Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
• • 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
  • A61K35/14—Blood; Artificial blood
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/085—Staphylococcus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/385—Haptens or antigens, bound to carriers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/44—Antibodies bound to carriers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/10—Cellular immunotherapy characterised by the cell type used
  • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
  • A61K40/41—Vertebrate antigens
  • A61K40/42—Cancer antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
  • A61P31/06—Antibacterial agents for tuberculosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
  • C12N5/06—Animal cells or tissues; Human cells or tissues
  • C12N5/0602—Vertebrate cells
  • C12N5/0634—Cells from the blood or the immune system
  • C12N5/0636—T lymphocytes
  • C12N5/0637—Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55516—Proteins; Peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55522—Cytokines; Lymphokines; Interferons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55522—Cytokines; Lymphokines; Interferons
  • A61K2039/55527—Interleukins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55522—Cytokines; Lymphokines; Interferons
  • A61K2039/55527—Interleukins
  • A61K2039/55533—IL-2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
  • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
  • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/50—Cellular immunotherapy characterised by the use of allogeneic cells

Definitions

• This invention relates to therapy using immune cells. More specifically, this invention relates to immune cell therapy that promotes IL-12 production in patients.
• the most precise, powerful and safest disease prevention and treatment mechanism known is the natural 'sterilizing' immune response which combines elements of both innate and adaptive immunity to clear the body of a large variety of foreign pathogens without medical intervention.
• the immune system is designed to 'remember' the cleared foreign antigens in order to quickly mount an immune response upon re-infection.
• Immune systems even those of cancer patients, can recognize and mount a response to foreign antigens, such as found on viruses and bacteria, sufficiently enough to completely destroy and eliminate them from the body.
• the ferocity and specificity of this sterilizing immune response can be witnessed in the manner in which an inadequately suppressed immune system can completely destroy large transplanted organs, such as a kidney, liver or heart, while sparing self tissues.
• the destructive effect of this immunity against foreign antigens would be beneficial if this effect could be redirected to tumors and/or other antigens that escape due to an insufficient immune response by the patient.
• Immunotherapy is dedicated to developing methods to harness, direct and control the immune response against a variety of infectious and noninfectious diseases including cancer.
• Therapeutic vaccines are a type of immunotherapy designed to educate the immune system. In patients with existing cancers, the vaccines are designed so the patient's immune system recognizes the tumor cells as foreign. If tumors are recognized by the immune system as a foreign pathogen, an immune response could theoretically be elicited which could cause immune cells to destroy large tumors and seek out and destroy metastatic tumor cells wherever they reside in the body. After successful immunotherapy, the ability of the immune system to 'remember' eliminated foreign cells would enable the immune system to eliminate any recurrent cancer cells without any additional treatment, much like the immune system protects against opportunistic infections.
• Thl/Th2 balance An individual's immune system response to diseases or to disease organisms can be either a Thl response or Th2 response.
• Thl/Th2 balance This increasingly popular classification method is referred to as the Thl/Th2 balance.
• Thl cells promote cell-mediated immunity, while Th2 cells induce humoral immunity.
• Cellular immunity (Thl) directs natural killer cells (NK), T-cells and macrophages to attack abnormal cells and microorganisms at sites of infection.
• Humoral immunity (Th2) results in the production of antibodies used to neutralize foreign invaders.
• Th2 polarization of CD4+ T cells has been shown to relate to cancer progression in most human and animal cancer studies, while Thl polarization is correlated with tumor regression and anti-tumor immunity.
• Cytokines are small cell- signaling protein molecules.
• the term cytokine is used as a generic name for a diverse group of soluble proteins and peptides that act as regulators normally at nano- to picomolar concentrations and which, either under normal or pathological conditions, modulate the functional activities of individual cells and tissues. These proteins also mediate interactions between cells directly and regulate processes taking place in the extracellular environment.
• Interleukins are a group of cytokines involved in immunomodulation and can be synthesized by a variety of cells in the immune system. There are a number of interleukins, such as IL-2, IL-4, IL-10 and IL-12, and each of these interleukins has a specific role within the immune system.
