WO2000003733A1 - Methodes et compositions pour traiter le cancer - Google Patents

Methodes et compositions pour traiter le cancer Download PDF

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Publication number
WO2000003733A1
WO2000003733A1 PCT/US1999/015716 US9915716W WO0003733A1 WO 2000003733 A1 WO2000003733 A1 WO 2000003733A1 US 9915716 W US9915716 W US 9915716W WO 0003733 A1 WO0003733 A1 WO 0003733A1
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virus
cancer
antigen
transfer factor
vaccine
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PCT/US1999/015716
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English (en)
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Vincent Marinkovich
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Vincent Marinkovich
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Priority to AU50970/99A priority Critical patent/AU5097099A/en
Publication of WO2000003733A1 publication Critical patent/WO2000003733A1/fr
Priority to US09/764,224 priority patent/US7112328B2/en

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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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18711—Rubulavirus, e.g. mumps virus, parainfluenza 2,4
    • C12N2760/18732—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent

Definitions

  • This invention relates to the field of therapeutic agents in medicine.
  • this invention relates to the field of cancer immunotherapy.
  • Monoclonal antibodies react with a single foreign substance (antigen) as do all antibodies, but their most valued characteristics are that they can be selected and created to react with a simple desired antigenic epitope, they can be made in large quantities, and they are relatively innocuous when injected into the human host.
  • the techniques for creating monoclonal antibodies were elaborated thirty years ago, although refinements in technology continue to date.
  • the present invention is directed to compositions and methods for cancer immunotherapy.
  • compositions for cancer immunotherapy may include a virus that infects cancer cells, monoclonal antibodies that recognize cancer cells, or other specific cancer cell receptor agonists to which a specific T-cell activity can be generated.
  • the administration of the composition is accompanied by the administration of transfer factor as a means of conferring upon the patient a specific T-cell response against a composition antigen.
  • the transfer factor may by administered before, during or after the administration of the cancer immunotherapy composition.
  • the vaccines may comprise a monoclonal antibody and transfer factor or a virus and transfer factor or a specific cancer cell receptor antagonist and transfer factor.
  • the patient may be previously immunized to the specific antigenic component of the composition molecule by standard immunogenic techniques.
  • the antigen may also be selected to correspond to a T-cell activity the patient already possesses.
  • the components of the vaccine may be administered at different times in sequence.
  • the monoclonal antibodies of the invention may be conjugated to an antigen.
  • the antigen will be an antigen that predominately elicits a cell mediated immune response rather than a hummoral immune response.
  • the antigen may be a virus to which the patient may be immunized or to which the patient has already developed an immune response.
  • viruses incude the mumps virus, the hepatitis virus and the encephalitis virus among others.
  • the antigen may be Aspf 1 from the fungus aspergillus, tuberculo protein, coccidioidin, or other antigens known to elicit a major T-cell (delayed immunity) response in humans.
  • the vaccines may also comprise a virus.
  • the virus will be a virus to which the patient has already developed an immune response.
  • viruses include the mumps virus, the hepatitis virus and the encephalitis virus.
  • viruses of the invention may also be modified to include an antigen such as Aspfl from the fungus aspergillus, tuberculo protein, coccidioidin, or other antigens known to elicit a major T-cell (delayed immunity) response in humans.
  • an antigen such as Aspfl from the fungus aspergillus, tuberculo protein, coccidioidin, or other antigens known to elicit a major T-cell (delayed immunity) response in humans.
  • kits whose components are useful in cancer immunotherapy.
  • the kits may include transfer factor, viruses and/or monoclonal antibodies.
  • the kit may also include components useful in administering the kit components.
  • the invention is also directed to methods of administrating the compositions and vaccines of the invention.
  • the transfer factor may be administered simultaneously or at different times from the other components of the vaccine.
  • Antibody A protein which is produced as a result of the introduction of an antigen and which has the ability to combine with the antigen that stimulated its production.
  • Monoclonal antibodies are chemically and immunologically homogenous antibodies produced by hybridomas.
