Enhancement of peak intensity of tumor treatment field by interleaved cooling periods

Abstract

An AC electric field (e.g., a TT field) may be induced in a target region within a subject by applying a series of AC pulses between electrode elements disposed on or within the subject's body during each of a plurality of first time intervals. Immediately following each first time interval, the electrode elements are cooled. The AC pulses within any first time interval have a level of amplitude that would cause overheating if the series of pulses lasted for an hour, but each of the series of pulses does not actually last for an hour. Conversely, each of the series of pulses is short enough to avoid overheating. Interleaving cooling periods between pulse periods allows for the use of higher current pulses, and the use of these higher current pulses may advantageously improve the efficacy of the treatment.

Description

[Background technology]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 325,230, filed March 30, 2022, the entire contents of which are incorporated herein by reference.

[0002] Tumor treating fields (TT fields) are alternating electric fields in the mid-frequency range (e.g., 100-500 kHz) that inhibit the proliferation of cancer cells. This non-invasive treatment targets solid tumors and is described in U.S. Pat. No. 7,565,205, which is incorporated herein by reference in its entirety. A 200 kHz TT field has been approved by the FDA for the treatment of glioblastoma (GBM). Alternating electric fields with frequencies between 50 kHz and 1 MHz can also be used to treat conditions other than tumors. For example, as described in U.S. Pat. No. 10,967,167, which is incorporated herein by reference in its entirety, alternating electric fields, e.g., 50 kHz to 200 kHz, can increase the permeability of the blood-brain barrier (BBB), allowing, e.g., chemotherapy drugs to reach the brain. Also, as described in U.S. Pat. No. 11,103,698, which is incorporated herein by reference in its entirety, alternating electric fields, e.g., 50 kHz to 500 kHz, can increase the permeability of cell membranes, allowing larger molecules to pass through the cell membrane.

[0003] Optune® is the standard approach for delivering TT fields to living organisms. Optune® includes a field generator and two pairs of transducer arrays (i.e., electrode arrays) that are placed on the patient's shaved head. One pair of arrays (L / R) is placed on the left and right of the tumor, and the other pair of arrays (A / P) is placed in front and behind the tumor. In a preclinical setting, TT fields can also be applied in vitro, for example, using a conventional Inovitro™ TT field lab bench system. In both Optune® and Inovitro®, the field generator (a) applies an AC voltage between the L / R transducer arrays (or electrodes) for 1 second to induce an electric field in one direction through the tumor, then (b) applies an AC voltage between the A / P transducer arrays (or electrodes) for 1 second to induce an electric field in another direction through the tumor, and then repeats this two-step sequence (a) and (b) for the duration of the treatment. Summary of the Invention [Means for solving the problem]

[0004] One aspect of the present application relates to a first method of inducing an AC electric field at a target region within a subject's body, the first method including applying a series of AC pulses between at least one first electrode element and at least one second electrode element during each of a plurality of first time intervals, the at least one first electrode element and the at least one second electrode element being disposed on or within the subject's body, and allowing the at least one first electrode element and the at least one second electrode element to cool during each of a plurality of second time intervals. Each of the plurality of second time intervals immediately follows a respective one of the plurality of first time intervals. The amplitude of the AC pulses within any first time interval is of a level that would cause at least one of the first electrode elements to exceed a temperature threshold between 37° C. and 43° C. if the series of pulses continued for one hour. However, the series of pulses within each of the first time intervals is short enough to actually prevent at least one of the first electrode elements from exceeding the temperature threshold and at least one of the second electrode elements from exceeding the temperature threshold.

[0005] In some examples of the first method, each of the plurality of second time intervals is at least as long as the immediately preceding first time interval. In some examples of the first method, each of the plurality of second time intervals is at least 5 minutes. In some examples of the first method, each of the second time intervals is sufficiently long to allow for a subsequent series of AC pulses to be applied without at least one first electrode element exceeding a temperature threshold and without at least one second electrode element exceeding a temperature threshold.

[0006] In some examples of the first method, the temperature threshold is between 38° C. and 40° C. In some examples of the first method, all pulses of the alternating current within any first time interval have the same amplitude. In some examples of the first method, during each first time interval, the amplitude of the alternating current pulses increases from an initial level to a final level and then remains at the final level for the duration of the first time interval.

[0007] In some examples of the first method, the step of cooling the at least one first electrode element and the at least one second electrode element during each of a plurality of second time intervals is performed by not applying an AC pulse between the at least one first electrode element and the at least one second electrode element during the second time interval.

[0008] In some examples of the first method, the step of allowing at least one first electrode element and at least one second electrode element to cool during each of the plurality of second time intervals is performed by applying a series of second amplitude pulses of alternating current between the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals, wherein an average amplitude of each of the series of second amplitude pulses is less than half the average amplitude of the series of pulses for the immediately preceding first time interval.

[0009] In some examples of the first method, the plurality of first time intervals includes at least 100 first time intervals and the plurality of second time intervals includes at least 100 second time intervals. Optionally, in these embodiments, each of the plurality of first time intervals is at least 1 minute long, each of the plurality of second time intervals is at least 1 minute long, and each of the series of pulses includes at least 50 pulses.

[0010] Another aspect of the present application relates to a second method of inducing an AC electric field at a target region within a subject's body. The second method includes applying a series of AC pulses between at least one first electrode element and at least one second electrode element during each of a plurality of first time intervals, where the at least one first electrode element and the at least one second electrode element are disposed on or within the subject's body. The second method also includes cooling the at least one first electrode element and the at least one second electrode element during each of a plurality of second time intervals, where each of the plurality of second time intervals immediately follows each of the plurality of first time intervals. The second method includes applying a series of AC pulses between at least one third electrode element and at least one fourth electrode element during each of a plurality of third time intervals, where the at least one third electrode element and the at least one fourth electrode element are disposed on or within the subject's body. The second method also includes cooling at least one third electrode element and at least one fourth electrode element during each of a plurality of fourth time intervals, where each of the plurality of fourth time intervals immediately follows a respective one of the plurality of third time intervals. The alternating current pulses within any of the first time intervals have a first level of amplitude such that, if the series of pulses lasts for one hour, at least one first electrode element will exceed a temperature threshold between 37°C and 43°C. However, the series of pulses within each of the first time intervals is short enough to actually prevent at least one first electrode element from exceeding the temperature threshold and at least one second electrode element from exceeding the temperature threshold. Similarly, the alternating current pulses within any of the third time intervals have a second level of amplitude such that, if the series of pulses lasts for one hour, at least one third electrode element will exceed the temperature threshold. However, the series of pulses within each of the third time intervals is short enough to actually prevent at least one third electrode element from exceeding the temperature threshold and at least one fourth electrode element from exceeding the temperature threshold.

[0011] In some examples of the second method, each of the plurality of second time intervals is at least as long as the immediately preceding first time interval, and each of the plurality of fourth time intervals is at least as long as the immediately preceding third time interval.

[0012] In some examples of the second method, the amplitudes of the AC pulses in the first time interval and the AC pulses in the third time interval are independently controllable. In some examples of the second method, the amplitude of the AC pulses in the first time interval is different from the amplitude of the AC pulses in the third time interval.

[0013] In some examples of the second method, each of the plurality of second time intervals is at least 5 minutes and each of the plurality of fourth time intervals is at least 5 minutes. In some examples of the second method, each of the plurality of first time intervals is at least 10 minutes and each of the plurality of third time intervals is at least 10 minutes.