• Thl cells produce Type 1 cytokines that are involved in inflammatory responses.
• Type 1 cytokines include, for example, IL-2, IL- 12, IL-15, IFN-gamma, TNF-alpha, TNF-beta, GM-CSF and C-C chemokines.
• Th2 cells produce Type 2 cytokines that are involved in humoral immune responses.
• Type 2 cytokines include, for example, IL-4, IL-5, IL-6, IL-10, IL-13 and TGF-beta.
• Thl and Th2 immune responses are counter-regulatory, such that increased Type 1 responses downregulate Type 2 responses and increased Type 2 responses downregulate Type 1 responses.
• IL-12 is a heterodimer composed of a p35 and a p40 subunit. It is produced primarily by Antigen Presenting Cells (APC). IL-12 can also be produced by monocytes and macrophages, dendritic cells and B-cells. IL-12 exerts immunomodulatory effects on T-cells and natural killer cells. Endogenous IL-12 is known to be involved in generating optimal Thl responses and can play an important role in cell-mediated immunity against intracellular pathogens.
• APC Antigen Presenting Cells
• IL-12 has been the subject of intense investigation because it modulates important components of the immune system and has been demonstrated to have dramatic anti-tumor effects in the laboratory and in animal studies. IL-12 has been implicated, for example, in inhibiting growth of human lung adenocarcinoma and acute myeloid leukemia. However, the use of exogenous IL-12 in a therapeutic regimen has been limited by high toxicity in humans.
• Fig. 1 is a graph illustrating the IL-12 level in a patient's plasma over more than a year. Allogeneic, activated Th-1 cells were administered to the patient at various times using various modes of administration.
• the present invention relates to compositions and methods that lead to detectable levels of IL-12 in the plasma of a patient.
• the present invention includes a composition that, when administered to a patient, can lead to the production of detectable levels of endogenous IL- 12 in the patient's plasma, without any significant toxicity.
• the endogenous IL-12 can surprisingly be detected in patients with cancer.
• the composition preferably includes allogeneic activated T-cells. T-cells are not capable of producing IL-12, therefore the T-cell composition administered to the patient elicits the production of IL-12 by the patient's own APC.
• the present invention also includes methods of inducing production of endogenous IL-12 in a patient by the patient's own immune system.
• the method includes administering a composition of allogeneic material, preferably allogeneic activated T-cells.
• the composition may be administered as a single dose or multiple doses.
• the allogeneic activated T-cells are administered in frequent, low doses.
• the allogeneic cells can be administered by intradermal, intravenous or intralesional routes.
• the frequency is not less than every 3 days.
• IL-12 is not found in patients with cancer because tumors can inhibit expression of IL-12.
• the methods described herein can overcome this inhibition and create an environment sufficient to induce expression of IL-12 in the plasma for extended periods of time, for example, several months or even a year.
• the presence of endogenous IL-12 in plasma does not lead to significant toxicity in the patient as does the administration of exogenous IL-12 as medicant.
• endogenous IL-12 it is meant that the IL-12 is synthesized in the patient by the patient's own immune system.
• the IL-12 can be synthesized by the patient's antigen presenting cells (APC).
• APC can include monocytes and macrophages, dendritic cells and B- cells.
• exogenous IL-12 it is meant that the IL-12 is not synthesized by the patient's own immune system.
• Exogenous IL-12 includes IL-12 isolated and/or purified IL-12 from another individual or IL-12 that is expressed by a DNA construct(s) that includes a gene for IL-12.
• the systemic production of endogenous IL-12 in the patient leads to minimal or no toxicity to the patient.
• the patient may experience transient symptoms such as transient flu-like symptoms.
• transient symptoms such as transient flu-like symptoms.
• toxic effects have limited the use in a therapeutic setting.
• the ability of the methods described herein to promote endogenous production of IL-12 that can lead to systemically detectable levels of IL-12 in the plasma without toxicity is surprising. This result enables the use of the patient's own immune system to harness the benefits created from the presence of IL-12 toward reduction and/or elimination of tumors and cancerous cells.
• IL-12 diseases that respond favorably to a Thl environment, specifically to IL-12.
• diseases include cancer, infectious diseases, including chronic viral and intracellular bacterial or mycobacterial diseases, such as hepatitis B, hepatitis C, HIV1, HIV2, HTLV1, HTLV2, HPV, mycobacterium tuberculosis, periodontal disease, and allergic diseases like atopic asthma.
• infectious diseases including chronic viral and intracellular bacterial or mycobacterial diseases, such as hepatitis B, hepatitis C, HIV1, HIV2, HTLV1, HTLV2, HPV, mycobacterium tuberculosis, periodontal disease, and allergic diseases like atopic asthma.
