WO1994028934A1 - Traitement adoptif de reconstitution immunitaire pour des patients atteints d'immunodeficiences acquises - Google Patents

Traitement adoptif de reconstitution immunitaire pour des patients atteints d'immunodeficiences acquises Download PDF

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Publication number
WO1994028934A1
WO1994028934A1 PCT/US1994/006248 US9406248W WO9428934A1 WO 1994028934 A1 WO1994028934 A1 WO 1994028934A1 US 9406248 W US9406248 W US 9406248W WO 9428934 A1 WO9428934 A1 WO 9428934A1
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patient
solution
hyperimmune
mononuclear
infusate
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PCT/US1994/006248
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English (en)
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Robert Howard Keller
William Mark Reiter
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Center For Special Immunology
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Priority to AU70986/94A priority Critical patent/AU7098694A/en
Publication of WO1994028934A1 publication Critical patent/WO1994028934A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1054—Lentiviridae, e.g. HIV, FIV, SIV gag-pol, e.g. p17, p24
    • 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
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464838—Viral antigens
    • 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 A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to a method of treatment of acquired immunodeficiencies.
  • this invention relates to an immune reconstitution therapy for a patient infected with the virus causing the acquired immune deficiency syndrome (AIDS) or any condition resulting in persistent lymphopenia.
  • AIDS acquired immune deficiency syndrome
  • the immune response gives rise to the formation of specific antibodies that circulate in the blood (humoral immunity) or to an increase in the number of specific reactive cells called lymphocytes (cell-mediated immunity) or both.
  • the specific antibodies and specialized lymphocytes react to the antigen causing the response and either destroy or neutralize the pathogenic agent, thus providing immunity.
  • This acquired immunity is the primary internal line of defense against invasive pathogens.
  • Lymphocytes are the precursor cells of both humoral and cell-mediated immunity and are formed and processed in the bone marrow, spleen and thymus. Lymphocytes are circulated through the body via the lymphatic system and are found in high concentrations in the lymph nodes, spleen, bone marrow and thymus. There are two classes of lymphocytes, the T-cells (thymus derived) and B-cells (bone marrow derived) and each of these can be further divided into subclasses. The T-cells have immunological specificity and act directly with antigens in the cell-mediated immune response. Of particular importance in acquired immune deficiency syndrome (AIDS) is a subclass of T-cells known as CD4+ lymphocytes that are specifically decimated by the AIDS virus.
  • AIDS acquired immune deficiency syndrome
  • AIDS is primarily characterized by a profound decrease of cell mediated immunity through the loss of CD4+ lymphocytes. Although the mechanism of pathogenesis in AIDS is still not fully understood, it has been suggested that loss of immunity may be caused by one or more of the following mechanisms: 1) direct cell killing by HIV through cell rupture, 2) transduction of an inappropriate signal to T-cells by the viral envelope protein gpl20 and resulting apoptosis, 3) production of anti-idiotypic antibodies, 4) formation of lymphotoxic cytokines (protein growth factors and immune factors) and 5) superantigen-induced programmed cell death and clonal T-cell loss (R. Gallo, Virus Hunting: AIDS, Cancer and the Human Retrovirus, Basic Books, NY 1991) .
  • CMV cytomegalovirus
  • passive hyperimmunotherapy may be a treatment for HIV infection that offers temporary augmentation of the failing immune syste .
  • a method for immunologically treating a patient infected with an agent causing an acquired immunodeficiency such as HIV in the case of AIDS or any condition resulting in persistent lymphopenia.
  • the method includes the steps of (A) administering to a patient in need of such treatment an effective amount of an immune serum globulin solution or a hyperim une solution containing a high titer of antibodies to the agent causing the acquired immunodeficiency and which is free of any contaminating agent, wherein the immune serum globulin solution or hyperimmune solution provides at least temporary protection against attack by the causative agent on later administered mononuclear cells, (B) administering to the patient an effective amount of a mononuclear infusate containing peripheral blood mononuclear cells (PBMCs) haplotype matched and cross- matched with the patient, and (C) periodically repeating steps (A) and (B) to obtain and sustain clinical improvement.