[0014] In some examples of the second method, each of the second time intervals is sufficiently long to allow a subsequent series of AC pulses to be applied without exceeding a temperature threshold of the at least one first electrode element and without exceeding a temperature threshold of the at least one second electrode element, and each of the fourth time intervals is sufficiently long to allow a subsequent series of AC pulses to be applied without exceeding a temperature threshold of the at least one third electrode element and without exceeding a temperature threshold of the at least one fourth electrode element.

[0015] In some examples of the second method, the temperature threshold is between 38° C. and 40° C. In some examples of the second method, all of the alternating current pulses within any first time interval have the same amplitude. In some examples of the second method, during each first time interval, the amplitude of the alternating current pulses increases from an initial level to a final level and then remains at the final level for the duration of the first time interval.

[0016] In some examples of the second method, each of the third time intervals overlaps with a corresponding first time interval. In some examples of the second method, each of the third time intervals is mutually exclusive with all of the first time intervals, and each of the first time intervals is mutually exclusive with all of the third time intervals.

[0017] In some examples of the second method, cooling the at least one first electrode element and the at least one second electrode element during each of a plurality of second time intervals is performed by not applying an AC pulse between the at least one first electrode element and the at least one second electrode element during the second time interval, and cooling the at least one third electrode element and the at least one fourth electrode element during each of a plurality of fourth time intervals is performed by not applying an AC pulse between the at least one third electrode element and the at least one fourth electrode element during the fourth time interval.

[0018] In some examples of the second method, the step of cooling the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals is carried out by applying a series of second amplitude pulses of alternating current between the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals, wherein an average amplitude of each series of second amplitude pulses is less than half of an average amplitude of the series of pulses in a preceding first time interval, and the step of cooling the at least one third electrode element and the at least one fourth electrode element during each of the plurality of fourth time intervals is carried out by applying a series of fourth amplitude pulses of alternating current between the at least one third electrode element and the at least one fourth electrode element during each of the plurality of fourth time intervals, wherein an average amplitude of each series of fourth amplitude pulses is less than half of an average amplitude of the series of pulses in a preceding third time interval.

[0019] In some examples of the second method, the plurality of first time intervals includes at least 100 first time intervals, the plurality of second time intervals includes at least 100 second time intervals, the plurality of third time intervals includes at least 100 third time intervals, and the plurality of fourth time intervals includes at least 100 fourth time intervals. Optionally, in these embodiments, each of the plurality of first time intervals is at least 1 minute long, each of the plurality of second time intervals is at least 1 minute long, each of the plurality of third time intervals is at least 1 minute long, and each of the plurality of fourth time intervals is at least 1 minute long, and each of the series of pulses includes at least 50 pulses.

[0020] Another aspect of the invention relates to a first device for inducing an alternating electric field at a target region within a subject's body. The first device includes a pulse generator and a controller. The pulse generator is configured to generate a series of alternating pulses between a first output terminal and a second output terminal, the amplitudes of which vary depending on a state of at least one control input. The controller is configured to send a signal to the at least one control input to cause the pulse generator to output a pulse having a first amplitude between the first output terminal and the second output terminal during each of a plurality of first time intervals. The controller is further configured to send a signal to the at least one control input to cause the pulse generator to output a pulse having a first amplitude between the first output terminal and the second output terminal during each of a plurality of second time intervals immediately following each of the plurality of first time intervals, the controller being further configured to send a signal to the at least one control input to cause the pulse generator to output a pulse having a second amplitude between the first output terminal and the second output terminal during each of a plurality of second time intervals, the second amplitude being less than half of the first amplitude, during each of a plurality of second time intervals immediately following each of the plurality of first time intervals. The controller is further configured to receive at least one first input signal from the at least one first temperature sensor and at least one second input signal from the at least one second temperature sensor, the plurality of first time intervals including at least ten first time intervals, the plurality of second time intervals including at least ten second time intervals, each of the plurality of first time intervals being at least one minute long, each of the plurality of second time intervals being at least one minute long, and each of the series of pulses including at least ten pulses.

[0021] In some embodiments of the first device, the controller is further configured to adjust the first amplitude during each of a plurality of first time intervals based on the at least one first input signal and the at least one second input signal. In some embodiments of the first device, each of the plurality of second time intervals is at least 5 minutes long. In some embodiments of the first device, the controller is further configured to terminate a predetermined first time interval based on the at least one first input signal and the at least one second input signal. In some embodiments of the first device, the controller is further configured to terminate a predetermined second time interval based on the at least one first input signal and the at least one second input signal.

[0022] Another aspect of the invention relates to a second device for inducing an alternating electric field at a target region within a subject's body. The second device includes a pulse generator and a controller. The pulse generator is configured to generate a series of alternating pulses between a first output terminal and a second output terminal, the amplitudes of which vary depending on a state of at least one control input. The controller is configured to send a signal to the at least one control input such that the pulse generator outputs a pulse having a first amplitude between the first output terminal and the second output terminal during each of a plurality of first time intervals. The controller is further configured to send a signal to the at least one control input such that, during each of a plurality of second time intervals immediately following each of the plurality of first time intervals, (i) the pulse generator does not output a pulse during each of the plurality of second time intervals, or (ii) the pulse generator outputs a pulse having a second amplitude between the first output terminal and the second output terminal during each of a plurality of second time intervals, the second amplitude being less than half of the first amplitude. The controller is further configured to receive at least one first input signal from the at least one first temperature sensor and at least one second input signal from the at least one second temperature sensor, the plurality of first time intervals including at least ten first time intervals, the plurality of second time intervals including at least ten second time intervals, each of the plurality of first time intervals being at least one minute long, each of the plurality of second time intervals being at least one minute long, and each of the series of pulses including at least ten pulses.

[0023] In the second device, the pulse generator is further configured to generate a series of alternating current pulses between the third output terminal and the fourth output terminal, the pulses having different amplitudes depending on the state of the at least one control input. The controller is further configured to send a signal to the at least one control input causing the pulse generator to output a pulse having a third amplitude between the third output terminal and the fourth output terminal during each of a plurality of third time intervals. The controller is further configured to send, during each of a plurality of fourth time intervals immediately following each of the plurality of third time intervals, a signal to the at least one control input causing the pulse generator to (i) not output a pulse during each of the plurality of fourth time intervals, or (ii) send a signal to the at least one control input causing the pulse generator to output a pulse having a fourth amplitude between the third output terminal and the fourth output terminal during each of the plurality of fourth time intervals, the fourth amplitude being less than half of the third amplitude. The controller is further configured to receive at least one third input signal from the at least one third temperature sensor and at least one fourth input signal from the at least one fourth temperature sensor. The plurality of third time intervals includes at least 10 third time intervals. The plurality of fourth time intervals includes at least 10 fourth time intervals. Each of the plurality of third time intervals is at least one minute long and each of the plurality of fourth time intervals is at least one minute long.

[0024] In some embodiments of the second device, the controller is further configured to adjust the first amplitude during each of the plurality of first time intervals based on the at least one first input signal and the at least one second input signal, and to adjust the third amplitude during each of the plurality of third time intervals based on the at least one third input signal and the at least one fourth input signal.

[0025] In some embodiments of the second device, the controller is further configured to terminate a given first time interval based on the at least one first input signal and the at least one second input signal, and to terminate a given third time interval based on the at least one third input signal and the at least one fourth input signal.

[0026] In some embodiments of the second device, the controller is further configured to terminate a given second time interval based on the at least one first input signal and the at least one second input signal, and to terminate a given fourth time interval based on the at least one third input signal and the at least one fourth input signal.