• methods to promote the endogenous production of IL-12 can have an anti-aging effects by maintaining cellular immunity. The balance of Thl to Th2 cells in normal individuals decreases as part of the aging process, making the elderly more susceptible to infectious diseases and cancer. Promotion of endogenous IL-12 production can increase the Thl/Th2 ratio, thus
• compositions of the present invention generally include foreign antigens, preferably alloantigens.
• the compositions also include at least one Thl cytokine and/or at least one DC effector molecule capable of inducing the maturation of DC to produce IL-12.
• the therapeutic composition generally includes the at least one Thl cytokine, and/or the at least one DC effector molecule combined together with the alloantigen.
• the composition preferably contains living allogeneic activated T-cells that are capable of providing each of the components of the composition in a single cell type.
• Thl cytokines such as interferon-gamma, tumor necrosis factor- alpha and interleukin-2 and express the DC maturation effector molecule CD40L on the cell surface
• the three components of the composition could be sourced from more than one cell type.
• the Thl cytokines may be sourced from one cell type in a composition and the alloantigen from a separate cell type and the DC effector molecules from a third cell type.
• one cell type could contain any two of the components and a second cell type contain the third.
• the cell types do not need to be living as long as they provide a source of the necessary components of the composition.
• composition components can be sourced from natural or bioengineered proteins.
• recombinant or purified Thl cytokines or DC maturation molecules or alloantigens could be used together or in combination with living cell components.
• the composition components could be combined on a "chip" or biodegradable platform. The components do not need to be delivered at the same time to a patient, but can be delivered in any sequence.
• the alloantigens in the therapeutic compositions must be provided in a manner that the antigen can be engulfed or presented to the immune system in order to be processed and presented to T-cells.
• the antigen can be a natural part of living cells or can be altered or bioengineered using molecular biological techniques.
• the antigen can be soluble or immobilized on a surface, an intact part of a living organism or cell, or a part of an attenuated organism.
• the alloantigens are allogeneic T-cells and in more preferred embodiments, allogeneic activated T-cells.
• the therapeutic composition includes alloantigens expressed on T-cells.
• the T-cells are preferably CD4+ T-cells, and more preferably Thl cells.
• the Thl cells can be in- vitro differentiated, expanded and activated from naive CD4+ precursor cells derived from normal blood donors.
• the cells are in an activated state at the time of administration.
• the cells are activated by cross-linking monoclonal antibodies directed to CD3/CD28 surface molecules. Crosslinking is preferably caused by immobilization of the CD3/CD28 monoclonal antibodies on a surface.
• the surface is a micro- or nanabead particle.
• the beads may be biodegradable beads.
• the therapeutic composition includes activated allogeneic Thl cells.
• activated Thl cells can be powerful inflammatory agents.
• These activated allogeneic Thl cells and methods for preparing them are described, for example, in U.S. Patent Numbers 7,435,592, 7,678,572, 7,402,431 and 7,592,431 and are incorporated herein by reference.
• the activated allogeneic Thl cells are intentionally mismatched to the patient.
• Thl inflammatory cytokines may be included in the therapeutic compositions.
• inflammatory Thl cytokines include: IL-1, IL-2, IL-6, IL-12, IL-15, IFN-gamma, TNF-alpha, TNF-beta, GM-CSF and C-C chemokines and do not include TGF- beta, IL-4 or IL-10.
• the cytokine component can be natural or recombinant cytokines or can be bioengineered molecules designed to interact with the receptors for a cytokine.
• the cytokines may be directly included in the therapeutic compositions.
• the therapeutic compositions can include living cells or other components that produce and secrete the cytokines.
• the cytokines are provided naturally through an activated cell source, as exogenous cytokines tend to be very toxic to patients while endogenous cytokines are not.
• the therapeutic compositions include T-cells in an activated state that are producing and secreting the inflammatory Thl cytokines and thus, can serve as the source of these cytokines in the therapeutic compositions.
• the therapeutic composition can include a factor or factors that cause the maturation of immature DCs.
• maturation factors which promote DC1 cell maturation and IL-12 production leading to interferon- gamma production and Thl adaptive immunity.
• DCs are capable of evolving from immature, antigen-capturing cells to mature, antigen-presenting, T cell-priming cells which convert antigens into immunogens and express cytokines, chemokines, costimulatory molecules necessary to initiate an immune response.
• T cell-mediated immune responses Thl vs. Th2
• DCs The ability of DCs to regulate immunity such as anti-tumor and anti-infectious disease immunity is dependent on DC maturation to promote Thl immunity.
• Human DCs are not a homogenous population. Besides inducing anti-tumor immunity, DCs can induce anergy or tolerance.
• DCs originate from CD34+ hematopoietic stem cells (HSC).
• HSC hematopoietic stem cells
