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WO2019018836A1 - Induction de la nécrose de cellules tumorales par perfusion locale étalonnée de fluides nocifs - Google Patents

Induction de la nécrose de cellules tumorales par perfusion locale étalonnée de fluides nocifs Download PDF

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Publication number
WO2019018836A1
WO2019018836A1 PCT/US2018/043220 US2018043220W WO2019018836A1 WO 2019018836 A1 WO2019018836 A1 WO 2019018836A1 US 2018043220 W US2018043220 W US 2018043220W WO 2019018836 A1 WO2019018836 A1 WO 2019018836A1
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Prior art keywords
treating
fluid
tumor
tumor according
organ
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Application number
PCT/US2018/043220
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English (en)
Inventor
Timothy Patrick Murphy
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Timothy Patrick Murphy
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Publication of WO2019018836A1 publication Critical patent/WO2019018836A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/02—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques
    • A61B18/0218—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques with open-end cryogenic probe, e.g. for spraying fluid directly on tissue or via a tissue-contacting porous tip
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/02—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques
    • A61B2018/0212—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by cooling, e.g. cryogenic techniques using an instrument inserted into a body lumen, e.g. catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A61F2007/126—Devices for heating or cooling internal body cavities for invasive application, e.g. for introducing into blood vessels