[0027] Some embodiments of the second device further include at least one first electrode element wired to the first output terminal, at least one second electrode element wired to the second output terminal, at least one third electrode element wired to the third output terminal, and at least one fourth electrode element wired to the fourth output terminal.

[0028] Optionally, in the embodiment described in the previous paragraph, the first temperature sensor includes a first thermistor in thermal contact with the at least one first electrode element, the second temperature sensor includes a second thermistor in thermal contact with the at least one second electrode element, the third temperature sensor includes a third thermistor in thermal contact with the at least one third electrode element, and the fourth temperature sensor includes a fourth thermistor in thermal contact with the at least one fourth electrode element. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is a schematic diagram of how a conventional Optune® system keeps the temperature of the electrode array below a safety threshold. [Figure 2A] FIG. 1 shows the results of an experiment measuring the peak current of AC pulses of six different shapes. [Figure 2B] FIG. 1 shows the results of an experiment measuring the cytotoxicity of six different AC pulse shapes. [Diagram 3] FIG. 1 is a block diagram of an embodiment in which a set of transducer arrays can be driven with alternating current pulses having an amplitude profile as described herein. [Figure 4] FIG. 4 shows an example of an amplitude profile of the L / R and A / P channels that can be implemented using the embodiment of FIG. 3 to generate alternating high current pulses interspersed with cooling periods. [Diagram 5] FIG. 5 is a detailed visualization of what the individual pulses of the alternating current look like during the time interval i1 / i3 in the embodiment of FIG. 4. [Figure 6] FIG. 11 shows another example of amplitude profiles for the L / R and A / P channels that can be implemented using the embodiment of FIG. 3, where high current pulses of alternating current are generated interleaved with cooling periods. [Figure 7] FIG. 7 is a detailed visualization of what the individual alternating current pulses of the L / R channels look like during time interval i1 of the embodiment of FIG. 6. [Figure 8] FIG. 11 shows yet another example of amplitude profiles for the L / R and A / P channels that can be implemented using the embodiment of FIG. 3, where high current pulses of alternating current are generated interleaved with cooling periods. [Figure 9] FIG. 13 shows an example of an amplitude profile that can be implemented using a unidirectional embodiment, where high current pulses of alternating current are generated interleaved with cooling periods. [Figure 10] FIG. 13 illustrates another example of an amplitude profile that can be implemented using a unidirectional embodiment to generate alternating high current pulses alternating with cooling periods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Various embodiments are described in detail below with reference to the accompanying drawings, in which like reference numerals represent like elements, and in which:

[0031] When using TT fields to treat a subject, there is a strong correlation between higher field strength and greater therapeutic effect, and increasing the field strength requires increasing the current applied to the electrode array. However, the current cannot be simply increased to any level, because increasing the current will heat up the electrode array. Also, the temperature of the electrode array must not exceed a safety threshold.

[0032] FIG. 1 is a schematic diagram of how a conventional Optune® system adjusts the current of the AC pulses applied to the electrode arrays to keep the temperature of the electrode arrays below a safety threshold. Specifically, when the system is first powered on, an initial current level (e.g., 0.5 amps) of AC pulses is output. The system then gradually increases the current of the AC pulses from the initial level while continuously monitoring the temperature at all four electrode arrays (using multiple thermistors located on each of the four electrode arrays) until the hottest array approaches a predetermined temperature threshold (e.g., 39° C.). In the example of FIG. 1, the left / right electrode arrays are hotter than the front / back electrode arrays, so the temperature of the left / right arrays becomes the limiting factor.

[0033] When the hottest array approaches the temperature threshold (i.e., at t=15 in the example of Figure 1, when the current of each pulse is approximately 1.1 A), the system stops increasing the AC pulse current (i.e., keeps it at a constant level) and continues to monitor the temperature of all four electrode arrays. At some point, when the temperature of the hottest array reaches the temperature threshold (e.g., t=25 in the example of Figure 1), the system reduces the AC pulse current to keep the temperature of all electrode arrays below the temperature threshold.

[0034] Similar to Optune®, the Inovitro™ TT field lab bench system automatically adjusts the AC current applied to the electrodes to keep the sample dish at 37°C. Figures 2A and 2B show the results of experiments performed using an Inovitro™ system modified to apply AC pulses of different shapes to a sample dish containing U87 cells. For each AC pulse of different shapes, we ascertain (1) the peak current that was used when the temperature stabilized at 37°C and (2) the cytotoxicity. In these experiments, the TT field is applied as follows: (a) AC current is applied to the L / R electrodes for 1 second or a fraction thereof, (b) AC current is applied to the A / P electrodes for 1 second or a fraction thereof, and the two-step sequence (a) and (b) are repeated for the duration of the experiment, which lasts 120 hours.

[0035] Figure 2A shows the peak current for each of the different shaped AC pulses. Bar #1 represents the control not treated with a TT field. Bar #2 represents the peak current when the AC current instantly jumped from zero to a peak at the beginning of each 1 second interval and instantly jumped from a peak to zero at the end of each 1 second interval. Bar #3 represents the peak current when the AC current rose from zero to a peak in the first 50 milliseconds of each 1 second interval and fell from a peak to zero in the last 50 milliseconds of each 1 second interval. This means that the AC current maintained its peak value for 900 milliseconds every 1 second interval. Bar #4 represents the peak current when the AC current rose from zero to a peak in the first 100 milliseconds of each 1 second interval and fell from a peak to zero in the last 100 milliseconds of each 1 second interval. This means that the AC current maintained its peak value for 800 milliseconds every 1 second interval.

[0036] Bar #5 represents the peak current when the AC current rises from zero to a peak in the first 300 milliseconds of each 1-second interval and then falls from the peak to zero in the last 300 milliseconds of each 1-second interval. This means that the AC current maintained its peak value for 400 milliseconds during each 1-second interval. Bar #6 represents the peak current when the AC current rises from zero to a peak in the first 350 milliseconds of each 1-second interval and then falls from the peak to zero in the last 350 milliseconds of each 1-second interval. This means that the AC current maintained its peak value for 300 milliseconds during each 1-second interval. Bar #7 represents the peak current when the AC current rises from zero to a peak in the first 400 milliseconds of each 1-second interval and then falls from the peak to zero in the last 400 milliseconds of each 1-second interval. This means that the AC current maintained its peak value for 200 milliseconds during each 1-second interval.

[0037] Figure 2B shows the cytotoxicity results obtained for different shapes of AC pulses. Each numbered bar in Figure 2B corresponds to a numbered bar in Figure 2A. In particular, the best cytotoxicity results were obtained for bars #6 and #7.

[0038] Additional experiments similar to those described above in relation to Figure 2A / Figure 2B were performed with U87 and 118 cell lines, totalling 6 experiments with a total of 231 dishes. Causal analysis revealed a Pearson correlation coefficient of 0.78 between peak current and cytotoxicity, and a Pearson correlation coefficient of 0.25 between rise / fall times and cytotoxicity for AC pulses of different shapes. From this data, it is reasonable to conclude that TT fields with higher peak currents applied for shorter time fractions are more effective than TT fields with lower peak currents applied for longer time fractions.

[0039] As explained above, conventional Optune® systems generate a series of AC pulses and select current levels for the AC pulses that do not overheat any of the electrode array (i.e., do not exceed a predetermined temperature threshold) even if the series of AC pulses continues indefinitely.