  • Monoclonal antibodies useful in the invention include monoclonal antibodies directed to various epitopes on cancer cells. Such cancer cells include lung, pancreas, liver, cervical, kidney, brain, breast and spleen cancer cells. These antibodies can be humanized. Such antibodies are commercially available and include of 17-1 A (Panorex), CC49, anti EGFr surface factor mab for prostate cancer; anti MC-10 antigen mab for breast cancer; available from the National Cancer Institute or from commercial producers, anti HER2 (Herceptin, Genentech) for breast cancer; anti CD20 antigen mab (Rituxan,
  • Cancer Antigen CA15-3 Breast Cancer
  • Cancer Antigen CA19-9 Gastrointestinal Cancer
  • Cancer Antigen CA242 Gastrointestinal Cancer
  • Carcinoembryonic Antigen CEA
  • Carcinoma Associated Antigen Melanoma Antigen; Melanoma Associated Antigen 100-7kDa; Melanoma Associated Antigen 25-110kDa; and Melanoma
  • Anti-Human Lung Carcinoma CHALU12, CHALU12 and CHLG-26
  • Anti-Human Hepatocellular Carcinoma CHALV1 , CHALV2 and CHALV3; Anti-
  • Human Alpha Fetoprotein B6, G7; Anti-Human Colorectal Carcinoma: Y94; Anti-Human Gastric Carcinoma: BY-1 (3H11 ); Anti-Human Colorectal Carcinoma/CD3 (Bispecific): BS-1 ; Anti-Human PSA: CHYH1 , CHYH2; Anti-Human PMA: YPMA-1 , YPMA-2; Anti-Human PSP: YPSP-1 , YPSP-2; and Anti-Human PSMA: Y-PSMA1 , YPSMA2.
  • Antigens are molecules which initiate an immune response. Antigens useful in the invention are those which initiate a cell- mediated immune response as compared to a humoral immune response. Antigens may include Asp f1 or other fungal antigens, viruses or virus components, tuberculo protein, coccidioidin, BCG, etc.
  • Viruses are genetic elements enclosed by a protein coat that are capable of infecting cells and moving from one cell to another to cause disease.
  • Viruses useful in the invention are those which infect cells which have become cancerous and with which the patient may or may not have already developed an immune response.
  • Viruses useful in the invention include the mumps virus which targets cells of the testes, pancreas, salivary glands and parotid glands; the hepatitis virus which targets liver cells; the encephalitis virus which targets brain cells; the Rubella virus; the Measles virus and the Varicella virus.
  • Transfer factor is a dialyzable extract of immune lymphocytes that is capable of transferring cell-mediated immunity in humans and in other animal species.
  • Immunized transfer factor is transfer factor that has been isolated from a host that has been immunized with an antigen.
  • Normal transfer factor is transfer factor that has been isolated from hosts who have not been specifically immunized but who have generated the necessary cellular immunity through natural exposure.
  • a vaccine is a preparation used as a preventive inoculation to confer immunity against a disease such as cancer.
  • a vaccine may include multiple components administered at different time periods.
  • the components of the vaccine may be in the pure state or in combination with other materials.
  • the vaccine components may be in combination with salts and buffers, may be in a dried state, in a solvent as a precipitate or in a aqueous solution.
  • the present invention relates to the use of immunotherapy in the treatment of cancer.
  • the present invention is directed to the use of modified monoclonal antibodies in the treatment of cancer.
  • This invention is further directed to the use of viruses in the treatment of cancer.
  • the invention is further directed to the selection of antigens for coupling to antibodies and viruses to which the patient has already initiated a cellular immune response or to which a cellular immune response can be induced.
  • the aim of cancer immunotherapy is to bolster a patient's immune system so that it is better able to combat cancer and remove cancer cells.
  • Immune responses involve a complex series of events. Antigens of an invading microorganism must come into contact with cells of the immune system (macrophages and lymphocytes) to initiate an immune response specific for the foreign material. The cells that respond are precommitted, because of their surface receptors, to respond to a particular epitope on the antigen in a process known as acquired immunity.
  • This acquired immunity response takes two forms that usually develop in parallel. The part played by each form will depend on a number of factors including the nature of the antigen, the route of entry and the individual who is infected.
  • the existence of the two forms of acquired immunity - humoral and cell-mediated -- results from the presence of the two major classes of lymphocyte: B-cells and T-cells.
  • Humoral immunity depends on the appearance in the blood of glycoproteins known as antibodies or immunoglobulins. These molecules are produced by plasma cells, that have developed from B- cells, and combine specifically with the antigen that stimulated their production. This union can lead to a number of consequences. For example, the antigen molecules or particles may become clumped, their toxic potential may be neutralized and their uptake by phagocytes and subsequent digestion facilitated whilst antigens such as cells or bacteria may also be lysed as a result of complement activation.