Definitions

  • the present invention relates to devices, systems, and processes useful as medical therapies for tumors, primary and metastatic, benign or malignant.
  • Loco-regional treatment of cancer has predominately focused on liver cancer and includes several different therapies, including ablation by local deposition of electromagnetic radiation, ablation by local injection of absolute ethanol or acetic acid, or trans-arterial treatment like embolization using particles, chemotherapy, liquid embolic agents, radioactive particles, or combinations thereof.
  • these treatments can be curative.
  • multifocal primary or metastatic liver cancer multiple randomized clinical trials have shown improvement in survival by embolization techniques.
  • intra-arterial embolization is limited outside of the liver because of the risk of infarction of the organ being treated if feeding arteries are occluded, as is typical of embolization procedures.
  • normal liver cells are mostly spared during embolization because of perfusion by the portal vein.
  • 3-bromopyruvate disrupts a cellular metabolic process, namely, it appears to disrupt glycolysis and is thus "suspected to be a Warburg-effect play against tumor cell metabolism" (see blogs.sciencemag.org/pipeline/archives/2017/08/17/3-bromopyruvate- what-a-mess).
  • 3-bromopyruvate disrupts the ability of tumor cells to generate ATP or energy; it does not appear to kill cells by disrupting the cellular membranes or denaturing cellular proteins.
  • a method of treating a tumor in an organ of a patient and at least one blood vessel which supplies blood to said organ and said tumor comprises infusing a fluid comprising at least one substance into the at least one blood vessel at a concentration and rate of said at least one substance sufficient to kill cells of said tumor by direct toxicity, said direct toxicity being mediated through direct disruption of cells, including rupturing cell membranes or denaturing cellular proteins, and not mediated through disruption of biochemical processes of said cells, said concentration and rate being insufficient to kill nontumorous organ cells.
  • a method of treating a tumor in an organ of a patient having feeding blood vessel which provided blood to said organ and to said tumor comprises infusing a fluid having a temperature above 104 degrees Fahrenheit into the feeding blood vessel at a rate sufficient to kill cells of said tumor, said rate being insufficient to kill nontumorous organ cells.
  • a method of treating a tumor in an organ of a patient and feeding blood vessel supplying blood to said organ and to said tumor comprises infusing a fluid having a temperature below 85 degrees Fahrenheit into the feeding blood vessel at a rate sufficient to kill cells of said liver tumor, said rate being insufficient to kill nontumorous liver cells.
  • FIG. 1 illustrates the arterial and portal venous circulation of the liver with an exemplary infusion device
  • FIG. 2 illustrates an alternative infusion route.
  • a range of 1 to 5 should be interpreted to include not only the explicitly recited limits of 1 and 5, but also to include individual values such as 2, 2.7, 3.6, 4.2, and sub-ranges such as 1-2.5, 1.8-3.2, 2.6-4.9, etc. This interpretation should apply regardless of the breadth of the range or the characteristic being described, and also applies to open-ended ranges reciting only one end point, such as "greater than 25,” or "less than 10.”
  • FIG. 1 is a schematic illustration showing the arterial and venous circulation of the liver including:
  • a method of medical treatment for tumors involves placing a catheter 20 with its tip 22 in a feeding blood vessel, in this example the hepatic artery 12, and infusing or injecting one or more substance(s) at a concentration and rate that is directly toxic to tumor cells but tolerated by normal cells.
  • a feeding blood vessel in this example the hepatic artery 12
  • Another example of a way to administer the treatment is by infusing in the portal vein 13.
  • Yet another example of a way to administer the treatment is by infusing in both the hepatic artery 12 and the portal vein 13, which can be performed simultaneously, serially, alternatingly, and at the same or different infusion rates and/or duty cycles.
  • the administration does not cause an
  • the methods described herein include prolonged calibrated infusion of noxious or toxic fluid solutions into the liver or other organ, containing elements that do not exert a medication-type effect on a target enzyme or molecule, such as interfering with cellular metabolic processes through interference with intracellular biochemical reactions, nor do they exert their oncolytic effect by ischemia, but rather that are directly toxic by mechanisms such as rupturing cell membranes, binding and disabling cellular structures critical to cell viability, or denaturing cellular proteins.
  • the term "medication” means that the solute in the solution, if any, is not known to exert therapeutic effects to treat any disease by interfering or altering any biochemical or molecular process at the in the body.
  • the administration is calibrated to result in death of tumor cells but not normal cells and also to result in death of tumor cells by mechanisms other than ischemia, and without thrombosis or occlusion of the artery being used for administration of the noxious substances.
  • tumor cells by "direct toxicity", essentially burning or freezing them with temperature, or with an acidic or basic substance, or 'drowning' them (over- hydration which swells and bursts the cells), or binding and interfering with organelles or intra-cellular components whose function is critical to cell viability, or increasing their metabolic demands beyond their ability, and similar mechanisms for other substances described herein.
  • liver tumors in other organs such as the lung or brain
  • the therapy described herein would be most amenable to use in the liver, although tumors in other organs, such as the lung or brain, can also be similarly treated.
  • the liver has dual blood supply, being perfused by the hepatic artery and by the portal vein. Although 3 ⁇ 4 of the normal liver's blood supply is via the portal vein, liver tumors, either primary or metastatic, have a strong preference for blood flow from the hepatic artery, and obtain the vast majority of their blood flow from the hepatic artery.