[0040] On the other hand, the embodiments described below exploit the conclusion that a TT field of higher peak current applied for a shorter time rate is more effective than a TT field of lower peak current applied for a longer time rate. More specifically, the embodiments described below set the current of the AC pulses at a level such that at least one electrode element exceeds the temperature threshold if the series of pulses continues for one hour. The reason these embodiments do not overheat when the current is set at this level is that the series of pulses is not allowed to continue for one hour. Instead, each series of AC pulses ends before any electrode element exceeds the temperature threshold and is immediately followed by a cooling period (a period during which the temperature of the electrode elements decreases). Only after the temperature has sufficiently decreased does the subsequent series of high current AC pulses begin.

[0041] FIG. 3 is a block diagram of an embodiment in which a set of transducer arrays 10 can be driven with alternating current pulses having an amplitude profile described herein. The system includes an alternating signal generator 20 designed to generate a first alternating output and a second alternating output at frequencies between 50 kHz and 1 MHz. When using the system to apply a TT field to a part of a human body (as shown in FIG. 3), the first alternating output is applied to a first pair of electrodes 10L and 10R located to the left and right of the tumor, and the second alternating output is applied to a second pair of electrodes 10A and 10P located in front and behind the tumor. The alternating signal generator 20 can also be used to apply a TT field to an in vitro culture (not shown) by applying the first alternating output to electrodes located on the left and right walls of an Inovitro® dish and the second alternating output to electrodes located on the front and back walls of the Inovitro® dish. In either case, the voltage generated by the alternating signal generator 20 should be high enough to drive a current that induces an electric field of at least 1 V / cm in at least some of the cancer cells. In some embodiments, the voltage generated by the AC signal generator 20 drives a current that induces an electric field of 1 V / cm to 10 V / cm in at least some of the cancer cells. In some embodiments, the voltage generated by the AC signal generator 20 is at least 75 VRMS.

[0042] The AC signal generator 20 is configured to generate a first AC output and a second AC output having independently controllable amplitudes depending on the state of at least one control input. The controller 30 continuously transmits control signals to the at least one control input, which control signals are configured to cause the first AC output and the second AC output to generate signals having an amplitude profile as described herein. Although the controller 30 and the AC signal generator 20 are shown as two separate blocks in FIG. 3, these two blocks may be integrated into a single hardware device.

[0043] The details of the construction of the controller 30 and the nature of the control signals vary depending on the design of the AC signal generator 20. In one example, the design of the AC signal generator 20 is similar to the AC signal generator described in U.S. Patent No. 9,910,453, the contents of which are incorporated herein by reference. This particular AC signal generator has two output channels, i.e., a first channel for L / R and a second channel for A / P. The instantaneous AC output voltage of either channel depends on the instantaneous output voltage of a DC-DC converter, which is controlled by writing control words to a digital-to-analog converter (DAC) with an update rate of, for example, 1 ms.

[0044] The controller 30 receives at least one first input signal from at least one first thermistor disposed in contact with at least one first electrode element, at least one second input signal from at least one second thermistor disposed in contact with at least one second electrode element, at least one third input signal from at least one third thermistor disposed in contact with at least one third electrode element, and at least one fourth input signal from at least one fourth thermistor disposed in contact with at least one fourth electrode element. By processing the first to fourth input signals, the controller can monitor the temperature of each electrode element and control the current to prevent overheating of the electrode elements. One example of a suitable approach for performing temperature measurements is the conventional approach used in Optune®. Another example is described in U.S. Pat. No. 11,097,101, which is incorporated herein by reference.

[0045] FIG. 4 shows an example of an amplitude profile for the L / R and A / P channels that can be implemented using the embodiment of FIG. 3 to generate alternating high current pulses alternating with cooling periods, and also shows the corresponding temperature plots for these two channels.

[0046] In the example of Figure 4, both the L / R and A / P channels begin operation with a conventional Optune® system between t=0 and t=25 minutes, as described above in connection with Figure 1. However, instead of stabilizing the current at a level that avoids overheating (e.g., approximately 1.1 A as described above in connection with Figure 1), the system does not apply an AC pulse for a period of time (e.g., between 25 and 35 minutes in Figure 4), which allows the electrode array to cool down (as can be seen in both temperature plots).

[0047] After a sufficient amount of cooling has occurred, the AC pulses are again initiated during time interval i1 / i3 in response to a command issued by the controller 30. During this time interval, the controller 30 instructs the AC signal generator 20 to apply a series of AC pulses between at least one first electrode element 10L and at least one second electrode element 10R, and also to apply a series of AC pulses between at least one third electrode element 10A and at least one fourth electrode element 10P. The AC pulses applied to 10L / 10R within time interval i1 have a first level of amplitude that would cause at least one first electrode element 10L to exceed a temperature threshold if the series of pulses continued for one hour (although the 1.5A amplitude of the L / R channels is higher than the 1.1A amplitude used between t=15 and t=25, and the temperature of electrode elements 10L / 10R has increased during time interval i1). However, it is important to note that the series of pulses is "not allowed" to continue for one hour. Instead, the controller 30 ensures that the series of AC pulses within time interval i1 is short enough to prevent electrode elements 10L and 10R from exceeding the temperature threshold.

[0048] The situation is similar for the AC pulses applied to 10A / 10P during time interval i3, except that in the illustrated example, the amplitude of the A / P channel is 1.7 A. Note that the current applied to the A / P channel can be set independently of the current applied to the L / R channels, and each of these currents is set to a level of amplitude that would cause overheating if the series of AC pulses continued for an hour.

[0049] Since the series of AC pulses within time interval i1 / i3 must be short enough to prevent electrode elements 10L / 10R / 10A / 10P from exceeding a temperature threshold, controller 30 issues a command to stop the series of high current AC pulses applied to electrode elements 10L / 10R and to stop the series of high current AC pulses applied to electrode elements 10A / 10P before overheating occurs (t=40 in the example of FIG. 4). The decision to stop the series of high current pulses can be based on the temperature reaching a threshold (e.g., 37° C., 38° C., 39° C., 40° C., 41° C.), optionally with a maximum time (e.g., after 2, 5, 7, or 10 minutes).

[0050] i2 / i4 is the time interval immediately following i1 / i3 after the series of high current AC pulses has stopped, during which the controller 30 cools down the electrode elements 10L / 10R / 10A / 10P. (Note that in the example of FIG. 4, the temperature drops from t=40 to t=50.) The time interval i2 / i4 is long enough to allow a subsequent series of AC pulses to be applied without the electrode elements 10L / 10R / 10A / 10P exceeding the temperature threshold. The controller 30 can decide to resume the next series of high current pulses based on the temperature of the electrode elements 10L / 10R / 10A / 10P reaching a lower threshold (e.g., 34° C., 35° C., 36° C.), optionally after a minimum cooling time (e.g., 2, 5, 6, 8, or 10 minutes). Alternatively, the time interval i2 / i4 can be a fixed time interval (eg, 5, 6, 8, or 10 minutes).

[0051] After time interval i2 / i4 has expired, the system alternates between the conditions described above in relation to time interval i1 / i3 (where AC pulses are applied to the electrode elements) and the conditions described above in relation to time interval i2 / i4 (where the electrode elements are cooled down). The controller 30 coordinates this alternation by repeating the commands described above in relation to these time intervals.

[0052] The embodiment of Figure 3 or Figure 4 has a significant advantage over conventional Optune® systems in that the peak current of the AC pulses of the embodiment of Figure 3 or Figure 4 is higher than that of Optune®. Also, as explained above in connection with Figures 2A-2B, a TT field with a higher peak current is more efficient than a TT field with a lower peak current, even when the latter is applied for a greater proportion of the available time.