  • the present invention it is important to reduce or minimize the humoral immunity response in order to provide time for the modified monoclonal antibodies and viruses of the invention to seek out their target cancer cells before they are inactivated by the immunoglobulins produced by the humoral immune response.
  • cell-mediated immunity was originally coined to describe localized reactions to organisms mediated by T-lymphocytes and phagocytes rather than by antibody. It is now used to describe any response in which antibody plays a subordinate role.
  • Cell-mediated immunity depends mainly on the development of T-cells that are specifically responsive to the inducing agent and is generally active against intracellular organisms. The effector cells can interact directly with the infected cell and destroy it, i.e., a cytotoxic effect, or produce molecules that stimulate other cells to destroy the intracellular parasite.
  • Cell mediated immune responses are not brought about by circulating antibody but by sensitized lymphoid cells.
  • a normal cell- mediated immune response develops when first exposure to the antigen gives rise to a population of antigen-specific memory T-lymphocytes. These cells continuously circulate around the body until they come across the antigen expressed on the surface of an antigen-presenting cell in association with MHC class II. The cells are stimulated by this interaction to proliferate and release lymphokines.
  • the lymphokines are responsible for the cell-mediated host defense mechanisms that involve not only the attraction and activation of macrophages but also the stimulation of precursor cytotoxic T-cells into effector cells. These events lead to the elimination of the foreign material, in this invention the specific cancer receptor cell agonist, (e.g., monoclonal antibody) and/or virus associated with the cancer cell.
  • This invention is directed to the use of modified monoclonal antibodies, viruses and modified viruses to target cancer cells and trigger a cell-mediated immune response in order to destroy the cancer cells.
  • monoclonal antibodies to cancer cells are prepared and modified.
  • the monoclonal antibodies of the invention are generally commercially available. Such monoclonal antibodies are preferably humanized monoclonal antibodies. Humanized monoclonal antibodies are known to produce reduced humoral immune responses as compared to the responses of mouse monoclonal antibodies. This difference is thought to result from the humanized antibodies being less dissimilar or foreign to the body's immune system so as to induce a reduced immune response.
  • the monoclonal antibodies of the invention recognize epitopes specific for cancer cells.
  • the monoclonal antibodies are modified by procedures well known in the art to conjugate one or more antigens to the monoclonal antibody. The antigens are selected based upon their ability to maximize the cell-mediated immune response while minimizing the humoral immune response.
  • an antigen to which a patient's immune system may already have a potent T-lymphocyte reactivity is attached to a monoclonal antibody which recognizes a specific cancer cell epitope.
  • the monoclonal antibody will be selected for its ability to seek out a cancer (e.g., monoclonal antibody 17-1 A or CC49 for pancreatic carcinoma). Through administration in the form of a vaccine, the modified monclonal antibody delivers an antigen to the cancer in vivo.
  • a cancer e.g., monoclonal antibody 17-1 A or CC49 for pancreatic carcinoma.
  • the modified monoclonal antibody attaches to the cancer cell, it makes the cancer cell represent a recognized foreign material to the T- cell population.
  • the destructive power of the T-cell is daunting and can easily destroy a cancer cell if activated in that direction.
  • an antigen useful in the invention which can be attached to the monoclonal antibody is the antigen Asp f 1.
  • This antigen is derived from the fungus aspergillus fumigatus which is a potent human pathogen whose threat is well controlled by a normal immune system because of pre-existing immunity, both cellular and humoral. However, this antigen is deadly for patients who are immunologically compromised.
  • live aspergillus organisms are not injected into the patient. Instead, the extracted protein or glycoprotein antigens from the organisms coupled to monoclonal antibodies which recognize cancer cell epitopes and are injected into the patient.
  • the antigen Asp f 1 is the most potent of the antigens present on the fungus aspergillus. All normal individuals have developed a strong T-cell response to this antigen by the time they reach adulthood. It is available as a purified fraction of the fungal lysate and as a product of recombinant technology (i.e., manufactured in bioengineered yeast organisms). The antigen can easily be attached to monoclonal antibodies by procedures well known in the art.
