JPWO2021077020A5

JPWO2021077020A5 -

Info

Publication number: JPWO2021077020A5
Application number: JP2022523039A
Authority: JP
Publication date: 2023-10-24

Claims

two or more electrodes configured to be in electrical communication with the subject's splenic nerve;
a nerve cuff configured to at least partially enclose the splenic nerve or splenic nerve vascular bundle;
emitting a predetermined pattern of electrical pulses associated with modulating the subject's immune system when the predetermined pattern of electrical pulses is used to stimulate the splenic nerve of the subject; an integrated circuit configured to operate the two or more electrodes;
implantable devices, including;

2. The apparatus of claim 1, wherein the predetermined pattern is associated with treating cancer in the subject.

3. The device of claim 2, wherein the cancer is colon cancer or rectal cancer.

the predetermined pattern increases the circulation or activity of NK cells or cytotoxic T cells in the subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject; 2. The apparatus of claim 1 , wherein the apparatus is associated with causing .

The predetermined pattern is associated with causing an increase in the circulation or activity of NK cells in the subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject. , the apparatus of claim 1 .

the predetermined pattern is associated with causing an increase in blood levels of inflammatory cytokines in the subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject; 6. A device according to any one of claims 1 to 5 .

the predetermined pattern is associated with causing a decrease in blood levels of inflammatory cytokines in the subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject; 6. A device according to any one of claims 1 to 5 .

8. The device according to claim 6 or 7 , wherein the inflammatory cytokine is a pro-inflammatory cytokine.

9. The device of claim 8 , wherein the proinflammatory cytokine is tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), or interleukin-1β (IL-1β).

8. A device according to claim 6 or 7 , wherein the inflammatory cytokine is an anti-inflammatory cytokine.

11. The device of claim 10 , wherein the anti-inflammatory cytokine is interleukin-10 (IL-10).

5. The predetermined pattern is associated with causing increased inflammation in a subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject. 5. The device according to any one of Item 5 .

The predetermined pattern increases blood levels of pro-inflammatory cytokines and/or anti-inflammatory cytokines in a subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject. 13. The device of claim 12 , associated with causing a decrease in blood levels of inflammatory cytokines.

5. The predetermined pattern is associated with causing a reduction in inflammation in a subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject. 5. The device according to any one of Item 5 .

The predetermined pattern increases blood levels of anti-inflammatory cytokines and/or inflammation in the subject when the plurality of electrical pulses of the predetermined pattern are used to stimulate the splenic nerve of the subject. 6. A device according to any one of claims 1 to 5 , associated with causing a decrease in blood levels of inducible cytokines.

16. The device of claim 13 or 15 , wherein the proinflammatory cytokine is tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), or interleukin-1β (IL-1β).

17. The device of any one of claims 13, 15, or 16, wherein the anti-inflammatory cytokine is interleukin-10 (IL-10).

the plurality of electrical pulses of the predetermined inflammatory pattern are associated with causing an increase in inflammation in the subject when the plurality of electrical pulses of the predetermined inflammatory pattern are used to stimulate the splenic nerve of the subject; a first mode of operation that provides;
a plurality of electrical pulses of a predetermined anti-inflammatory pattern associated with causing a reduction in inflammation in a subject when the plurality of electrical pulses of the predetermined inflammatory pattern are used to stimulate the splenic nerve of the subject; a second mode of operation for providing pulses;
18. The apparatus of any one of claims 1-17 , wherein the controller is configured to select an operating mode from a plurality of operating modes.

19. The apparatus of claim 18 , wherein the operating mode is selected based on a trigger signal.

20. The apparatus of claim 19 , comprising a wireless communication system and configured to wirelessly receive the trigger signal.

21. The method of claims 1-13 and 18-20 , wherein at least one of the two or more electrodes is configured to provide a plurality of electrical pulses emitted at a frequency of about 25 Hz or higher. The device according to any one of the items.

Claims 1-13, wherein at least one of the two or more electrodes is configured to provide a plurality of electrical pulses emitted at a frequency between about 30 Hz and about 100 Hz, and the device according to any one of 18 to 21 .