[0053] It is important to note that the current amplitude traces in Figure 4 represent the amplitude of pulses of alternating current generated during a particular time interval. For example, in the example shown in Figure 4, during the interval of time i1, the magnitude of each AC pulse in the L / R channel is 1.5 A, and during the interval of time i3, the magnitude of each AC pulse generated in the A / P channel is 1.7 A. Because the time scale in Figure 4 is very long (i.e., 60 minutes), and each individual pulse may be on the order of a second in duration, there may be hundreds of AC pulses within any interval such as i1 / i3.

[0054] FIG. 5 is a detailed visualization of what the magnitude of each AC pulse is during the interval of time i1 / i3 in the embodiment of FIG. 3 or FIG. 44. In this FIG. 5 example, the top trace shows the magnitude of the first two AC pulses in a series of pulses generated every 2 seconds in the L / R channel, with a peak current of 1.5 A and relatively slow rise and fall times. Similarly, the bottom trace shows the magnitude of the first two AC pulses in a series of pulses generated every 2 seconds in the A / P channel, with a peak current of 1.7 A and relatively slow rise and fall times. (FIG. 5 does not show the sinusoidal waveforms in the AC pulses, because the time scale of a 50 kHz to 1 MHz sinusoidal waveform is an order of magnitude smaller than the time scale of FIG. 5.) Notably, in the example shown in FIG. 5, the pulses in the L / R channel and the pulses in the A / P channel are out of phase with each other. Note that FIG. 5 is merely an illustrative example, and all of the parameters of these pulses, such as pulse repetition time, pulse width, rise time, fall time, etc., can be changed.

[0055] Returning to FIG. 3 or FIG. 4, in some embodiments, each of the multiple cool-down intervals i2 / i4 (i.e., 10 minutes in the example shown in FIG. 4) is at least as long as the immediately preceding pulse generation interval i1 / i3 (i.e., 5 minutes in the example shown in FIG. 4). In some embodiments, each of the multiple cool-down intervals is 1 to 2 times as long as the immediately preceding pulse generation interval. In some embodiments, each of the multiple cool-down intervals is 1.5 to 2.5 times as long as the immediately preceding pulse generation interval. In some embodiments, each of the multiple cool-down intervals is 2 to 3 times as long as the immediately preceding pulse generation interval.

[0056] In some embodiments, the AC pulse of the L / R channel in time interval i1 and the AC pulse of the A / P channel in time interval i3 have independently controllable amplitudes. In some embodiments, the AC pulse of the L / R channel in time interval i1 and the AC pulse of the A / P channel in time interval i3 have different amplitudes. In some embodiments, the AC pulse of the L / R channel in time interval i1 and the AC pulse of the A / P channel in time interval i3 have the same amplitude.

[0057] In some embodiments, each of the cooling intervals i2 / i4 is at least 5 minutes. In other embodiments, each of the cooling intervals i2 / i4 is at least 2, 6, 8, or 10 minutes.

[0058] In some embodiments, all pulses of alternating current of the L / R channels within any particular one of the time intervals i1 have the same amplitude. In other embodiments, during each time interval i1, the amplitude of the alternating current pulse increases from an initial level to a final level (e.g., using a linear increase profile, an exponential increase profile, or an increase profile of a different shape), and then remains at the final level for the duration of the first time interval.

[0059] In some embodiments, including the example shown in Figure 4, no AC pulses are applied to the L / R or A / P channels during the cool-down interval of time i2 / i4. Alternatively, low current pulses (i.e., AC pulses having an average amplitude less than half the average amplitude of the AC pulses generated during the interval of time i1 / i3) may be applied during the cool-down interval of time i2 / i4.

[0060] In the example shown in FIG. 4, time interval i3 (the time when AC pulses are generated in the A / P channels) overlaps with time interval i1 (the time when AC pulses are generated in the L / R channels).

[0061] In some embodiments, there are at least 10 first time intervals i1, at least 10 second time intervals i2, at least 10 third time intervals i3, and at least 10 fourth time intervals i4. In these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least 1 minute long, and each series of pulses includes at least 10 pulses. In some embodiments, there are at least 100 first time intervals i1, at least 100 second time intervals i2, at least 100 third time intervals i3, and at least 100 fourth time intervals i4. Optionally, in these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least 1 minute long, and each series of pulses includes at least 50 pulses. Optionally, in these embodiments, each of the first and third time intervals i1, i3 is independently at least 2, 3, 4, or 5 minutes long, and each of the series of pulses within those intervals includes at least 100, 150, 200, or 250 pulses. Optionally, in these embodiments, each of the second and fourth time intervals i2, i4 is independently at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes long, and each of the series of pulses within those intervals includes at least 100, 150, 200, 250, 300, 350, 400, 450, or 500 low current pulses, or no pulses at all.

[0062] Figure 6 shows another example of L / R and A / P channel amplitude profiles that can be implemented using the embodiment of Figure 3 to generate alternating high current pulses that are alternating with cooling periods, along with corresponding temperature plots for these two channels. This embodiment is similar to the embodiment of Figure 4 above, except that the A / P channel alternating high current pulses are shifted to different time slots. The first 35 minutes of this Figure 6 example are the same as the example of Figure 4 above.

[0063] After a sufficient amount of cooling has occurred, the AC pulses are started again during a time interval i1 in response to a command issued by the controller 30. During this time interval, the AC signal generator 20 applies a series of AC pulses between at least one first electrode element 10L and at least one second electrode element 10R. The AC pulses applied to 10L / 10R during the time interval i1 have a first level of amplitude such that if the series of pulses lasts for one hour, at least one first electrode element 10L will exceed the temperature threshold. However, it is important to note that the series of pulses cannot last for one hour. Instead, the series of AC pulses during the time interval i1 is in fact short enough to prevent the electrode elements 10L and 10R from exceeding the temperature threshold.

[0064] Since the series of AC pulses within time interval i1 must be short enough to keep electrode elements 10L / 10R from exceeding a temperature threshold, controller 30 issues a command to stop the series of high current AC pulses applied to electrode elements 10L / 10R before overheating occurs (t=40 in the example of FIG. 6). The decision to stop the series of high current AC pulses can be based on the temperature reaching a threshold (e.g., 37° C., 38° C., 39° C., 40° C., or 41° C.), and can optionally be set to a maximum time (e.g., after 2, 5, 7, or 10 minutes).

[0065] i2 is the time interval immediately following i1 after the series of high current AC pulses has stopped, during which the controller 30 cools down the electrode elements 10L / 10R. (Note that in the example of FIG. 6, the temperature of the L / R channels drops from t=40 to t=50.) The time interval i2 is long enough to allow the next series of AC pulses to be applied without the electrode elements 10L / 10R exceeding the temperature threshold. The controller 30 can decide to resume the next series of high current AC pulses, optionally after a minimum cooling time (e.g., 2, 5, 6, 8, or 10 minutes), based on the temperature of the electrode elements 10L / 10R reaching a lower threshold (e.g., 34° C., 35° C., or 36° C.).

[0066] After time interval i2 has expired, the system alternates between the conditions described above in relation to time interval i1 (where AC pulses are applied to the electrode elements) and the conditions described above in relation to time interval i2 (where the electrode elements are cooled down). Controller 30 coordinates this alternation by repeating the commands described above in relation to these time intervals.

[0067] The embodiments of Figures 3 or 6 have a significant advantage over conventional Optune® systems in that the peak current of the AC pulses of the embodiments of Figures 3 or 6 is higher than that of Optune®. Also, as explained above in connection with Figures 2A-2B, a TT field with a higher peak current is more efficient than a TT field with a lower peak current, even when the latter is applied for a greater proportion of the available time.