  • Recombinant aspergillus antigens are commercially available in pure form and are preferable to crude extracts of the fungus. However, in an alternative embodiment, the latter can be conjugated to the monoclonal antibody. In yet another embodiment, purified or crude extracts of other fungi or bacteria are conjugated onto the monoclonal antibodies to deliver a recognizable antigen to the cancer surface to which a strong killer T-cell response would be directed.
  • the process of attaching an antigen to an antibody without altering the receptor (cancer cell) binding characteristics of the antibody is well known to immunochemists. Such procedures involve the purification of the antibody, dialysis and/or column chromotography and equilization of the purified antibody in buffer. Next, the antigen is conjugated to the antibody. Finally, the conjugated antibody is purified from unconjugated antigen. The procedure is outlined in detail below.
  • the product is injected intravenously.
  • the modified monoclonal antibody may be supplemented by the addition of immunized and/or normal transfer factor as discussed below.
  • the antibody and the transfer factor are administered in the form of a vaccine where the antibody and transfer factor may be administered at different times.
  • the transfer factor induces or increases the immune response.
  • the antigen attached to the monoclonal antibody may be a virus.
  • the virus is selected based upon the patient having a well developed immune response to the virus.
  • the virus may be administered directly because it is known to selectively attach to the cells which are malignant.
  • the virus may also be modified to include additional antigens.
  • the virus is a mumps virus for pancreatic, salivary or testicular cancers.
  • Viruses and Cancer Immunotherapy may be injected directly as a form of cancer immunotherapy.
  • Viruses useful in the invention are those which infect cells susceptible to cancer and with which the patient has developed an immune response, for example, the mumps virus.
  • the mumps virus is known to be reactive with certain secretory cells, including those of the pancreas, the salivary glands of the mouth, and the testes.
  • the normal adult has a well developed immunity to the mumps virus throughout life.
  • the procedure of this invention is utilized as a means to redirect a cancer patient's immune system to the presence of mutated cancer cells in the body so that individual's T cells can destroy the cancerous mutation and restore health.
  • the mumps virus in injected in heavy doses and repeatedly so that the mumps virus can become attached to the cancer cells of the cancer patient.
  • the virus becomes attached to the pancreatic cancer cells.
  • the mumps virus may be administered in the form of a vaccine and may be supplemented by the addition of immunized and/or normal transfer factor.
  • the attachment of the mumps virus to the pancreatic cancer cells causes these cancerous cells to be identified as mumps viruses to the immune system.
  • the addition of transfer factor further increases this response. Consequently, a vigorous immune response is unleashed against the virus (cancer).
  • the immune response is so massive that it destroys the primary cancer in the pancreas and also searches for, finds and destroys the metastatic cells as well.
  • the virus may be the hepatitis virus for the treatment of liver cancer since the hepatitis virus targets liver cells.
  • the virus may be the encephalitis virus for the treatment of brain cancer since the encephalitis virus targets brain cells.
  • the viruses of the invention may be coupled to antigens by procedures well known in the art.
  • the antigens will be selected based upon their ability to elicit a cellular immune response as described above for monoclonal antibodies.
  • a preferred antigen is asp f 1.
  • EDC Ethyl-3-[3- Dimethylamino propyl] Carbodiimide Hydrochloride
  • the carbodiimide moiety of EDC initially reacts with available carboxy groups on either the monoclonal antibody, virus and/or the antigen to form an active O-acylurea intermediate. This unstable intermediate reacts with a primary amine to form an amide bond with the release of a soluble urea derivative. The reaction usually takes less than 2 hours.
  • EDC coupling is a very efficient, one-step method for forming a wide variety of antigen-monoclonal antibody, virus-monoclonal antibody and virus-antigen conjugates. Conjugation may occur at either the C- or N-terminal of the peptides or at any carboxyl- or amine- containing side chains.
  • Conjugation between monoclonal antibodies and antigens can readily be achieved with EDC by the following procedure. This procedure is also readily applicable to virus-antigen conjugation and virus-monoclonal antibody conjugation and may include the following steps. 1. Reconstitute 2 mg of monoclonal antibody with 200 ⁇ l deionized water. 2. Dissolve up to 2 mg of the antigen to be coupled in 0.5 ml of conjugation buffer (0.1 M MES, 0.9 M NaCI, 0.02% NaN 3 , pH