• DC1 and DC2 are the two principal subpopulations of human DCs, and their characteristics vary greatly in phenotype, migration, and function.
• DC1 cells are effective T cell stimulators, inducing a tumor specific immune response.
• CDl lc+DCl cells primarily induce Thl differentiation, whereas DC2 cells, which express the receptor for IL- 3 (CD 123), mainly promote a Th2 response. Both DC populations are significantly lower in patients with cancer than in healthy donors. DC1 cells produce IL- 12 upon maturation and DC2 cells produce IL- 10.
• cytokines such as IL- 10 and IL-12 during the DC maturation process influences DC induction of a Thl or Th2 immune response.
• mature DC In addition to expressing high levels of antigen-presenting molecules and costimulatory molecules, mature DC must release large amounts of IL-12 in order to stimulate a Thl immune response. Release of IL- 10, blocks the DC maturation process by interfering with up-regulation of costimulatory molecules and production of IL-12, subsequently limiting the ability of DCs to initiate a Thl response.
• a variety of factors can induce maturation of DC to become DC1, IL-12 producing cells following antigen uptake and processing, including: whole bacteria or bacterial-derived antigens (e.g. lipopolysaccharide, LPS), inflammatory cytokines such as IFN-gamma, TNF- alpha, IL- 1, GM-CSF, ligation of select cell surface receptors (e.g. CD40), viral products (e.g. double-stranded RNA), Fas engagement on immature DCs, for example, induces both maturation and release of IL- 1 beta and IFN-gamma.
• whole bacteria or bacterial-derived antigens e.g. lipopolysaccharide, LPS
• inflammatory cytokines such as IFN-gamma, TNF- alpha, IL- 1, GM-CSF
• ligation of select cell surface receptors e.g. CD40
• viral products e.g. double-stranded RNA
• chemokines e.g. IL-8, MIP- 1 alpha, MIP- 1 beta.
• CD40L is included as a factor for maturation of the DCs. Inclusion of other factors that cause maturation of the DCs is also within the scope of the invention.
• the therapeutic compositions include T-cells in an activated state which express high density CD40L on the surface. CD40L is a potent effector molecule for DC maturation to produce IL- 12.
• the therapeutic composition includes activated allogeneic T-cells, at least one type I cytokine and at least one factor that causes maturation of DCs. Compositions including these components are described, for example, in pending U.S. Patent Application Ser. No. 12/967,910 filed on Dec. 14, 2010 and incorporated herein by reference.
• Intratumoral administration of the therapeutic compositions after ablation of some of the tumor cells in order to release tumor associated antigens into the microenvironment can provide a potent adjuvant effect for the maturation of DC to DC1 phenotype which produces IL- 12 and promotes development of Type 1 anti-tumor immunity and the down regulation of tumor immunoavoidance mechanisms.
• Administration of the therapeutic composition can also be accomplished by other methods including, for example, intravenous, intradermal, intrathecal, intraperitoneal, intralesional, intrapleural administration and the like.
• the composition is first administered intradermally, as the skin is rich in immature DC called Langerhans cells.
• Thl cytokines such as interferon-gamma, tumor necrosis factor-alpha, IL-2 and GM-CSF and a DC maturation factor, such as CD40L
• the Langerhan's cells uptake the alloantigen and mature to DC1, IL-12 producing cells. These mature cells migrate to the lymphnodes and promote development of Thl immunity.
• Intradermal injections of the composition can "prime" a patient to become immune to the alloantigen in the composition. Multiple intradermal injections can increase the number of Thl memory cells specific for the alloantigens in the circulation of the patient, which in turn changes the Thl/Th2 balance. Injection of 1 xlO 6 cells to 1 x 10 7 allogeneic activated Thl cells is a preferred intradermal dose, 1 x 10 cells in 1ml of fluid is the most preferred.
• the intradermal dosing is preferably repeated multiple times in order to build up the number of circulating Thl memory cells.
• the intradermal dosing frequency is preferably about 3-4 injections every 7 days, more preferably every 3-4 days.
• the intradermal dosing is followed by an intratumoral dosing of the composition to create an in-situ vaccine.
• the intratumoral dosing is preferably conducted following the in-situ ablation of some of the tumor cells in the target lesion.
• the ablation is preferably caused by use of extreme cold (cryoablation) or heat (radiation), but can be also done using a variety of methods including alcohol ablation, chemotherapy and/or monoclonal antibody drugs.
• a preferred intratumoral dose is between about 1 x 107 and 1 x 108 cells, most preferably about 3 x 10 cells. It is preferred that a first intratumoral dose be injected immediately following the ablation and a second within about 7 days, preferably within about 3- 4 days following the first injection. This process of ablation followed by intratumoral injection of the composition can be repeated as necessary.
• the method also preferably includes administering the composition intravenously in order to cause the activation of host immune cells (both innate and adaptive) and their extravasation to sites of inflammation, including tumor locations.