  • PBMCs peripheral blood mononuclear cells
  • an immune serum globulin solution is administered to the patent.
  • the immune serum globulin solution comprises from about 10 to about 15 g of immunoglobulin.
  • a hyperimmune solution containing a high titer of antibodies to the agent causing the acquired immunodeficiency is administered to the patient.
  • the hyperimmune solution comprises plasma derived from at least one healthy HIV+ asymptomatic donor.
  • the hyperimmune solution comprises immune serum globulin, preferably from about 10 to about 15 g of immune globulin containing high titers of anti-HIV antibodies.
  • cytokines, thy ic hormones, fetal thymic tissue transplant or combinations thereof are also administered to the patient.
  • the immune serum globulin solution or hyperimmune solution, and mononuclear infusate are preferably sequentially administered every 2 to 6 weeks, and most preferably, every 28 days. It is preferred that the mononuclear infusate be administered within about 1 week after administration of the immune serum globulin solution or hyperimmune serum, preferably within about 48 hours and most preferably, within 24 hours after administration of the hyperimmune serum.
  • a method for immunologically treating a patient infected with HIV which includes the steps of: A) haplotype and cross-matching the patient with a healthy and virus free donor for peripheral blood mononuclear cells (PBMCs) ,
  • PBMCs peripheral blood mononuclear cells
  • step D) administering to the patient an effective amount of immune serum globulin solution or hyperimmune solution containing a high titer of anti-HIV antibodies, and which is free of contaminating virus, so as to establish at least temporary protection against HIV attack on later administered PBMCs, E) administering an effective amount of a mononuclear infusate containing the PBMCs haplotype and cross-matched with the patient obtained in step B) ; and F) periodically repeating steps B) , C) , D) and E) as long as clinical improvement is sustained.
  • high titer of antibody to HIV is used herein to mean an anti-HIV antibody titer of at least
  • the phrase "substantially free of contaminating red blood cells” means 5% or less red blood cells are present in the solution.
  • the present invention is directed to an immune replacement therapy to reestablish immunocompetence in AIDS patients whose immune system has failed.
  • the present immune replacement therapy is used in the treatment of acquired immunodeficiencies such as, for example, AIDS, non-HIV idiopathic CD4+ lymphopenia or any agent causing persistent lymphopenia.
  • the therapeutic regimen of this invention includes the repeated combined sequential use of an infusion of a solution of immune serum globulin or a hyperimmune serum globulin containing a high titer of antibodies to the infectious agent, such as HIV in the case of AIDS, and an infusion of haplotype and cross-matched peripheral blood lymphocytes, including CD4+ T-cells.
  • the solution containing the high titer of antibodies to the infectious agent is referred to as the "hyperimmune solution” and is, for example, an anti-HIV hyperimmune gammaglobulin (anti-HIV IgG) or plasma (Ig) shown to contain a high titer of antibodies to HIV or any other infusible solution containing a high titer of HIV antibodies.
  • the solution of immune serum globulin is referred to as "IVIG” and is, for example, pooled plasma prepared from pooled serum obtained from a plurality of donors. The infusate of haplotype and cross-matched
  • PBMCs contains only mononuclear cells with less than 5% red blood cells and less than 5% granulocytes and is referred to herein as the mononuclear infusate.
  • the present therapy provides both a humoral (IgG or plasma (Ig) ) and cellular (PBMC) approach to the treatment of acquired immunodeficiency conditions.
  • the immune serum globulin solution and, alternatively, the hyperimmune solution containing a high titer of antibodies to HIV may function in the AIDS patient to: (1) replace antibodies involved in protecting the patient against various infectious diseases (Berrstew, et al. J. Pediatric, 1985, 107:352-357); (2) provide protection against attack by HIV on the haplotype and cross-matched donor mononuclear infusate, and (3) function as a clearance mechanism for HIV, which is liberated into the patient's plasma as a result of the interaction of the infused donor mononuclear cells with the patient's HIV infected cells. This, however, does not represent an inclusive list of all mechanisms that may be operative.