  • cross-linking agents are useful in antigen-monoclonal antibody, virus-monoclonal antibody and virus-antigen conjugation, for example, N-hydroxysuccinimide and N-hydroxysulfosuccinimide.
  • the heterobifunctional crosslinker SMCC and sulfo-SMCC available from Pierce Chemical Company also have general utility in preparing conjugates.
  • Maleimide-antigen derivatives can also be prepared.
  • glutaraldehyde and metaperiodate derivatives can be prepared.
  • This reagent contains N-hydroxysulfosuccinimide (sulfo-NHS) and maleimide functional groups.
  • the sulfo-NHS ester is reacted with a primary amine on the antigen to form a stable amide bond.
  • the antigen will have maleimide groups on its surface that are reactive toward sulfhydryl groups to form stable thioether bonds on the monoclonal antibody or virus.
  • the antigen-monoclonal antibody conjugate or virus-antigen conjugate can be purified as discussed above.
  • Hetero-cross-linked antibodies may also be prepared using the heterobifunctional agent succinimidyl-3-(2-pyridyldithiol) propionate as described by Titus, et al., J. Immunol. 138:4018.
  • the monoclonal antibodies and viruses of this invention can be administered along with transfer factor.
  • Transfer factor is utilized to increase the immune response.
  • Transfer factor may be administered along with the virus or monoclonal antibody, before the addition of the virus or monoclonal antibody or after addition of the virus or monoclonal antibody.
  • Transfer factor is an extract from the peripheral blood lymphocytes of normal and immunized individuals which when injected into another individual confers upon the recipient the immunity of the donor's lymphocytes in the form of activated T-lymphocytes.
  • Transfer factor may be isolated and purified by procedures well known in the art. Such procedures include those described in U.S. Patent Numbers 4,816,563 and 5,840,700.
  • Transfer factor can be administered either by injection or can be administered orally. Oral administration is via pill or capsule. Injection of transfer factor can be intravenously, intramuscularly or subcutaneously or a combination of routes. When injected, the dose of transfer factor required to impart immunity or increase the immune response in a human is between approximately 1 ng and 500 ng with a preferred does range of between 25ng and 250 ng with a most preferred dose of approximately 50 ng.
  • the patient's immune system is passively sensitized to that epitope with transfer factor from a sensitized individual.
  • transfer factor from immunized donors to confer such T-cell activity on the recipient is an additional maneuver to enhance the likelihood of a successful destruction of all cancer cells by the patient's own T-cell attack.
  • transfer factor is an extract of peripheral blood lymphocytes which can confer on the recipient the cellular immune activity (T-cell) of the donor.
  • T-cell cellular immune activity
  • a patient without significant T-cell activity against an antigen e.g., Asp f1
  • Transfer factor is extracted by procedures described in the Example section.
  • patients with cancer particularly pancreatic cancer are injected with mumps virus followed by transfer factor from normal and recently immunized donors to focus a killer T-cell immune activity against the mumps virus and, consequently, against the cancer.
  • the treatment program is continued until the cancer is completely destroyed and the patient restored to health.
  • the vaccines of the invention may be supplied in the form of a kit.
  • the kit would include as a first component a monoclonal antibody or a virus.
  • the monoclonal antibody will be specific for a cancer cell and may be modified as discussed above.
  • the virus will be a virus that infects cancer cells.
  • the monoclonal antibody and virus may be in dry or liquid form. If the virus and monoclonal antibody are in dry form, the kit may include a solution to solubilize the dried material.
  • the kit may also include transfer factor in liquid or dry form. If the transfer factor is in dry form, the kit will include a solution to solubilize the transfer factor.
  • the kit may also include containers for mixing and preparing the vaccine components. Such kits would include instruction materials for administration of the vaccine.
  • the kit may also include the various needles, tubing, etc., necessary to administer the vaccine.
  • the typical treatment program consists of an initial 500 mgm given intravenously in a single bolus followed monthly with 100 mgm infusions for 4 additional months of modified monoclonal antibody, virus or modified viruses.
  • the treatment will generally be followed by the administration of transfer factor either orally or intravenously as discussed above.
  • the transfer factor may be administered before, during or after the administration of monoclonal antibody, virus or modified viruses.
