WO2019204391A1 - Cellules cancéreuses inactivées par cryogénisation pour l'immunothérapie anticancéreuse - Google Patents

Cellules cancéreuses inactivées par cryogénisation pour l'immunothérapie anticancéreuse Download PDF

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Publication number
WO2019204391A1
WO2019204391A1 PCT/US2019/027806 US2019027806W WO2019204391A1 WO 2019204391 A1 WO2019204391 A1 WO 2019204391A1 US 2019027806 W US2019027806 W US 2019027806W WO 2019204391 A1 WO2019204391 A1 WO 2019204391A1
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cells
inactivated
cancer cells
cryogenically
cancer
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PCT/US2019/027806
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English (en)
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Robert Caruso
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Robert Caruso
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/13—Tumour cells, irrespective of tissue of origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • the invention relates to methods for cancer immunotherapy, and more specifically, to methods for using cryo-inactivated cancer cells for cancer immunotherapy.
  • Cancer is the umbrella term for a range of conditions in which cells mutate and grow abnormally, in many cases invading other tissues and compromising the body’s functions. While some cancers can be very aggressive, quickly metastasizing and compromising function, most precancerous cells will never form tumors or cause significant trouble - the body’s immune system locates and destroys them through a complex process that’s only partially understood.
  • Surgical procedures may be used for diagnostic purposes (e.g., biopsy of suspected cancerous cells) or for excision of cancerous tumors.
  • Chemotherapy may be used to selectively destroy cancer cells, either as a sole treatment, or with the intent of reducing tumor size for later surgical excision.
  • Radiation either by way of exposure to targeted radiation from an external source, or by way of implantation of radioactive elements within or near a cancerous tumor (called brachytherapy), may be used either as a primary treatment, or to reduce the size of a tumor for later surgical excision.
  • BCG Bacillus Calmette-Guerin
  • One aspect of the invention relates to a method of individualized cancer immunotherapeutic treatment.
  • the method comprises extracting cancerous cells, cryo-inactivating the cells, and reimplanting the cryo-inactivated cancerous cells in the patient from whom they were extracted.
  • the method may involve an initial phase, in which cryo-inactivated cells are first reimplanted, and then an ongoing treatment or maintenance phase in which cryo-inactivated are reimplanted one or more times at defined intervals after the initial reimplantation.
  • Another aspect of the invention relates to a method for preparing cancerous cells for immunotherapeutic reimplantation in a human or animal body.
  • the method comprises treating the cancerous cells with one or more cycles of cryogenic freezing followed by thawing.
  • the method may also comprise reducing or shaping the cell mass to a particular size or shape for reimplantation.
  • Yet another aspect of the invention comprises a method for treating cancer.
  • the method comprises extracting a bodily fluid from a patient, separating one or more cancerous cells from the bodily fluid, cryogenically inactivating the cancerous cells, and reimplanting the cryogenically-inactivated cells in the body.
  • the bodily fluid may be, e.g., blood or lymphatic fluid. Separation may be achieved by a process such as plasmapheresis.
  • the method may involve performing a second reimplantation from the same batch of cryogenically-inactivated cells, or it may comprise reimplanting newly harvested and cryogenically-inactivated cells.
  • FIG. 1 is a high-level schematic flow diagram of a method for preparing and using cryo-inactivated cancer cells in individualized immunotherapeutic treatment according to one embodiment of the present invention.
  • FIG. 1 is a high-level schematic flow diagram of a method, generally indicated at 10, for preparing and using cryo-inactivated cancer cells in individualized immunotherapeutic treatment according to one embodiment of the invention.
  • method 10 involves extracting cancerous cells from a patient, cryogenically inactivating those cells, preparing the cryo-inactivated cells for reimplantation, and reimplanting them into the patient.