  • the haplotype- atched mononuclear infusate serves to
  • cytokines and/or thymic humoral stimulants and/or thymic tissue transplants enhances the development of stem cells from the patient's bone marrow and stimulates the resultant development of T-cells from this stem pool.
  • thymic humoral stimulants and/or thymic tissue transplants e.g. fetal thymic tissue transplants
  • the administration of any of these adjuvant modalities will follow, by from about 1 to 28 days, the administration of the mononuclear infusate.
  • the hyperimmune solution is obtained from HIV+ donors who are free of clinically evident disease prior to plasmapheresis and who exhibit a normal immunophenotypic profile.
  • normal immunophenotypic profile is meant a peripheral blood CD4+ lymphocyte count of at least 500 cells/mm 3 and a relative CD4+ lymphocyte frequency greater than 28%.
  • the hyperimmune solution is, for example, plasma which after an initial screening is collected from healthy, asymptomatic HIV+ donors.
  • the plasma is collected, for example, by a plasmapheresis method whereby the donor's blood, when being drawn, is mixed with a dextrose-sodium citrate-citric acid buffer, which prevents the blood from clotting.
  • the blood corpuscles can be separated from the plasma by centrifuging, for example, and reinjected into the donor. In this way, the obtained plasma constitutes the raw material for additional processing or, which after viral inactivation may be used without further processing except for viral inactivation.
  • the donor plasma is tested for antibodies to HIV employing any sensitive screening method.
  • the plasma from such donors or other hyperimmune solution should have a p24 titer of at least about 1:125, preferably higher than 1:125.
  • Donor plasma may also be tested by nephelometry to determine Ig values.
  • Plasma having an Ig (i.e., IgG+IgA+IgM) value of at least about 2.0 g/liter is acceptable for use in the present invention.
  • Plasma having a sufficiently high titer of p24 antibody and Ig value are pooled and can be further processed or used directly to infuse patients.
  • Pooled plasma for direct use in the present immune replacement therapy contains at least about 2.0g/liter of Ig (IgG+IgA+IgM) .
  • pooled plasma is treated to destroy HIV.
  • the plasma before use is, preferably, treated with 0.25% beta-propiolactone or is heated at 63°C for 30 min to destroy HIV and any other contaminating particles.
  • the plasma is also tested by standard immunochemical assay to ensure that it is hepatitis B and hepatitis C negative.
  • pooled plasma from a plurality of HIV-negative donors is used to obtain an immune serum globulin (IVIG) , which is used to infuse patients.
  • IVIG immune serum globulin
  • Any method for obtaining an injectable immunoserum globulin from pooled plasma may be used. For example, the Cohn fractionation method (J.Am.Chem.Soc.
  • the immune serum globulin comprises IgG and is usually about 90% IgG monomer.
  • the serum globulin generally also contains other globulins such as IgA, IgM and the like.
  • IgA IgA
  • IgM immunoglobulins
  • IVIG Immune Globulin Intravenous (Human) U.S.P.
  • IVIG is available commercially from Armour Pharmaceutical Company, Kankakee, IL, in lyophilized single and multi-dose form.
  • a lot of IVIG is generally prepared from pooled serum of about 2,000 to 10,000 screened donors in order to maximize antibody diversity.
  • Commercially available IVIG generally contains sucrose, glucose, maltose or another pharmaceutically acceptable stabilizer in concentrations ranging from about 2 to 10%.
  • IVIG The clinical utility of IVIG appears to exceed the role of simple replacement therapy, although the mechanism whereby it modulates the immune system remains to be determined. Since human IVIG is not treated as foreign by the human recipient, it becomes part of the endogenous immounoglobulin pool and thus, its dosage is not strictly limited.
