processing module.
  • Aspect 60 is a treatment planning system for determining a patient-specific electroporation-based treatment protocol comprising: a processing module operably configured for performing the following stages: receiving and processing information from medical images of a target tissue and preparing a reconstruction model of the target tissue; using (i) the model of the target tissue, (ii) one or more patient-specific characteristics (such as tissue type (e.g., myocardium, benign neoplastic tissue, malignant neoplasm, etc ), patient immune status, disease severity, comorbidities, and treatment location), and (iii) one or more desired cell death mechanism, constructing one or more protocols each providing a treatment region with parameters for electroporating the target tissue capable of achieving one or more of the desired cell death mechanisms; and a processor for executing the stages of the processing module.
  • tissue type e.g., myocardium, benign neoplastic tissue, malignant neoplasm, etc
  • patient immune status e.g., disease severity, comorbidities
  • FIG. 1 is an illustration showing the types of cell death associated with electroporationbased ablative therapy.
  • FIGS. 2A-B are representative illustrations showing regions of cell death following H-FIRE treatment with a 10-1-10 waveform delivered with solid monopolar probes (FIG. 2A) and for a 2-5-2 waveform delivered with actively cooled probes (FIG. 2B).
  • FIG. 3 A is a schematic illustrating a system for delivering electrical pulses according to an embodiment of the invention.
  • FIG. 3B is a drawing of a custom concentric cylinder electrode setup according to an embodiment of the invention.
  • FIG. 3C is a graph showing computed and experimentally obtained changes in temperature over time for different pulse parameters according to embodiments of the invention.
  • FIG. 3D is a drawing showing electric field and temperature profiles within the hydrogel according to an embodiment of the invention.
  • FIG. 3E is a graph showing the radial dependence of electric field and temperature for administration of electrical pulses according to an embodiment of the invention.
  • FIGS. 4A, 4C, and 4E are drawings showing pulse schemes for traditional IRE, including pulse widths of 90 ps (FIG. 4A) and 70 ps (FIG. 4C), and for H-FIRE (FIG. 4E).
  • FIGS. 4B, 4D, and 4F are drawings illustrating electroporation and cell death outcomes of the pulse parameters shown in FIGS. 4A, 4C, and 4E, respectively.
  • FIG. 5A is a is a fluorescence microscopy image of live-dead staining of cells treated with various pulse schemes.
  • FIG. 5B is a graph showing the areas of lesions produced from electroporating cells using various pulse schemes.
  • FIG. 5C is a graph showing the electric field threshold for several pulse schemes.
  • FIG. 6A is an electric field distribution map showing the applied electric field between two plate electrodes.
  • FTG. 6B is a drawing showing the percent difference between the applied electric field shown in FIG. 6A and the intended electric field.
  • FIG. 6C is an illustration showing the release of DAMPs as detected using a colorimetric assay following electroporation of tumor cells.
  • FIG. 7A is a graph showing the concentration of extracellular ATP present following electroporation of cells using various pulse schemes.
  • FIG. 7B is a graph showing the concentration of extracellular ATP present 24 hours following electroporation of cells using various pulse schemes.
  • FIG. 8A is a graph showing the absorbance of cells that were harvested and lysed after exposure to electroporation using various pulse schemes.
  • FIG. 8B is a graph showing the increase in caspase 3/7 activity for cells electroporated using a variety of pulse schemes.
  • FIG. 9A is a graph showing fluorescence measurements of cells electroporated using a variety of pulse schemes.
  • FIG. 9B is a graph showing the increase in caspase 1 activity for cells electroporated using a variety of pulse schemes.
  • FIG. 10 is an illustration showing the cell death distribution for an ablation area exposed to electrical pulses from one, two, and three pairs of electrodes.
  • FIG. 11 is an illustration showing the presence of pro-inflammatory signaling molecules and types of cell death associated with short and long pulses, such as apoptosis, necrosis, pyroptosis, programmed necrosis etc.
  • HFIRE uses several pulse parameters that can be customized to create a tailored cell death profde for optimal immune responses.
  • the short bursts of bi-polar electric fields utilized by HFIRE generate nanoscale defects in cell membranes leading to cell death.