  • cryogenically-inactivated, reimplanted cells may have an immunological benefit to the patient. While there are many ways of inactivating or destroying cancerous cells, doing so cryogenically is far more likely to preserve antigen structure (including tertiary and quaternary protein structure) than other methods, like radiation therapy or ablation by exposure to radio frequency (RF) or ultrasound waves, because the cancer cell’s antigens, many of which are bound to the cell membrane, are quickly frozen, which reduces the possibility that they will be denatured in the process.
  • RF radio frequency
  • the term“cancer” refers to a cell or group of cells that grow abnormally and have the potential to invade or spread to other parts of the body.
  • the cancer cells in embodiments of the present invention may be in any stage of growth or development, and may be pre-cancerous.
  • the terms“cancer” and“cancer cells” should be construed to include cells that would be considered to be clinically pre-cancerous.
  • tumor may refer to either a benign or a malignant growth in general usage, for purposes of the present description, it should be construed to refer to a malignant growth, i.e., a cancerous tumor. Tumors may be simple masses of cells, or they may have various degrees of vascularization, i.e., blood vessel growth.
  • the antigens in question are typically membrane-bound proteins.
  • structure refers to their primary, secondary, tertiary, and quaternary protein structure. It should be understood, though, that method 10 may not require perfect preservation of antigen structure - there may be some denaturation or some alteration in the original structure, so long as the remaining structure is sufficient to provoke an immune response.
  • the fact that the antigen structure is preserved does not necessarily mean that the cancerous cell itself is preserved: during the inactivation process, the cell undergoes catastrophic change, and in many cases, the cell membrane will burst.
  • portions of this description refer to reimplantation of a mass of cryogenically-inactivated cells, a single fragment of cell membrane with preserved antigens may be sufficient to provoke an immune response, and this description should be construed to encompass situations in which only a few cell fragments are reimplanted.
  • method 10 begins at task 11 and continues with task 12, in which cancerous cells are extracted from a patient.
  • treating clinicians will choose to extract cells from the patient, either for diagnostic purposes (e.g., to confirm a diagnosis or stage of tumor development) or for treatment purposes (e.g., to excise or reduce the volume of a tumor).
  • Traditional techniques can be used to extract the cancerous cells, for example, needle biopsy, excisional biopsy, or complete tumor extirpation.
  • task 12 may involve extracting that fluid and separating the cancerous cells from it, e.g., by plasmapheresis.
  • Method 10 continues with task 14, in which the extracted cells are cryogenically inactivated.
  • a cryogen is a material that exists at a very low temperature. Cryogens have very low boiling points, typically far below 0°C and, in some cases, close to 0°K (i.e., absolute zero). Many cryogens are liquefied or solidified gases - liquid nitrogen and dry ice (i.e., solidified carbon dioxide) are two of the more common and familiar cryogens.
  • cryogens are used because the temperature differential between the cryogen and human tissue will induce rapid cooling and freezing of the tissue.
  • the material used to induce freezing may be a traditional cryogen, or it may be a material with a much higher boiling point (e.g., an industrial refrigerant, ammonia, etc.).
  • Current accepted medical practice in cryogenic tissue ablation procedures is to freeze the tissue to a temperature of at least -40°C, and this temperature will be sufficient in at least some embodiments of method 10. As will be described below in more detail, a series of freeze/thaw cycles may be used to ensure adequate cell death in the targeted tissue.
  • Cancer cells may be dipped in a cryogen, sprayed with a cryogen, placed in a cryogenic freezer, or exposed to a cryogen in any other way in the course of task 14.
  • a cryogenic probe i.e., a device that is cooled by cryogens
  • the temperature of the extracted cells may be monitored with various types of instrumentation, including thermocouples, thermistors, infrared cameras, or other types of temperature probes, in order to ensure that it is reaching appropriately low temperatures for inactivation.
  • task 14 may include one or more freeze/thaw cycles, both to ensure that the cells are fully inactivated and to prevent reimplantation of cryogenically frozen cells that may damage surrounding tissue.