[0068] Similar to the situation described above in relation to FIG. 4, the current amplitude trace in FIG. 6 represents the amplitude of the pulses of alternating current generated during a particular time interval. FIG. 7 is a detailed visualization of what the amplitudes of the individual alternating current pulses in the L / R channels look like during time interval i1 in the embodiment of FIG. 3 or FIG. 6. In this example of FIG. 7, the trace shows the amplitude of the first two alternating current pulses, with a peak current of 1.5 A and relatively slow rise and fall times, of a series of pulses generated every 2 seconds in the L / R channels. (FIG. 7 does not show the sinusoidal waveforms within any pulse of alternating current, because the time scale of a sinusoidal waveform from 50 kHz to 1 MHz is orders of magnitude smaller than the time scale of FIG. 7.) It should be noted that FIG. 7 shows only one example, and all parameters of these pulses, such as pulse repetition time, pulse width, rise time, fall time, etc., can be changed.

[0069] The operation of the A / P channel in this FIG. 6 embodiment is similar to that of the L / R channel, except that the high current AC pulse in the A / P channel is offset in time so that it is not generated simultaneously with the high current AC pulse in the L / R channel, and the current in the A / P channel is 1.7 A.

[0070] Returning to FIG. 3 or FIG. 6, in some embodiments, each of the multiple cool-down intervals i2, i4 (i.e., 10 minutes in the example shown in FIG. 6) is at least as long as the immediately preceding pulse generation interval i1, i3 (i.e., 5 minutes in the example shown in FIG. 6). In some embodiments, each of the multiple cool-down intervals is 1 to 2 times as long as the immediately preceding pulse generation interval. In some embodiments, each of the multiple cool-down intervals is 1.5 to 2.5 times as long as the immediately preceding pulse generation interval. In some embodiments, each of the multiple cool-down intervals is 2 to 3 times as long as the immediately preceding pulse generation interval.

[0071] In some embodiments, the AC pulse of the L / R channel in time interval i1 and the AC pulse of the A / P channel in time interval i3 have independently controllable amplitudes. In some embodiments, the AC pulse of the L / R channel in time interval i1 and the AC pulse of the A / P channel in time interval i3 have different amplitudes. In some embodiments, the AC pulse of the L / R channel in time interval i1 and the AC pulse of the A / P channel in time interval i3 have the same amplitude.

[0072] In some embodiments, each of the cooling intervals i2, i4 is at least 5 minutes. In other embodiments, each of the cooling intervals i2 / i4 is at least 2, 6, 8, or 10 minutes.

[0073] In some embodiments, all of the alternating pulses of the L / R channels within any one of the time intervals i1 have the same amplitude. In other embodiments, during each of the time intervals i1, the amplitude of the alternating pulses rises from an initial level to a final level and then remains at the final level for the duration of the first time interval.

[0074] In some embodiments, including the example shown in Figure 6, no AC pulses are applied to the L / R or A / P channels during the cool-down intervals of times i2, i4. Alternatively, low current pulses (i.e., AC pulses having an average amplitude less than half the average amplitude of the AC pulses generated during time intervals i1, i3) can be applied during the cool-down intervals of time intervals i2, i4.

[0075] As noted above, in the embodiment of Figure 6, the high current pulses of the AC current in the A / P channel are shifted to different time slots compared to the embodiment of Figure 4. In some embodiments (including the example shown in Figure 6), each of the third time intervals i3 is mutually exclusive with every first time interval i1, and each of the first time intervals i1 is mutually exclusive with every third time interval i3.

[0076] In some embodiments, there are at least 10 first time intervals i1, at least 10 second time intervals i2, at least 10 third time intervals i3, and at least 10 fourth time intervals i4. In these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least 1 minute long, and each series of pulses includes at least 10 pulses. In some embodiments, there are at least 100 first time intervals i1, at least 100 second time intervals i2, at least 100 third time intervals i3, and at least 100 fourth time intervals i4. Optionally, in these embodiments, each of the first, second, third, and fourth time intervals i1-i4 is at least 1 minute long, and each series of pulses includes at least 50 pulses. Optionally, in these embodiments, each of the first and third time intervals i1, i3 is independently at least 2, 3, 4, or 5 minutes long, and each of the series of pulses within those intervals includes at least 100, 150, 200, or 250 pulses. Optionally, in these embodiments, each of the second and fourth time intervals i2, i4 is independently at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes long, and each of the series of pulses within those intervals includes at least 100, 150, 200, 250, 300, 350, 400, 450, or 500 pulses, or no pulses at all.

[0077] It should be noted that in the examples shown in Figures 4 and 6, each second time interval i2 (i.e., cooling interval) is shown to be longer than the immediately preceding first time interval i1 (where a series of AC pulses is applied between the first electrode elements and to the second electrode elements), and each fourth time interval i4 (i.e., cooling interval) is shown to be longer than the immediately preceding third time interval i3 (where a series of AC pulses is applied between the third electrode elements and to the fourth electrode elements). However, this is not necessarily the case in all embodiments. Instead, each second time interval i2 may be shorter than the immediately preceding first time interval i1, and each fourth time interval i4 may be shorter than the immediately preceding third time interval i3.

[0078] An example of this situation is shown in FIG. 8, where each first time interval i1 and each third time interval i3 is 10 minutes long, and each second time interval i2 and each fourth time interval i4 is 5 minutes long. Notably, in this timing relationship, at least one channel (i.e., L / R or A / P) always operates at peak current (see FIG. 8). It should be noted that FIG. 8 shows only one example of potential durations of the first through fourth time intervals i1-i4, which durations can vary. In one preferred variation of the situation shown in FIG. 8, each first time interval i1 and each third time interval i3 is 15 minutes long, and each second time interval i2 and each fourth time interval i4 is 10 minutes long. In a second preferred variation of the situation shown in FIG. 8, each first time interval i1 and each third time interval i3 is 30 minutes long, and each second time interval i2 and each fourth time interval i4 is 15 minutes long. In any of these preferred timing relationships, at least one channel (ie, L / R or A / P) always operates at peak current.

[0079] In vivo experimental data revealed that the second preferred variation of the situation shown in FIG. 8 provides higher currents in both channels simultaneously than the conventional approach used in Optune®. More specifically, when using the second preferred approach in mice, at least one of the channels operated at a current above 90 mA 80.2% of the time. Meanwhile, when using the conventional approach in mice, at least one of the channels operated at a current above 90 mA 55.5% of the time. Furthermore, the average current using the second preferred approach was 17.45% higher than the prior art approach in one in vivo experiment in mice and 20.9% higher in another in vivo experiment in mice.

[0080] If the first and third time intervals i1, i3 are longer than the second and fourth time intervals i2, i4, the visualization of the magnitude of the individual pulses of the alternating current will be different depending on whether one or both channels are active at any given time. For example, in FIG. 8, only the L / R channel is active between t=35 and t=40, so the magnitude of the individual pulses of the alternating current in that time interval resembles the situation shown in FIG. 7. On the other hand, in FIG. 8, both channels are active between t=40 and t=45, so the magnitude of the individual pulses of the alternating current in that time interval resembles the situation shown in FIG. 5. It should be noted that FIGS. 5 and 7 respectively only show illustrative examples, and all parameters of these pulses, such as pulse repetition time, pulse width, rise time, fall time, etc., can be changed.