Claims 1-13 and 15, wherein at least one of the two or more electrodes is configured to provide a plurality of biphasic electrical pulses comprising an anodic phase followed by a cathodic phase. 23. The device according to any one of items 22 to 22 .

21. Any of claims 1-11 and 14-20 , wherein at least one of the two or more electrodes is configured to provide a plurality of electrical pulses emitted at a frequency of less than 25 Hz. The device according to item 1.

Claims 1-11 , 14-20, wherein at least one of the two or more electrodes is configured to provide a plurality of electrical pulses emitted at a frequency of about 3 Hz to about 20 Hz. , and 24 .

Claims 1 to 11, 14 to 14 , wherein at least one of the two or more electrodes is configured to provide a plurality of biphasic electrical pulses comprising a cathode phase followed by an anodic phase. 20, and the device according to any one of 24 to 25 .

27. The device of any preceding claim, configured to electrically stimulate the splenic nerve using one or more electrical pulses of about 1 ms or less in length.

28. The device of any preceding claim, configured to electrically stimulate the splenic nerve using one or more electrical pulses having an amplitude of about 250 μA to about 10 mA.

29. The device of any preceding claim, configured to electrically stimulate the splenic nerve using one or more electrical pulses at a frequency of about 100 Hz or less.

30. The device of any preceding claim, configured to electrically stimulate the splenic nerve using a pulse train comprising a plurality of biphasic electrical pulses.

31. The apparatus of claim 30 , wherein the biphasic electrical pulse includes an anodic phase followed by a cathodic phase.

31. The apparatus of claim 30 , wherein the biphasic electrical pulse includes a cathode phase followed by an anodic phase.

33. Any of claims 1-32, wherein the device electrically stimulates the splenic nerve using a plurality of pulse trains comprising two or more electrical pulses, the pulse trains being separated by a dwell time of about 50 ms or more. Apparatus according to paragraph 1.

34. The apparatus of claim 33 , wherein the residence time is about 50 milliseconds to about 2 minutes.

35. The apparatus of claim 33 or 34 , wherein the residence time is about 500 ms or more.

The plurality of pulse trains includes at least a first pulse train followed by a second pulse train, and the electrical pulses in the first pulse train have amplitudes that are smaller than the amplitudes of the electrical pulses in the second pulse train. 36. The device according to any one of 33 to 35 .

37. A device according to any preceding claim, wherein the splenic nerve is electrically stimulated using tonic electrical pulses.

38. The device of any preceding claim, wherein the nerve cuff is a spiral nerve cuff configured to wrap at least partially around the splenic neurovascular bundle.

receive ultrasound,
39. A device according to any preceding claim, comprising an ultrasound transducer configured to convert energy from the ultrasound waves into electrical energy for powering the device.

40. A device according to any preceding claim, configured to electrically stimulate the splenic nerve in response to a trigger signal.

41. The method of any one of claims 1-40 , configured to provide a plurality of electrical pulses using at least one of the two or more electrodes in response to a trigger signal. Device.

42. A device according to claim 40 or 41 , wherein the trigger signal is received wirelessly by the device.

43. A device according to any one of claims 40 to 42 , wherein the trigger signal is encoded in ultrasound received by the device.

44. A device according to any preceding claim, comprising a sensor configured to measure a physiological condition.

45. A device according to any preceding claim, configured to monitor splenic nerve activity.

46. A device according to any one of claims 44 or 45 , configured to emit backscattered waves encoding information related to splenic nerve activity or physiological status.

47. The apparatus of claim 46 , wherein the backscattered waves encoding the information related to the splenic nerve activity or the physiological state are configured to be received by an external device.

48. A device according to claim 46 or 47 , wherein the backscattered waves further encode information related to the state of the device or one or more electrical pulses emitted by the device.

49. The apparatus according to any one of claims 46 to 48 , wherein the backscattered waves are ultrasound backscattered waves.

50. A system comprising a device according to any preceding claim and an interrogator comprising a wireless communication system configured to wirelessly communicate or power the device.

An anticancer agent for use in a method of treating cancer, the method comprising:
using a fully implanted device comprising one or more electrodes in electrical communication with the splenic nerve sufficient to modulate the subject's immune system and treat the cancer in the subject. electrically stimulating the splenic nerve of
administering the anticancer agent to the subject;
anti-cancer drugs, including