  • the extracted cancerous cells may be subjected to two freeze/thaw cycles, three freeze/thaw cycles, etc., with each freeze/thaw cycle involving, for example, a ten-minute freezing period followed by a ten-minute thawing period.
  • the number of freeze/thaw cycles may depend on the mass and shape of the tumor, the type and stage of the cancer, and conventional heat transfer considerations. Larger or more oddly-shaped tumors may require more freeze/thaw cycles than smaller tumors.
  • Task 14 may be done either in vivo or ex vivo, and in some cases, tasks 12 and 14 may be performed in reverse order.
  • a surgeon confronted with a small tumor may choose to cryogenically ablate that tumor in situ using a commercially-available cryoablation system, such as the CRYOCARE CSTM cryoprobe system (Endocare, Inc., Austin, Texas).
  • a cryoprobe system may help to reduce the possibility of damage to surrounding normal tissue, and cryoablation may serve the purpose of inactivation in some embodiments of the invention.
  • Cells may then be extracted from the body once inactivated and used in further tasks of method 10.
  • task 14 is performed, it would be performed in a sterile field with sterile technique, so as to avoid contaminating the sample and infecting the patient.
  • Method 10 continues with task 16, in which the cryo-inactivated cells are prepared for reimplantation.
  • Task 16 may include any sub-tasks necessary or desirable for preparing the cells for reimplantation. It may include cutting or shaping the extracted, inactivated cell mass, for example, to a preselected shape and volume. For example, a volume of 0.5 cubic centimeters may be an appropriate volume to reimplant in at least some embodiments.
  • Task 16 may also involve packaging or inserting the cell mass into a tool that will be used to reimplant the tissue later. For example, a large-bore needle may be used for reimplantation, and in that case, task 16 may involve shaping the extracted cell mass into“pellets” suitable for insertion with that large-bore needle.
  • Task 16 may also involve examining the extracted, inactivated cells. As was described briefly above, genetic and pathology studies are often performed on extracted cancer cells. Such studies may be done as a part of method 10 or entirely separate from method 10. If the extracted cells are examined in task 16, that examination may focus on attributes that are relevant to method 10. For example, if there is any question as to whether the extracted cancerous cells have been properly cryogenically inactivated for reimplantation, they may be studied in task 16 to establish this (using standard techniques in pathology).
  • method 10 involves reimplantation of cryo-inactivated cancer cells
  • reimplantation need not occur immediately after extraction.
  • extracted, cryo-inactivated cancer cells may be stored for days, weeks, months, or even years for later treatment of the patient, as will be explained in more detail below.
  • task 16 may also involve preparing some of the inactivated cell mass for storage and future reimplantation. Depending on the embodiment and the particular patient’s situation, that may involve re-freezing a portion of the extracted cells.
  • the extracted cell mass may be shaped and re- frozen, so that the frozen mass can be easily inserted into the tool that will be used to implant it. In those cases, the cell mass may undergo a final thawing cycle only after it has been completely readied for insertion.
  • tumors may be“broken up” and, for example, mixed with a liquid carrier for reimplantation, if desired.
  • any methods of preparation may be used in task 16.
  • subjecting the cryo- inactivated cancer cells to severe mechanical stresses, like shear may run the risk of denaturing or removing antigens.
  • Method 10 continues with task 18, in which the cryo-inactivated cancer cells are reimplanted in the patient.
  • the location of insertion and the method of insertion may vary depending on the type and extent of cancer and, in some cases, the clinician’s preferences. It may be helpful to reimplant the cells in locations where there are a larger number of antigen-presenting cells, so that the antigens of the inactivated, reimplanted cancer cells are exposed to the immune system as quickly and thoroughly as possible, in hopes of generating a robust immune response. For that reason, subcutaneous reimplantation may be suitable in at least some embodiments of method 10, because the dendritic cells under the skin are antigen- presenting cells and are generally present in large numbers. However, other locations are possible for reimplantation.
  • cells may be reimplanted at or close to the location in which they were extracted.