  • FIG. 1 shows the characteristics of four types of cell death associated with electroporation-based ablative therapy: apoptosis, pyroptosis, necrosis, and programmed necrosis.
  • IRE-induced cell death is primarily characterized as apoptosis
  • pyroptosis has also been identified for H-FIRE treatment as an inflammatory form of cell death that may lead to a more effective local and systemic immune response (Ringel-Scaia, 2019).
  • HFIRE treatment can induce necroptosis (MLKL- dependent cell death) (Wasson, 2020).
  • one or more of the electrical pulses can be monopolar. In embodiments, one or more of the electrical pulses is bipolar. In embodiments, the electrical pulses are delivered with an AC current, DC current, or a combination of AC and DC currents.
  • each pulse comprises a positive and/or negative polarity pulse width of up to about 100 ps, such as up to 100 ns, 250 ns, 500 ns, 1 ps, 2 ps, 5 ps, 10 ps, 15 ps, 20 ps, 25 ps, 40 ps, 50 ps, 75 ps, or 100 ps, or any range in between any of these ranges or endpoints.
  • each of the electrical pulses comprises an interphase delay (a delay between positive and negative polarity portions of a bipolar pulse) of up to about 100 ps, such as up to about 100 ns, 250 ns, 500 ns, 750 ns, 1 ps, 2 ps, 3 ps, 4 ps, 5 ps, 6 ps, 7 ps, 8 ps, 9 ps, 10 ps, 15 ps, 20 ps, 25 ps, 50 ps, or 75 ps, or any range in between any of these ranges or endpoints.
  • the electrical pulses change polarity instantly or without an interphase delay.
  • the pulses of the plurality of electrical pulses are separated by an interpulse delay.
  • the plurality of electrical pulses may be administered with no delay, or effectively no delay, between pulses. If administered with an inter-pulse delay, the delay between pulses can be up to 100 times, 50 times, 20 times, 10 times, or 5 times the pulse length, such as 3 times the pulse length, 2 times the pulse length, equal to the pulse length, or less than the pulse length.
  • the delay between pulses can be 10%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, or 90% of the pulse length.
  • the total pulse length (including positive pulse, interphase delay, negative pulse width, and interpulse delay) is in the nanosecond to microsecond range, including from 1 picosecond to 1 ms, or from below 1 microsecond, or from at least 0.1 microsecond up to 5 microseconds, or from 0.5 microseconds up to 2 microseconds or up to 10 microseconds, such as up to 100 ns, 250 ns, 500 ns, 1 ps, 2 ps, 5 ps, 10 ps, 15 ps, 20 ps, 25 ps, 40 ps, 50 ps, 75 ps, 100 ps, 125 ps, or 150 ps, or even up to about 200 ps or any range in between any of these ranges or endpoints, including as endpoints any number encompassed thereby.
  • the total energized time is up to about 100 ms, such as up to about Ips, 5ps, 10 ps, 20 ps, 30 ps, 40 ps, 50 ps, 60 ps, 70 ps, 80 ps, 90 ps, 100 ps, 125 ps, 150 ps, 200 ps, 250 ps, 500 ps, 1 ms, 2 ms, 5 ms, 10 ms, 25 ms, 50 ms, or 75 ms.
  • the X-X-X convention referred to in this disclosure can mean any one or more of a pulsing protocol of the following formats: pulse ontime-pulse offtime-pulse ontime; positive pulse-delay/offtime-negative pulse; negative pulse-delay/offtime-positive pulse; positive portion of a pulse-delay/offtime-negative portion of pulse, etc.
  • IRE pulses were administered as monopolar pulses at a frequency of one pulse per second.
  • the plurality of electrical pulses can have a pulsing scheme that incorporates one or more inter-burst delays, such as pulsing schemes of bursts of pulses comprising schemes of 1-1-1 ps, 2-1-2 ps, 5-1-5 ps, or 10-1-10 ps with up to a 1 -second delay between bursts.
  • pulsing schemes of bursts of pulses comprising schemes of 1-1-1 ps, 2-1-2 ps, 5-1-5 ps, or 10-1-10 ps with up to a 1 -second delay between bursts.