  • Patient #1 was diagnosed to have a pancreatic cancer with metastases to the liver showing marked progression of hepatic metastases. The situation was said to be incurable and the treatment goals were palliative.
  • Computed Tomography (CT) scans of the upper abdomen showed numerous hypodensities scattered throughout all segments of both lobes of the liver of patient #1. All hypodensities measured less than 1 centimeter in diameter. There was a relatively hypodense and amorphous mass with ill-defined margins approximately 2x3x4 centimeters in the areas of the pancreas.
  • the diagnosis at the time was inflammatory or neoplastic disease of the pancreas.
  • the CT focused liver biopsy showed mild hepatic benign inflammatory disease.
  • a repeat CT scan directed biopsy twenty days later showed clear islands of adenocarcinoma in the liver, thus confirming the pancreatic malignancy.
  • Chemotherapy was begun twenty-six days later and continued weekly for six cycles through one month. After a 14 day break, chemotherapy was given again weekly for 3 weeks. The patient was told that he had, at most, a few months to live, and that the progression of the cancer would continue until death.
  • the patient was started on a mumps virus vaccine and transfer factor therapy at the end of the 6 cycle chemotherapy period, receiving 1.0 ml of transfer factor (equivalent to 10 8 lymphocytes) three times a week.
  • Each mumps injection contained a 0.5 ml immunizing dose of live mumps virus vaccine, manufactured by Merck Pharmaceuticals, according to the schedule shown below. (See Table 1 - Mumps Vaccine and Transfer Factor Injection Data).
  • Transfer factor is obtained from peripheral blood lymphocytes of donors previously sensitized to the aspergillus antigen
  • Asp f 1 and from donors who were given immunizing doses of mumps virus vaccine (0.5 ml) two weeks prior to phoresis.
  • the former TF was used with the mab - Asp f1 conjugate therapy.
  • the mumps reactive TF was used in the treatment in which the patient was given mumps virus vaccine before TF.
  • the lymphocytes are collected by a double leukophoresis at the Stanford Phoresis Center, counted, disrupted by freeze-thaw cycles and dialyzed.
  • the dialysis fluid contains the transfer factor. It is reconstituted to contain the transfer factor obtained from 10 8 lymphocytes per 1.0 ml of final extract in buffered normal saline.
  • the leukophoresis samples from two donors immunized with mumps vaccine yielded 28 ml and 53 ml of transfer factor, respectively.
  • the antigen Asp f 1 was conjugated to the monoclonal antibody 17-1 A (Panorex) from the National Cancer Institute. Panorex was chosen because it was commercially available and had monoclonal antibody activity against the pancreas. Once the Panorex and Asp f1 were combined, skin tests were performed on patient # 1 with Panorex alone, Panorex plus Asp f1 and with Asp f 1 alone. The patient showed a negative response to the monoclonal antibody, a strongly positive response to pure Asp f 1 and an equally strong response to the Asp f1 conjugated monoclonal antibody at 48 and 72 hours.
  • the Asp f 1 conjugate was administered to the patient following the standard protocol for the procedure for administration of the monoclonal antibody Herceptin available from Genentech. The procedure is as follows:
  • the recommended initial loading dose is 4 mg/kg Asp f 1 conjugate administered as a 90-minute infusion.
  • the recommended weekly maintenance dose is 2 mg/kg Asp f 1 conjugate and can be administered as a 30-minute infusion if the initial loading dose is well tolerated.
  • the Asp f1 conjugate may be administered in an outpatient setting.
  • each vial of Asp f1 conjugate is reconstituted with 20 mL of BWFI, USP, 1.1% benzyl alcohol preserved to yield a multi-dose solution containing 21 mg/mL Asp f1 conjugate. If the patient has known hypersensitivity to benzyl alcohol, the Asp f1 conjugate must be reconstituted with sterile water for Injection. The amount (mg) of Asp f 1 needed, based on a loading dose of 4 mg Asp f1/kg body weight or a maintenance dose of 2 mg Asp f 1 conjugate/kg body weight is determined. Next, the volume of 21 mg/mL Asp f1 solution is calculated, withdraw from the vial and added to an infusion bag containing 250 mL of 0.9% sodium chloride,
  • Treatment is administered in an outpatient setting by administration of a 4 mg/kg Asp-f 1 conjugate by loading dose by intravenous (IV) infusion over 90 minutes. Transfer factor was administered as described in Example 1. Patient #1 was observed for fever and chills and some chills were noted.
  • the patient was also simultaneously treated by an oncologist.
  • the oncologist administered chemotherapy in the amount of 5FU.
  • This treatment is very toxic to lymphocytes.
  • the patient went into rapid decline (presumably as a result of the killing off of the patient's lymphocytes by the administration of the 5FU) and died 2 weeks later.
  • the administration of the compositions of this invention should be carefully monitored when used in combination with traditional chemotherapy.