• the intravenous dose of the composition preferably includes administering the composition intravenously in order to cause the activation of host immune cells (both innate and adaptive) and their extravasation to sites of inflammation, including tumor locations.
• composition of allogeneic activated Thl cells preferably includes about 1 x 10 to 1 x 10 cells
• the intravenous infusions can be repeated several times, preferably on a monthly basis.
• the allogeneic Thl cells of the composition preferably produce large amounts of the Type 1 cytokines: IL2, IFN- ⁇ , TNF- alpha and GM-CSF.
• Type 1 cytokines IL2, IFN- ⁇ , TNF- alpha and GM-CSF.
• the presence of inflammatory Thl cytokines in a microenvironment where immature DC are engulfing and processing antigens can help promote maturation to DC1, IL-12 producing DC.
• IL-12 can stimulate the level of IFN- ⁇ that in turn can lead to promotion of a Thl immunity.
• IFN- ⁇ is a pivotal Type 1 cytokine necessary to promote Type 1 anti-tumor immunity.
• IFN- ⁇ can mediate anti-tumor effects by directly inhibiting tumor cell growth and inducing T cell-mediated anti-tumor responses.
• IFN- secretion can independently contribute to the NK cell response and enhance the NK cell response activated by IL-12.
• the preferred medicament containing activated allogeneic Thl cells can be derived from precursors purified from normal, screened blood donors.
• the cells should be supplied as a sterile, low endotoxin dosage form formulated for either intradermal or intratumoral injection, or intravenous infusion.
• the cells may also be formulated for intraperitoneal, intrapleural or epidural infusions.
• the donors are preferably tested to be negative for HIV1, HIV2, HTLV1, HTLV2, HBV, HCV, RPR (syphilis), and the cells are preferably tested to be negative for mycoplasma, EBV and CMV.
• the activated allogeneic cells are HLA mismatched with the patient.
• the methods of the present invention generally relate to producing detectable levels of endogenous IL-12 in the patient's plasma.
• the methods include administering the compositions of the present invention in such a way as to engineer the patient's immune system to produce endogenous IL-12 at detectable levels in the patient's plasma.
• the methods described herein can increase the circulating numbers of Thl immune cells in cancer patients, shifting the balance from Th2 environment to a Thl environment. Additionally, the methods may also include steps that elicit an anti-tumor specific Thl immunity and/or activate components of the innate and adaptive immune responses to generate a sustained Thl cytokine environment in order to down-regulate tumor immunoavoidance.
• the methods of the present invention can include administering a composition containing a foreign antigen to promote Thl immunity in the patient against the foreign antigen.
• the method may also include ablating all or a portion of the tumor that results in at least some tumor necrosis.
• a variety of methods can be used to generate tumor necrosis in the patient.
• the method may also involve creating an inflammatory microenvironment in proximity to the site of tumor necrosis, i.e the site of the tumor lesion.
• the method can also include activating the adaptive and innate immune cells of the patient to maintain a prolonged Thl environment.
• a key component of the method includes the use of a medicant or composition containing activated allogeneic T cells as described above.
• the objective of this method of treatment is generally to increase the amount of circulating Thl cells in cancer patients.
• the number of circulating Thl cells can be built up in the cancer patient by administering one of the therapeutic compositions described above to the patient that includes a foreign antigen.
• the patient is administered activated allogeneic Thl cells that are injected intradermally.
• intradermal injections are on a weekly schedule once a week for about 3-4 weeks.
• the intradermal injections may be administered multiple times about every 3-4 days.
• Intradermal injections may be administered every two days or up to a year apart.
• the injection schedule should be designed to enhance the footprint of Thl memory cells in circulation.
• the alloantigens expressed on the foreign cells can stimulate a potent immune rejection response.
• Thl cytokines in the composition or the expression of Thl cytokines by the allogeneic cells can provide the inflammatory adjuvant environment necessary to steer the immune response to the alloantigens toward Thl memory immunity. This can create an increased pool of Thl memory cells in circulation in the patient specific for the alloantigens contained within the allogeneic Thl cells. Multiple administrations can act as booster shots, increasing the number of circulating memory Thl cells specific for the alloantigens.
• the administration of allogeneic activated T cells may be followed by additional steps to enhance the patient response. These steps can include, for example, ablation of the tumor that causes tumor necrosis along with intratumoral administration of additional allogeneic activated T cells. Additional administration of the allogeneic activated cells intravenously may also be performed. These methods are described in the U.S. Patent No. 7,972,594 to Har-Noy incorporated herein by reference.