  • noxious substances in liquid form for example, into the hepatic artery at the properly calibrated rate and concentration, it is possible to achieve a toxic effect in liver tumor cells while only a sub- lethal amount is delivered to nontumorous liver cells.
  • noxious fluids could be administered into the portal vein to achieve oncolysis.
  • Similar therapy may be possible for other solid tumors in organs such as the prostate, brain, and the lung.
  • Another way to achieve this treatment is to inject short-acting biodegradable particles of a size and shape that occlude the artery temporarily and leech out noxious substances as they degrade while degrading rapidly enough to preserve patency of the blood vessel.
  • the methods described herein include as one method titration of the infusion rate of a toxic solution so that the cumulative dose administered into the feeding blood vessel is not enough to cause toxicity resulting in organ failure or death in the person, because of dilution of the toxic solution in the vascular system of the entire body after the solution has passed out of the liver, and therefore the concentration of the toxic substance in circulating systemic blood is below the critical toxic threshold concentration.
  • the concentration in the liver is higher than in the systemic circulating blood.
  • One exemplary methodology is to start with a known toxic dose of a substance, for example, the "LD-50" dose (i.e., the dose of a substance that, if administered
  • the LD-50 dose may be in the form of a blood concentration, or in the form of a total dose. If the LD-50 is in the form of a total dose, a calculation of the blood concentration in mg/dl would be done using the following formula:
  • the hepatic artery may for example be found to flow at a rate of 5 ml/sec, as estimated by that method at the time of treatment of a particular patient.
  • the initial infusion starts at a reduced (e.g., half) concentration of the estimated LD-50 concentration, in this example at a rate of 2.5 ml/sec. This initial infusion is run at that rate until a very low concentration of the estimated LD-50 concentration.
  • exemplary processes are repeated until: a) tumors are killed; or b) organ or systemic toxicity is observed. That would represent a treatment cycle. Treatment cycles could be repeated if tumors initially shrink but then subsequently begin to grow.
  • Another exemplary method would be infusion of a standard medical fluid, such as a normal saline solution or Ringer' s lactate solution, for example, that has been heated to a temperature where the cells are intolerant of prolonged infusion, but not hot enough to coagulate or occlude the hepatic artery.
  • a standard medical fluid such as a normal saline solution or Ringer' s lactate solution, for example, that has been heated to a temperature where the cells are intolerant of prolonged infusion, but not hot enough to coagulate or occlude the hepatic artery.
  • a standard medical fluid such as a normal saline solution or Ringer' s lactate solution, for example, that has been heated to a temperature where the cells are intolerant of prolonged infusion, but not hot enough to coagulate or occlude the hepatic artery.
  • Such a fluid could be heated, for example, to 95° centigrade and infused at half of the calculated arterial flow rate, and the toxicity measured by measuring levels
  • the methods described herein are a type of loco-regional therapy. Local infusion via the hepatic artery of chemo-therapy drugs is well-known; however, chemotherapy drugs are designed for systemic administration, and usually exert their effect in killing tumor cells on interfering with cellular division or mitosis, rather than direct rupture of cell membranes, denaturing cell membranes, coagulative necrosis, or other directly toxic effects.
  • chemotherapy drugs are designed for systemic administration, and usually exert their effect in killing tumor cells on interfering with cellular division or mitosis, rather than direct rupture of cell membranes, denaturing cell membranes, coagulative necrosis, or other directly toxic effects.
  • Some examples of compounds that could be used in the methods described herein, alone or in combination with any other such compounds, including many with known LD- 50' s, are:
  • mice mice 4.3 mg/kg 0.0043 [62] from scorpions
  • Amatoxin (from Amanita 300- rat 0.0007 [67] phalloides mushrooms) 700 ⁇ ⁇ ⁇ ⁇ ⁇
  • Tetrodotoxin TX
  • mice oral 334 0.000334 [68] from blue-ringed octopus
  • the organ, or portion thereof which includes the tumor of interest is infused with the substance (which is, again, technically not a poison) at a lower infusion rate and time than would be known to be toxic to cells, monitoring the patient over time, and infusing again at an increased rate until a) tumors are killed, or b) organ or systemic toxicity is observed.
  • the substance which is, again, technically not a poison
  • noxious substances could be incorporated into biodegradable or permanent microspheres and then injected into blood vessels supplying organs that contain tumors, configured in such a way that they either do not occlude the blood vessel or that they occlude it briefly so that its patency long-term is not compromised, said noxious substances leeching out into the blood or tissue at a dose that is tolerable to the person but not to the tumors.
  • Either therapy by infusion or injection of microspheres that leech noxious substances could be used not only to selectively kill tumors, but if done at high enough rates also to ablate or kill organs or segments of organs that contain tumors.
  • ethanol acetic acid, hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, hypertonic saline, hypotonic saline, and distilled water (which is a type of hypotonic saline).
  • Yamagata M, Tannock IF The chronic administration of drugs that inhibit the regulation of intracellular pH: in vitro and anti-tumour effects. Br J Cancer. 1996;73(11): 1328-1334.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Genetics & Genomics (AREA)
  • Plasma & Fusion (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