  • the total number of pulses delivered or the number of pulses per burst ranges from 1 to about 5,000 pulses, such as from at least 1 up to 3,000 pulses, or at least 2 up to 2,000 pulses, or at least 5 up to 1,000 pulses, or at least 10 up to 500 pulses, or from 10 to 100 pulses, such as from 20 to 75 pulses, or from 30 to 50 pulses, such as 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, or 90 pulses.
  • a single burst of electrical pulses is delivered.
  • multiple bursts are delivered, each comprising up to about 100 pulses, such as up to about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 pulses.
  • the pulses or bursts are delivered at a frequency in the range of about 0 Hz to 100 MHz, such as from above 0 Hz or 1 Hz up to 100 MHz, such as from 2 Hz to 100 Hz, or from 3 Hz to 80 Hz, or from 4 Hz to 75 Hz, or from 15 Hz to 80 Hz, or from 20 Hz to 60 Hz, or from 25 Hz to 33 Hz, or from 30 Hz to 55 Hz, or from 35 Hz to 40 Hz, or from 28 Hz to 52 Hz, or a frequency ranging from about 100 Hz to 100 MHz, such as in the Hz range from 100 Hz or 1 Hz up to 100 Hz, or from 2 Hz to 100 Hz, or from 3 Hz to 80 Hz, or from 4 Hz to 75 Hz, or from 15 Hz to 80 Hz, or from 20 Hz to 60 Hz, or from 25 Hz to 33 Hz, or from 30 Hz to 55 Hz, or from 35
  • the plurality of electrical pulses are administered at a voltage in the range of 0 V to 10,000 V, such as above 0 V or 1 V up to 10,000 V, and/or from 500 V up to 3,000 V, and/or from 1,000 V up to 2,000 V, such as up to 250 V, up to 300 V, up to 350 V, up to 600 V, up to 650 V, up to 800 V, up to 1,200 V, up to 1,500 V, up to 5,000 V, up to 7,500 V, or for example from 100 V to 15,000 V, such as from 500 V up to 3,000 V, and/or from 1,000 V up to 2,000 V, such as up to 250 V, up to 300 V, up to 350 V, up to 600 V, up to 650 V, up to 800 V, up to 1,200 V, up to 1,500 V, up to 15,000 V, up to 7,500 V, from 4,000 V to 12,000 V, such as less than 450 V, or less than 425 V, such as from above 0 V to 400 V
  • the shape of the electrical pulses delivered can be any desired waveform, including square, triangular, trapezoidal, exponential decay, sawtooth, sinusoidal, and/or such waveforms comprising one or more pulses of alternating polarity.
  • the electrical pulses are administered from two or more electrodes, and from any number of electrodes, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 electrodes, and in any configuration relative to one another, such as being delivered by way of one or more pairs of electrodes.
  • the gradient of cell death can be tailored using active cooling.
  • FIG. 2A shows representative regions of cell death following treatment with a 10-1-10 waveform using solid monopolar probes.
  • FIG. 2B shows representative regions of cell death following treatment with a 2-5-2 waveform with actively cooled probes.
  • Embodiments of the present invention include methods directed to selecting pulsing protocols to achieve a desired cell death mechanism and immune response.
  • a user can choose to elicit specific cell death outcomes depending upon the application and desired dynamics of immune infiltration after treatment. For example, in most oncological applications, clinicians will seek to employ treatment parameters that yield the strongest immune stimulation.
  • Bursts of pulses with pulse durations of ⁇ 5 ps are likely to achieve strong immune stimulation with the highest likelihood of success.
  • treatment voltage, repetition rate, and probe design can be tuned to ensure that tissue is not thermally damaged.
  • Bursts employing shorter pulse durations are less efficient in terms of ablating tissue, so high voltages are needed to achieve targeted ablation sizes.
  • Waveforms with longer pulse durations do not appear to be as effective at stimulating cytotoxic T cells.
  • Monopolar pulsing schemes are known to elicit strong electrochemical effects near the electrodes, which could disrupt or enhance the targeted volume of cell death, as well as the distribution of each cell death pathway. The above considerations will aid in the selection of the precise pulse duration, interphase delay, and interpulse delay that yield the desired pro-inflammatory cell death mechanisms.