• the administration of the therapeutic compositions or medicaments using the methods described herein can promote the systemic production of endogenous IL-12 in the patient by the patient's own immune system.
• the concentration of the endogenous IL-12 in the patient is sufficient that the IL-12 can be detected in the patient's plasma.
• the detectable levels of IL-12 are endogenous and not a result of any that might be present in the therapeutic composition because generally the components of the composition are eliminated by the patient's immune system in the rejection response elicited by the administration of allogeneic material.
• the composition contains T-cells which can not produce IL-12.
• any of the IL-12 detected in the patient's plasma is a result of the IL-12 produced by the patient's own immune system.
• the IL-12 is produced by the patient's immune cells, for example, the patient's own monocytes, natural killer cells and dendritic cells. These cells will have matured under the influence of the inflammatory or Type I cytokines generated by the administration of the compositions described herein.
• the concentration of the IL-12 in the patient's plasma can vary but is generally at least about 8000pg/ml.
• the concentration of the IL-12 in the patient's plasma is preferably between about 8000pg/ml to 200,000pg/ml.
• the concentration of the IL-12 detected in the plasma of the patient does not lead to toxicity issues.
• administration of exogenous IL-12 has been known to be toxic to patients.
• Patients that seroconvert to IL-12 expression in the plasma have an increased survival compared to patients that do not express IL- 12 in their serum.
• the level of IL-12 may not correlate with survival, only the presence of IL-12 is crucial.
• the increase in IL-12 is generally detected after a period of time after the administration of the composition.
• the IL-12 can be detected in the plasma.
• the IL-12 in the plasma can be detected by using a variety of methods.
• IL-12 has two subunits called the p40 and p35 chains and antibodies specific to p40 are preferred for detection.
• Several methods are available to detect the presence of IL-12. Detection of IL-12 can include, for example, ELISA, and cytokine bead array.
• the methods described herein can be suitable for a variety of patients, including humans. The methods may also be used on other mammals.
• the present invention also includes methods of treating a disease in a patient.
• the diseases can include cancerous tumors as described above, hematological malignancies, as well as diseases caused by pathogenic agents. Other diseases that are susceptible to a Thl response in a patient can also be treated using the methods described herein.
• the patient is administered the allogeneic composition according to the methods described herein.
• the patient's plasma is then monitored for the presence of IL-12.
• Intradermal Injections-Intradermal injections of activated allogeneic Thl cells were administered.
• the cells were suspended in 1ml at a density of 1 x 10 cells/ml.
• Intratumoral /ftjeciio/is-Intratumoral injection was administered in the necrotic center of an ablated tumor within one hour of ablation.
• Cryoablation was done with the use of a CryoCare-28 Percutaneous Probe System (Endocare, CA, USA). This system used the Joule-Thomson effect to cool the end of a cryoprobe in a closed system. In accordance with the gas coefficient and the dimension of the nozzle, different gaseous elements generate different thermal exchange events at the area close to the nozzle. Argon gas was used for cooling (-187°C), and helium was used for heating (67°C).
• the planned target tumor lesion was identified and located under CT image guidance. A sterile field was created and local anesthesia administered to the planned probe insertion site. A guide probe was inserted percutaneously and verified by CT to be within the target tumor lesion. One or two freeze-thaw cycles were performed. A single probe of 2- or 5-mm was used according to the size of the target tumor. The time of freezing was approximately 5-20 minutes dependent on the achievement of an "ice-ball", visible on CT. Thawing was achieved by input of helium during a period equivalent to the freezing time before the second freezing process was initiated. The procedure requires ablation of a sample of the tumor lesion and does not require complete tumor ablation with tumor- free margins.
• Tables 1, 2 and 3 show the timing of the specific treatments and the level of IL-12 in the patient's plasma on the indicated days.
• Fig. 1 is a graph illustrating the IL-12 expression by the patient' s immune system during the study.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Immunology (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Zoology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Microbiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biomedical Technology (AREA)
• Mycology (AREA)
• Biotechnology (AREA)
• Cell Biology (AREA)
• Wood Science & Technology (AREA)
• Genetics & Genomics (AREA)
• Virology (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Hematology (AREA)
• Biochemistry (AREA)
• General Engineering & Computer Science (AREA)
• Pulmonology (AREA)
• Molecular Biology (AREA)
• Developmental Biology & Embryology (AREA)
• Tropical Medicine & Parasitology (AREA)
• AIDS & HIV (AREA)
• Toxicology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (17)