La thérapie par perfusion destinée à des tumeurs primaires ou métastatiques comprend la perfusion de fluides qui se trouvent dans l'alimentation de vaisseaux sanguins à des concentrations et débits qui tuent des cellules tumorales mais ne tuent pas les cellules normales. Les fluides perfusés peuvent être des toxines connues, ou des substances généralement considérées comme non toxiques qui, à des débits suffisamment élevés, provoquent néanmoins la mort des cellules cancéreuses.
PCT/US2018/043220 2017-07-21 2018-07-23 Induction de la nécrose de cellules tumorales par perfusion locale étalonnée de fluides nocifs WO2019018836A1 (fr)

Applications Claiming Priority (4)

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US201715656418A 2017-07-21 2017-07-21
US15/656,418 2017-07-21
US201715798563A 2017-10-31 2017-10-31
US15/798,563 2017-10-31

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4935450A (en) * 1982-09-17 1990-06-19 Therapeutical Systems Corporation Cancer therapy system for effecting oncolysis of malignant neoplasms
US6620189B1 (en) * 2000-02-28 2003-09-16 Radiant Medical, Inc. Method and system for control of a patient's body temperature by way of a transluminally insertable heat exchange catheter
US7125541B2 (en) * 1992-03-05 2006-10-24 The University Of Texas System Board Of Regents Combined methods for tumor vasculature targeting and tumor treatment with radiotherapy
US20080300571A1 (en) * 2007-05-30 2008-12-04 Lepivert Patrick Process and device for selectively treating interstitial tissue

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4935450A (en) * 1982-09-17 1990-06-19 Therapeutical Systems Corporation Cancer therapy system for effecting oncolysis of malignant neoplasms
US7125541B2 (en) * 1992-03-05 2006-10-24 The University Of Texas System Board Of Regents Combined methods for tumor vasculature targeting and tumor treatment with radiotherapy
US6620189B1 (en) * 2000-02-28 2003-09-16 Radiant Medical, Inc. Method and system for control of a patient's body temperature by way of a transluminally insertable heat exchange catheter
US20080300571A1 (en) * 2007-05-30 2008-12-04 Lepivert Patrick Process and device for selectively treating interstitial tissue

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALNAIM, L: "Therapeutic drug monitoring of cancer chemotherapy", JOURNAL OF ONCOLOGY PHARMACEUTICAL PRACTICE, vol. 13, 2007, pages 207 - 221, Retrieved from the Internet <URL:https://www.researchgate.net/publication/47810615_Therapeutic_drug_monitoring_in_cancer_chemotherapy> *
J. VAN DER ZEE: "Heating the patient: a promising approach?", ANNALS OF ONCOLOGY, vol. 13, no. 8, 1 August 2002 (2002-08-01), pages 1173 - 1184, XP055098423, Retrieved from the Internet <URL:https://doi.org/10.1093/annonc/mdf280> *
LIN, YC ET AL.: "Ablation of Liver Tumor by Injection of Hypertonic Saline", AMERICAN JOURNAL OF ROENTGENOLOGY, vol. 184, no. 1, 2005, pages 212 - 219, XP002742435 *
MCCARTY, M ET AL.: "Manipulating Tumor Acidification as a Cancer Treatment Strategy", ALTERNATIVE MEDICINE REVIEW, vol. 15, no. 3, September 2010 (2010-09-01), pages 264 - 272, XP055563077 *
STEPHEN, RL ET AL.: "Effect of osmotic pressure on uptake of chemotherapeutic agents by carcinoma cells", CANCER RESEARCH, vol. 50, no. 15, 1 August 1990 (1990-08-01), pages 4704 - 4708, XP055563083 *

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