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  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des compositions, des vaccins, et des kits d'immunothérapie cancéreuse, ces compositions, vaccins, et kits pouvant comprendre un facteur de transfert. Les compositions, vaccins, et kits de cette invention comprennent également des anticorps monoclonaux modifiés dirigés sur les cellules cancéreuses, d'autres agonistes spécifiques du récepteur des cellules cancéreuses, ou des virus infectant les cellules cancéreuses. Cette invention concerne enfin des méthodes d'immunothérapie cancéreuse utilisant les compositions et les vaccins susmentionnés.
PCT/US1999/015716 1998-07-16 1999-07-12 Methodes et compositions pour traiter le cancer WO2000003733A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU50970/99A AU5097099A (en) 1998-07-16 1999-07-12 Methods and compositions for cancer treatment
US09/764,224 US7112328B2 (en) 1998-07-16 2001-01-16 Composition for targeted cell treatment

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US9308498P 1998-07-16 1998-07-16
US60/093,084 1998-07-16

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/764,224 Continuation-In-Part US7112328B2 (en) 1998-07-16 2001-01-16 Composition for targeted cell treatment

Publications (1)

Publication Number Publication Date
WO2000003733A1 true WO2000003733A1 (fr) 2000-01-27

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PCT/US1999/015716 WO2000003733A1 (fr) 1998-07-16 1999-07-12 Methodes et compositions pour traiter le cancer

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AU (1) AU5097099A (fr)
WO (1) WO2000003733A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7850962B2 (en) 2004-04-20 2010-12-14 Genmab A/S Human monoclonal antibodies against CD20
US8529902B2 (en) 2002-10-17 2013-09-10 Genmab A/S Human monoclonal antibodies against CD20
US20150104425A1 (en) * 2006-07-24 2015-04-16 CortControl, Inc. Medical food for high cortisol breast cancer
US20150366941A1 (en) * 2014-06-19 2015-12-24 Cortcontrol Human disease treatment with medical food formulation

Citations (2)

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Publication number Priority date Publication date Assignee Title
FR2128267A1 (en) * 1971-03-09 1972-10-20 Asada Teruo Anti-cancer medicament - contg mumps viruses from saliva of patients
EP0010738A1 (fr) * 1978-10-25 1980-05-14 A/S Alfred Benzon Facteur de transfert et procédé pour sa préparation

Patent Citations (2)

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FR2128267A1 (en) * 1971-03-09 1972-10-20 Asada Teruo Anti-cancer medicament - contg mumps viruses from saliva of patients
EP0010738A1 (fr) * 1978-10-25 1980-05-14 A/S Alfred Benzon Facteur de transfert et procédé pour sa préparation

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M. MOSER ET AL.: "Cloning and expression of recombinant Aspergillus fumigatus allergen I/a (rAsp f I/a) with IgE binding and type I skin test activity.", THE JOURNAL OF IMMUNOLGY, vol. 149, no. 2, 15 July 1992 (1992-07-15), Baltimore, MD, USA, pages 454 - 460, XP000566387 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8529902B2 (en) 2002-10-17 2013-09-10 Genmab A/S Human monoclonal antibodies against CD20
US7850962B2 (en) 2004-04-20 2010-12-14 Genmab A/S Human monoclonal antibodies against CD20
US20150104425A1 (en) * 2006-07-24 2015-04-16 CortControl, Inc. Medical food for high cortisol breast cancer
US20150366941A1 (en) * 2014-06-19 2015-12-24 Cortcontrol Human disease treatment with medical food formulation

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