  • targeted ablation volumes may be desired along with less immune stimulation.
  • cardiac treatments acute post-treatment inflammation is associated with increased risk of arrhythmogenicity and recurrence of atrial fibrillation (Andrade, J. G. et al., “Early recurrence of atrial tachyarrhythmias following radiofrequency catheter ablation of atrial fibrillation”, PACE -Pacing Clin. Electrophysiol. 35, 106-116, 2012).
  • waveforms capable of inducing “quiet” cell death may be more favorable.
  • Bipolar burst waveforms with very short pulse durations i.e. ⁇ 1 ps
  • IRE pulse parameters (Table 1) play a major role in the type of cell death initiated, and the tissue volume experiencing a given cell death mechanism affects immunogenicity. These pulse parameters - along with the chosen geometric configuration - can be tuned to generate a predetermined distribution of different cell death mechanisms.
  • the preferred cell death mechanisms may depend upon but are not limited to: tissue type (e.g., myocardium, benign neoplastic tissue, malignant neoplasm, etc.), patient immune status and overall health, disease severity, comorbidities, and/or treatment location. Manipulation of electrode and treatment parameters will dictate the degree of acute and delayed inflammation. The extent of innate and adaptive immunity can be controlled to generate the optimal immune profile given each patient’s unique case.
  • HepG2, ATCC HB-8065, Manassas, VA cells were cultured in Eagle’s Minimum Essential Medium (EMEM, ATCC) and human glioblastoma (U- 251, Sigma-Aldrich 09063001, St. Louis, MO) cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM, ATCC); each was supplemented with 10% FBS (Fisher Scientific, Hampton, NH) and 1% penicillin-streptomycin (Fisher Scientific). Cells were incubated at 37 °C with 5% CO2 and sub-cultured regularly at -80% confluency.
  • EMEM Minimum Essential Medium
  • DMEM Dulbecco’s Modified Eagle Medium
  • the extent of inflammatory cell death was quantified through measuring the release of DAMPs such as ATP and HMGB 1.
  • DAMPs such as ATP and HMGB 1.
  • Caspase 3 Caspase 1 and MLKL activation were measured as metrics for apoptosis, pyroptosis, and necroptosis, respectively.
  • Caspase 1 activation was detected with a fluorometric assay while MLKL activation was measured using western blot analysis.
  • cells were lysed using RIPA buffer. The lysate was then studied for the marker of interest.
  • the monolayer of cells was treated with a non-uniform electric field and the ablation areas were measured 24 hours after the treatment.
  • the live and dead areas were visualized through fluorescent microscopy (FIG. 5A).
  • the ablation areas were measured using Image J and correlated to corresponding electric fields characterized through a model in comsol (FIG. 5B).
  • Electric field thresholds were used to normalize the applied field among waveforms.
  • FIG. 5C depicts the electric field thresholds for all applied waveforms. Cell death is expected when exposed to fields equal to or above the thresholds.
  • the release of ATP could directly correlate to levels of inflammation.
  • the level of ATP in the supernatant was measured as a representative of release of DAMPs leading to increased inflammation (FIGS. 7A-B).
  • An ATP assay was performed for several waveforms (1-1-1, 5-1-5, 10-1-10, and IRE) and fields (0.5, 1, 1.5, and 2 times the electric field threshold). The applied electric fields were adjusted to achieve the same level of cell death across the various pulse parameters (lower voltages were applied for longer pulses). It was observed that the level of ATP release is field dependent. The majority of the ATP is released from the treated cells within half an hour of treatment (FIG. 7A). At 24 hours, some ATP release was still observed but at much lower amounts (FIG.
  • apoptosis levels were measured through caspase 3/7 activity at the electric field threshold and at 1.5 and 2 times the electric field threshold. Cells were harvested at 6 hours and lysed. Samples were adjusted to have the same levels of protein. Caspase activation was measured using a colorimetric assay (FIG. 8A-B). An increase in active caspase 3 concentration was found for shorter pulses, and with increases in electric field. Not much caspase activity was observed in the IRE and 10-1-10 groups.