  • a number of different insertion methods may be used. Open and endoscopic surgical procedures are possible and suitable methods of reimplantation. Depending on the location of reimplantation, though, large-bore needle insertion may achieve the desired results with minimal trauma to the patient.
  • any suitable medical tool or tools may be used. For example, a scalpel may be used to make a small incision in the skin, and a needle or catheter inserted beneath the skin to deliver the inactivated cancer cells. Trocars may be used to punch through dense tissue to reach particular reimplantation sites. Other methods will be apparent to those of ordinary skill in the art.
  • task 18 may be performed any number of times.
  • a patient may be given an initial inoculation with his or her own cryo-inactivated cancer cells, followed by additional inoculations at particular intervals, e.g., two weeks, three months, six months, etc.
  • additional inoculations at particular intervals, e.g., two weeks, three months, six months, etc.
  • Each time, preserved, cryo- inactivated cells from the original extraction may be used.
  • this resembles the way that BCG is used as an inoculant in bladder cancers: an initial (i.e., inductive) treatment, followed by time-spaced follow-up treatments, usually two treatments spaced 3 months apart, followed by treatments spaced 6 months apart for a total of 2-3 years of treatment after the initial inoculation.
  • Treatments according to embodiments of the present invention may follow roughly the same schedules.
  • the follow-up treatments may be used to continue stimulating the immune system to meet treatment goals.
  • this possibility of repeated treatments is represented by task 20, a decision task. If the treatment goals have been reached (task 20:YES), method 10 ends at task 22. If the treatment goals have not been reached (task 20:NO), method 10 returns to task 18 and more inactivated cells are reimplanted as a follow-up treatment. Of course, either the entirety of method 10 or other individual tasks may be repeated as needed.
  • treatment goals refers to any goal that a physician or other treating medical practitioner may set for a patient, given the patient’s history, the nature and stage of the particular cancer, and the expected prognosis, among other factors.
  • treatment goals may include stabilization or lack of progression of the cancer; cure or remission; survival; disease-free survival; or progression-free survival.
  • Each patient’s treatment goals may be different.
  • One potential advantage of method 10 is that the immunotherapeutic treatment uses the patient’s own inactivated cancer cells at a particular point in the growth of the cancer. Thus, the immunotherapy may be highly selective for both the particular cancer and its particular stage of development.
  • method 10 may be performed on an early stage cancer just after detection with repeated reimplanations of the originally -extracted and cryo- inactivated cells for continuing treatment or maintenance at particular intervals of time if needed. If, after some time, the treatment has not shown satisfactory results, method 10 may be repeated, with more cells extracted, inactivated, and reimplanted.
  • the newly-extracted cells may be at a different stage of development than cells extracted just after detection, and thus, the newly -extracted cells may present different antigens than the original extracted, inactivated cells. In other words, the treatment can be made to correspond precisely to the stage and development of the disease.
  • a new reimplantation site may be chosen, or a different technique may be used to reimplant the cells in task 18.
  • task 20 of method 10 divides treatment into two phases, an initial treatment phase and a follow-on or maintenance phase.
  • the characteristics of the treatment may be the same in each phase, or they may be different.
  • inactivated cells may be reimplanted in solid form under the skin by surgical placement or by subcutaneous injection of a prepared mass of cells using a large-bore needle. Following treatments may use the same batch of cells in the same or lesser quantity, and in the same or different form. For example, follow-on treatments may use a lesser quantity of cells in a liquid carrier, introduced subcutaneously in any convenient location, at a location close to the tumor site, or in another location.
  • a liquid carrier was described briefly above: its composition and characteristics may be chosen so as to reduce the likelihood of damaging the antigens of the cryo-inactivated cells. For example, it may be buffered to a specific pH, and may be isotonic as compared with any remaining intracellular fluid.
  • FIG. 1 illustrates that the clinician continues to re-implant cells from the initial extraction, the clinician may decide to extract new cells from a remaining tumor and use those cells in a follow-on or maintenance iteration of method 10.