Applications Claiming Priority (8)

Related Child Applications (2)

Publications (2)

Family

ID=47108207

Family Applications (1)

Country Status (12)

Cited By (2)

Families Citing this family (4)

Citations (6)

Family Cites Families (45)

• 2012
  • 2012-05-02 BR BR112013028285A patent/BR112013028285A2/pt not_active Application Discontinuation
  • 2012-05-02 AU AU2012250807A patent/AU2012250807A1/en not_active Abandoned
  • 2012-05-02 CN CN201910193492.3A patent/CN109876138A/zh active Pending
  • 2012-05-02 CA CA2838046A patent/CA2838046C/en active Active
  • 2012-05-02 SG SG10201901391RA patent/SG10201901391RA/en unknown
  • 2012-05-02 EP EP12779711.6A patent/EP2704732B1/en active Active
  • 2012-05-02 CN CN201280021818.0A patent/CN103687602A/zh active Pending
  • 2012-05-02 SG SG2013081302A patent/SG194753A1/en unknown
  • 2012-05-02 PH PH1/2013/502252A patent/PH12013502252B1/en unknown
  • 2012-05-02 JP JP2014509386A patent/JP6393186B2/ja active Active
  • 2012-05-02 US US13/581,745 patent/US9233156B2/en active Active
  • 2012-05-02 KR KR1020137032017A patent/KR102121492B1/ko active Active
  • 2012-05-02 WO PCT/US2012/036123 patent/WO2012151279A2/en not_active Ceased
• 2013
  • 2013-10-31 IL IL229177A patent/IL229177B/en active IP Right Grant
• 2015
  • 2015-12-08 US US14/962,728 patent/US11045541B2/en not_active Expired - Fee Related
• 2017
  • 2017-04-12 JP JP2017079200A patent/JP6615148B2/ja active Active
  • 2017-06-15 AU AU2017204058A patent/AU2017204058A1/en not_active Abandoned
• 2019
  • 2019-07-01 AU AU2019204699A patent/AU2019204699A1/en not_active Abandoned
• 2021
  • 2021-05-20 US US17/326,009 patent/US11883490B2/en active Active
• 2024
  • 2024-01-17 US US18/415,111 patent/US20240148865A1/en active Pending

Patent Citations (6)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events