[0081] In the embodiments described above in relation to Figures 3-8, an alternating electric field is applied to the subject's body (or in vitro dish) using two pairs of electrode elements. One pair is placed to the left and right of the target area, and the second pair is placed in front and behind the target area. This configuration is advantageous in many situations, especially when the alternating electric field has a directional effect (such as in the case of a TT field). However, in other situations, an alternating electric field applied in only one direction may be sufficient. These situations include, for example, using an alternating electric field to increase the permeability of the blood-brain barrier of a subject. The hardware for these unidirectional embodiments is similar to that shown in Figure 3, except that the L / R and one of the A / P channels shown in Figure 3 are omitted.

[0082] FIG. 9 shows an example of an amplitude profile that can be implemented using this unidirectional embodiment to generate alternating high current pulses alternating with cooling periods, along with the corresponding temperature plot for a single channel. The operation of the single channel is similar to that of the L / R channel described above in connection with FIG. 4. This FIG. 9 embodiment has a significant advantage over conventional Optune® systems in that the peak current of the AC pulses is higher than that of Optune®. Also, as described above in connection with FIGS. 2A-2B, a TT field with a higher peak current is more effective than a TT field with a lower peak current, even when the latter is applied for a greater percentage of the available time.

[0083] FIG. 10 shows another example of an amplitude profile that can be implemented using this unidirectional embodiment, which generates alternating high current pulses alternating with cooling periods, and also shows the corresponding temperature plot of a single channel. This example is similar to the example of FIG. 9, except that not all AC pulses of the L / R channels in any time interval i1 have the same amplitude. Instead, during each time interval i1, the amplitude of the AC pulse increases from an initial level to a final level (e.g., using a linear increase profile as shown, or another increase profile, including but not limited to a logarithmic or exponential increase profile), and then remains at the final level for the duration of the time interval i1. Optionally, the amplitude of the AC pulse can also be decreased before the end of any time interval i1 / i3.

[0084] It should be noted that although the increase within each of the time intervals i1 is shown for the first time in relation to FIG. 10, a similar increase function may be incorporated into any of the time intervals i1, i3 of any of the embodiments described above in relation to FIGS. 3-8.

[0085] The concepts described above in relation to Figures 2-10 can be applied to both in vivo and in vitro settings. In the in vitro experiments described above, the modified Inovitro® system used conductive electrodes placed on the exterior surface of the dish's sidewalls, with the ceramic material of the sidewalls acting as a dielectric, so that the electric field was capacitively coupled to the cultures. However, in alternative embodiments, the electric field can be applied directly to the cells without capacitive coupling (e.g., by modifying the Inovitro™ system configuration so that the conductive electrodes are placed on the interior surface of the sidewalls rather than the exterior surface of the sidewalls).

[0086] The concepts described herein can be applied to an in vivo situation by applying an alternating electric field to a target region of a living subject's body. This can be accomplished, for example, by placing electrodes on or under the subject's skin such that application of an alternating voltage between a selected subset of the electrodes applies an alternating electric field to the target region of the subject's body. For example, if the cells of interest are in the subject's lungs, one pair of electrodes can be placed on the front and back of the subject's chest and a second pair of electrodes can be placed on the right and left sides of the subject's chest.

[0087] In some in vivo embodiments, the electrodes are capacitively coupled to the subject's body (e.g., by using an electrode that includes a conductive plate with a dielectric layer disposed between the conductive plate and the subject's body), although in alternative embodiments the dielectric layer may be omitted, in which case the conductive plate is in direct contact with the subject's body.

[0088] Although the above description has focused on the application of alternating electric fields to cancer cells in vitro and / or in vivo, the same concepts can be used to apply alternating electric fields to a subject's body for other purposes, such as increasing the permeability of the blood-brain barrier or increasing the permeability of cell membranes, as described in U.S. Pat. Nos. 10,967,167 and 11,103,698.

[0089] Although the present invention has been disclosed with reference to certain embodiments, many modifications, variations and variations of the described embodiments are possible without departing from the field and scope of the invention, as defined in the appended claims. Thus, the present invention is not limited to the described embodiments, but has the full scope defined by the language of the following claims and their equivalents.

Claims

1. 1. A method of inducing an alternating electric field at a target region within a subject, comprising: applying a series of alternating current pulses between at least one first electrode element and at least one second electrode element during each of a plurality of first time intervals, the at least one first electrode element and the at least one second electrode element being disposed on or within a body of a subject; allowing the at least one first electrode element and the at least one second electrode element to cool during each of a plurality of second time intervals, each of the plurality of second time intervals immediately following each of the plurality of first time intervals; wherein the alternating current pulses within any said first time interval have an amplitude at a level that would cause at least one of said first electrode elements to exceed a temperature threshold of 37°C to 43°C if the series of pulses continued for one hour, but the series of pulses during each of said first time intervals is short enough to actually prevent at least one of said first electrode elements from exceeding its temperature threshold and to prevent said at least one second electrode element from exceeding its temperature threshold.

2. The method of claim 1 , wherein each of the plurality of second time intervals is at least as long as the immediately preceding first time interval.

3. The method of claim 1 , wherein each of the plurality of second time intervals is at least five minutes.

4. 2. The method of claim 1, wherein each of the second time intervals is sufficiently long to allow a subsequent series of alternating current pulses to be applied without the at least one first electrode element exceeding a temperature threshold and without the at least one second electrode element exceeding a temperature threshold.

5. The method of claim 1 , wherein the temperature threshold is between 38° C. and 40° C.

6. The method of claim 1 , wherein all of the alternating pulses within any first time interval have the same amplitude.

7. 2. The method of claim 1, wherein during each of said first time intervals, an amplitude of the alternating current pulse increases from an initial level to a final level and then remains at the final level for the duration of said first time interval.

8. 2. The method of claim 1, wherein cooling the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals is performed by not applying an AC pulse between the at least one first electrode element and the at least one second electrode element during the second time intervals.

9. 2. The method of claim 1, wherein cooling the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals is performed by applying a series of second amplitude pulses of alternating current between the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals, wherein an average amplitude of each of the series of second amplitude pulses is less than half of an average amplitude of a series of pulses in a immediately preceding first time interval.

10. The method of claim 1 , wherein the plurality of first time intervals includes at least 100 first time intervals and the plurality of second time intervals includes at least 100 second time intervals.

11. 11. The method of claim 10, wherein each of the plurality of first time intervals is at least one minute long, each of the plurality of second time intervals is at least one minute long, and each series of pulses includes at least 50 pulses.

12. moreover, applying a series of alternating current pulses between at least one third electrode element and at least one fourth electrode element during each of a plurality of third time intervals, the at least one third electrode element and the at least one fourth electrode element being disposed on or within the subject's body; allowing the at least one third electrode element and the at least one fourth electrode element to cool during each of a plurality of fourth time intervals, each of the plurality of fourth time intervals immediately following each of the plurality of third time intervals; 2. The method of claim 1, wherein the alternating current pulses in any said third time interval have an amplitude of a second level that would cause at least one of said third electrode elements to exceed a temperature threshold if the series of pulses continued for one hour, but the series of pulses during each of said third time intervals is short enough to actually prevent said at least one third electrode element from exceeding the temperature threshold and to prevent said at least one fourth electrode element from exceeding the temperature threshold.

13. each of the plurality of second time intervals is at least as long as the immediately preceding first time interval; The method of claim 12 , wherein each of the plurality of fourth time intervals is at least as long as the immediately preceding third time interval.

14. 13. The method of claim 12, wherein the alternating current pulses in the first time interval and the alternating current pulses in the third time interval have independently controllable amplitudes.