  • Method 10 may be used alone or in combination with other types of treatments.
  • a general immunostimulant like BCG may be used in conjunction with method 10 as an adjuvant immunotherapy.
  • the immunostimulant may be any antigen that can stimulate an immune response, although it is helpful if that antigen is benign or unlikely to create a disease state.
  • some traditional cancer therapies may be used in conjunction with method 10 and other methods according to embodiments of the invention.
  • many types of chemotherapy are unlikely to affect the cancer cells’ antigens, and thus, at least some forms of chemotherapy may be used concurrently with method 10.
  • combining method 10 with other forms of treatment may be a question of the order in which the treatments are performed.
  • radiation is likely to denature the cells’ antigens.
  • radiation treatment may be given after cell extraction in task 12 but before reimplantation in task 18.
  • radiation may be used after reimplantation if the reimplantation site is different than the site where radiation is targeted or brachytherapy is used.
  • the process of extracting cells is cytoreductive, i.e., it reduces the tumor volume and may thus improve the patient’s symptoms.
  • cytoreductive i.e., it reduces the tumor volume and may thus improve the patient’s symptoms.
  • volume of cells may be extracted in task 12
  • multiple“doses” of the cryo-inactivated cells may be given to the patient over time, extracting as large a mass of cancerous cells as possible may be preferable both for its cytoreductive effect and in order to have sufficient cells with which to perform the rest of method 10.
  • task 12 may involve extracting cancerous cells from several different factions in a single set of procedures. Some embodiments may also include additional tasks prior to task 12 that focus on identifying the extent of a patient’s tumor, factions, or metastases and prioritizing the factions from which cells should be extracted first.
  • the inoculant/reimplanted cells in task 18 of method 10 may comprise a variety of cells, or portions thereof, from different factions and, if desired, from different stages of development.
  • a single inoculation or reimplantation may comprise cells from different portions of a single tumor or from a primary tumor and from one or more secondary tumors (i.e., metastases), taken at different points in time.
  • secondary tumors i.e., metastases

Abstract

L'invention concerne des méthodes de traitement immunothérapeutique de cancers et de préparation de cellules cancéreuses inactivées destinées à un traitement immunothérapeutique. Dans un mode de réalisation, des cellules cancéreuses sont extraites d'un patient, inactivées par cryogénisation, et réimplantées chez le même patient. L'étape d'extraction peut comprendre une séparation des cellules cancéreuses depuis des fluides corporels. La méthode d'inactivation par cryogénisation serait à même de préserver les antigènes ou protéines de surface des cellules, y compris leur structure protéique tertiaire et quaternaire, permettant ainsi aux cellules inactivées réimplantées de provoquer une réponse immunitaire contre le cancer du patient. Les patients peuvent recevoir des doses répétées de leurs propres cellules cancéreuses inactivées par cryogénisation dans la durée afin de continuer à stimuler la réponse immunitaire contre le cancer. Les méthodes de préparation des cellules cancéreuses inactivées destinées à une réimplantation peuvent impliquer la sélection d'une masse appropriée de cellules, la mise en forme des cellules et, si nécessaire, l'étude des cellules pour obtenir leurs caractéristiques anatomopathologique, génétique et moléculaire, ou d'autres informations.
PCT/US2019/027806 2018-04-19 2019-04-17 Cellules cancéreuses inactivées par cryogénisation pour l'immunothérapie anticancéreuse WO2019204391A1 (fr)

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WO2021016261A3 (fr) * 2019-07-22 2021-04-08 Todd Alamin Traitements de cellules et méthodes thérapeutiques de reperfusion
WO2022087110A1 (fr) * 2020-10-20 2022-04-28 The Regents Of The University Of California Cellules cancéreuses atténuées et procédés associés

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WO2022087110A1 (fr) * 2020-10-20 2022-04-28 The Regents Of The University Of California Cellules cancéreuses atténuées et procédés associés

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