  • Caspase 1 activity was also measured as it is indicative of pyroptosis.
  • Cells were harvested at 0.5 hours, samples were adjusted to have the same levels of protein, and caspase activation was measured using a fluorometric assay (FIGS. 9A-B).
  • FGS. 9A-B fluorometric assay
  • treatment parameters i.e. pulse width, the applied field, interpulse delay, electrode orientation, cooling strategies, etc.
  • treatment parameters i.e. pulse width, the applied field, interpulse delay, electrode orientation, cooling strategies, etc.
  • type(s) of immune response for example, pyroptosis is highly inflammatory whereas apoptosis is not
  • level of inflammatory response from non-inflammatory to highly inflammatory
  • a multi electrode array can be utilized to obtain various forms of cell death response in different areas of the target. As shown in FIG. 10, a multi electrode array can be used to tailor the type of cell death to favor pyroptosis, apoptosis, or necrosis. It can also be envisioned that one pair of electrodes could be used to apply longer low magnitude pulses to achieve one form of cell death (i.e. pyroptosis) and another pair used to achieve other form of cell death (i.e. apoptosis).
  • FIG. 11 is an illustration of an example cell death distribution and pro-inflammatory signaling molecule concentration for short and long pulses.
  • the dominant cell death mechanism is expected to shift when altering the pulse width.
  • higher levels of apoptosis are expected to be obtained when shorter pulses are applied.
  • increased levels of pyroptosis are expected to be observed with longer pulses.
  • higher levels of DAMPs e.g. ATP, HMGB1, etc.
  • proinflammatory mediators such as IL-1/? or IL-18 are expected to be released when applying longer pulses.
  • Any method described herein can be embodied in software or set of computer executable instructions capable of being run on a computing device or devices.
  • the computing device or devices can include one or more processor (CPU) and a computer memory.
  • the computer memory can be or include a non-transitory computer storage media such as RAM which stores the set of computer-executable (also known herein as computer readable) instructions (software) for instructing the processor(s) to carry out any of the algorithms, methods, or routines described in this disclosure.
  • a non-transitory computer readable medium can include any kind of computer memory, including magnetic storage media, optical storage media, nonvolatile memory storage media, and volatile memory.
  • Non-limiting examples of non-transitory computer-readable storage media include floppy disks, magnetic tape, conventional hard disks, CD-ROM, DVD-ROM, BLU-RAY, Flash ROM, memory cards, optical drives, solid state drives, flash drives, erasable programmable read only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), non-volatile ROM, and RAM.
  • the computer-readable instructions can be programmed in any suitable programming language, including JavaScript, C, C#, C++, Java, Python, Perl, Ruby, Swift, Visual Basic, and Objective C.
  • Embodiments of the invention also include a non-transitory computer readable storage medium having any of the computer-executable instructions described herein.

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Abstract

La présente invention concerne des systèmes et des procédés de planification de traitement et/ou d'administration d'impulsions électriques qui provoquent des mécanismes de mort cellulaire souhaités. Des modes de réalisation de l'invention comprennent la sélection de paramètres d'impulsion pour adapter le type de mort cellulaire. Comme les mécanismes de mort cellulaire peuvent varier en fonction des paramètres d'impulsion et que la réponse immunitaire induite par électroporation est un résultat direct de la voie de la mort cellulaire provoquée, différents degrés d'immunogénicité et d'infiltration de cellules immunitaires peuvent être sélectionnées avec différents protocoles d'impulsion. Des modes de réalisation de la présente invention comprennent des procédés conçus pour sélectionner des protocoles d'impulsion afin de réaliser un mécanisme de mort cellulaire et une réponse immunitaire souhaitée. Dans certains modes de réalisation, un utilisateur peut choisir de provoquer des résultats spécifiques en matière de mort cellulaire par application et dynamique souhaitée d'infiltration immunitaire après traitement. Par exemple, dans la plupart des applications oncologiques, les cliniciens chercheront à utiliser les paramètres de traitement qui produisent la plus forte stimulation immunitaire.
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