15. The method of claim 12 , wherein an amplitude of the alternating current pulse in the first time interval is different from an amplitude of the alternating current pulse in the third time interval.

16. each of the plurality of second time intervals is at least five minutes; The method of claim 12 , wherein each of the plurality of fourth time intervals is at least five minutes.

17. each of the plurality of first time intervals is at least 10 minutes; The method of claim 12 , wherein each of the plurality of third time intervals is at least 10 minutes.

18. each of the second time intervals being sufficiently long to allow a series of subsequent alternating current pulses to be applied without the at least one first electrode element exceeding a temperature threshold and without the at least one second electrode element exceeding a temperature threshold; 13. The method of claim 12, wherein each of the fourth time intervals is sufficiently long to allow a subsequent series of alternating current pulses to be applied without the at least one third electrode element exceeding a temperature threshold and without the at least one fourth electrode element exceeding a temperature threshold.

19. The method of claim 12, wherein the temperature threshold is between 38°C and 40°C.

20. The method of claim 12 , wherein the pulses of alternating current within any one of the first time intervals all have the same amplitude.

21. 13. The method of claim 12, wherein during each of said first time intervals, an amplitude of an alternating pulse increases from an initial level to a final level and then remains at the final level for the duration of said first time interval.

22. The method of claim 12 , wherein each of the third time intervals overlaps with a corresponding first time interval.

23. each of the third time intervals is mutually exclusive with every first time interval; The method of claim 12 , wherein each of the first time intervals is mutually exclusive with every third time interval.

24. cooling the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals is performed by not applying an AC pulse between the at least one first electrode element and the at least one second electrode element during the second time intervals; 13. The method of claim 12, wherein cooling the at least one third electrode element and the at least one fourth electrode element during each of the plurality of fourth time intervals is performed by not applying an AC pulse between the at least one third electrode element and the at least one fourth electrode element during the fourth time interval.

25. cooling the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals is performed by applying a series of second amplitude pulses of alternating current between the at least one first electrode element and the at least one second electrode element during each of the plurality of second time intervals, wherein an average amplitude of each of the series of second amplitude pulses is less than half an average amplitude of a series of pulses in a immediately preceding first time interval; 13. The method of claim 12, wherein cooling the at least one third electrode element and the at least one fourth electrode element during each of the plurality of fourth time intervals is performed by applying a series of alternating fourth amplitude pulses between the at least one third electrode element and the at least one fourth electrode element during each of the plurality of fourth time intervals, wherein an average amplitude of each of the series of fourth amplitude pulses is less than half the average amplitude of a series of pulses for a immediately preceding third time interval.

26. 13. The method of claim 12, wherein the plurality of first time intervals includes at least 100 first time intervals, the plurality of second time intervals includes at least 100 second time intervals, the plurality of third time intervals includes at least 100 third time intervals, and the plurality of fourth time intervals includes at least 100 fourth time intervals.

27. 27. The method of claim 26, wherein each of the plurality of first time intervals is at least one minute long, each of the plurality of second time intervals is at least one minute long, each of the plurality of third time intervals is at least one minute long, and each of the plurality of fourth time intervals is at least one minute long, and each series of pulses includes at least 50 pulses.

28. 1. An apparatus for inducing an alternating electric field at a target region within a subject, comprising: a pulse generator configured to generate, between the first and second output terminals, a series of pulses of alternating current having different amplitudes depending on the state of at least one control input; a controller configured to send a signal to the at least one control input such that the pulse generator outputs a pulse having a first amplitude between the first output terminal and the second output terminal during each of a plurality of first time intervals; the controller is further configured, during each of a plurality of second time intervals immediately following each of the plurality of first time intervals, to: (i) send a signal to at least one control input that causes the pulse generator to not output a pulse during each of the plurality of second time intervals; or (ii) send a signal to at least one control input that causes the pulse generator to output a pulse having a second amplitude between the first output terminal and the second output terminal during each of the plurality of second time intervals, the second amplitude being less than half of the first amplitude; The controller is further configured to receive at least one first input signal from at least one first temperature sensor and at least one second input signal from at least one second temperature sensor; the plurality of first time intervals includes at least ten first time intervals; the plurality of second time intervals includes a time interval of at least 10 seconds; each of the plurality of first time intervals is at least one minute long; each of the plurality of second time intervals is at least one minute long; Each of the series of pulses comprises at least 10 pulses.

29. 30. The apparatus of claim 28, wherein the controller is further configured to adjust the first amplitude during each of the plurality of first time intervals based on at least one first input signal and at least one second input signal.

30. 30. The apparatus of claim 28, wherein each of the plurality of second time intervals is at least five minutes long.

31. 30. The apparatus of claim 28, wherein the controller is further configured to terminate a first predetermined time interval based on the at least one first input signal and the at least one second input signal.

32. 30. The apparatus of claim 28, wherein the controller is further configured to terminate a second predetermined time interval based on the at least one first input signal and the at least one second input signal.

33. The pulse generator includes: further configured to generate a series of AC pulses between the third output terminal and the fourth output terminal, the series of pulses having an amplitude responsive to a state of the at least one control input; the controller is further configured to send a signal to at least one control input to cause the pulse generator to output a pulse having a third amplitude between a third output terminal and a fourth output terminal during each of a plurality of third time intervals; the controller is further configured, during each of a plurality of fourth time intervals immediately following each of the plurality of third time intervals, to: (i) send a signal to at least one control input that causes the pulse generator to not output a pulse during each of the plurality of fourth time intervals, or (ii) send a signal to at least one control input that causes the pulse generator to output a pulse having a fourth amplitude between the third output terminal and the fourth output terminal during each of the plurality of fourth time intervals, the fourth amplitude being less than half of the third amplitude; the controller is further configured to receive at least one third input signal from at least one third temperature sensor and at least one fourth input signal from at least one fourth temperature sensor; the plurality of third time intervals includes at least ten third time intervals; the plurality of fourth time intervals includes at least ten fourth time intervals; each of the plurality of third time intervals is at least one minute long; 30. The apparatus of claim 28, wherein each of the plurality of fourth time intervals is at least one minute in length.

34. 34. The apparatus of claim 33, wherein the controller is further configured to adjust a first amplitude during each of a plurality of first time intervals based on the at least one first input signal and the at least one second input signal, and to adjust a third amplitude during each of a plurality of third time intervals based on the at least one third input signal and the at least one fourth input signal.

35. 34. The apparatus of claim 33, wherein the controller is further configured to terminate a first predetermined time interval based on the at least one first input signal and the at least one second input signal, and to terminate a third predetermined time interval based on the at least one third input signal and the at least one fourth input signal.

36. 34. The apparatus of claim 33, wherein the controller is further configured to terminate a second predetermined time interval based on the at least one first input signal and the at least one second input signal, and to terminate a fourth predetermined time interval based on the at least one third input signal and the at least one fourth input signal.

37. moreover, at least one first electrode element wired to the first output terminal; at least one second electrode element wired to the second output terminal; at least one third electrode element wired to the third output terminal; 34. The apparatus of claim 33, further comprising: at least one fourth electrode element wired to the fourth output terminal.

38. The first temperature sensor is a first thermistor in thermal contact with the at least one first electrode element; the second temperature sensor including a second thermistor in thermal contact with the at least one second electrode element; the third temperature sensor including a third thermistor in thermal contact with the at least one third electrode element; 38. The apparatus of claim 37, wherein the fourth temperature sensor includes a fourth thermistor in thermal contact with the at least one fourth electrode element.

Images