  • hyperimmune sera with increased levels of specific antibodies directed toward a particular infecting agent is needed in the treatment of AIDS.
  • hyperimmune sera is generally only a few- fold enriched for specific antibodies.
  • hyperimmune sera are pooled from fewer donors than are used in preparation of IVIG, they are less likely to contain as wide a spectrum of antibodies against other pathogens.
  • one distinct advantage of administration of IVIG may be derived from its potential coverage of a wide spectrum of microbial agents, albeit with a lower titer of antibodies against a specific microbial agent than is present in the hyperimmune serum.
  • the mononuclear infusate is obtained from donors who have been haplotyped and cross-matched with the patients.
  • a critical factor to the success of the present immune replacement therapy is the performance of cross-matching of the donor mononuclear infusate and the patient's functional, albeit compromised, immune system.
  • Cross- matching is performed to prevent any untoward reactions between the patient's immune system and the mononuclear infusate.
  • Donors are screened for HLA Class I and Class II histocompatibility antigens. Any donor matching at least one of the patient's HLA haplotypes at each major locus (A, B and Dr) is acceptable. While first order relatives often are compatible donors, unrelated donors may also be used insofar as their HLA haplotype matching is acceptable.
  • Peripheral blood lymphocytes for use in the mononuclear infusate may be obtained by any standard American Association of Blood Banks (AABB) approved apheresis method.
  • AABB American Association of Blood Banks
  • continuous flow automated apheresis using a blood cell separator and anticoagulant and citrate dextrose solution may be used.
  • standard apheresis equipment provides only about 80-90% purity of lymphocytes with contaminating red blood cell hematocrit of up to 20%. Any amount of contaminating red blood cells above about 5% poses potential red blood cell incompatibilities, which must then be resolved.
  • the red blood cells are removed by any standard technique such as, for example, gradient centrifugation.
  • peripheral blood lymphocytes are obtained through the use of an apheresis machine capable of separating peripheral blood lymphocytes with only 0-5% contaminating red blood cells, and less than 5% contaminating granulocytes such as the Cobe Spectra apheresis apparatus, made by Cobe Spectra.
  • the Cobe Spectra apheresis apparatus separates peripheral blood lymphocytes from blood, with only 1-5% contaminating red cell hematocrit, which eliminates the need to further process the PBMCs or cross-match to avoid red blood cell incompatibilities.
  • the obtained donor mononuclear cells are assessed for both percentage and absolute number of lymphocytes and are immunophenotypically characterized. Immunophenotyping is carried out, for example, by screening donor cells with a panel of anti-CD4+, CD8+ and stem cell antigen (CD34+) probes.
  • peripheral blood lymphocytes preferably CD4+ lymphocytes
  • peripheral blood lymphocytes are obtained from the patient's or donor's peripheral blood, purged of latent and active HIV virus by culture techniques, for example, and then extracorporally expanded to obtain clinically relevant numbers of PBMCs.
  • a number of autoantibodies against B cells are known and at least one autoantibody against T-cells, and one alloantibody against T-cells have been observed in AIDS patients.
  • it is also embodied in the present protocol to ascertain whether the patient has autoantibodies against ly phoid cells and determine against which lymphoid type the autoantibody is directed.
  • the screening of the sera to detect autoantibodies is important to preclude transfusion or other reactions such as graft versus host (GVH) or host versus graft reactives or transient reaction against lymphocytes infused (TRALI) .
  • GVH graft versus host
  • TRALI transient reaction against lymphocytes infused
  • any method for detecting autoantibodies can be used.
  • B- and T-cells are separated from a sample of donor mononuclear infusate by a standard panning technique and each fraction reacted with the patient's serum.
  • Heat inactivation and/or chemical inactivation e.g. dithiothreitol (DTT) inactivation is used to ascertain the affinity of any IgM autoantibodies in the patient's serum for B-cells or T- cells. If the patient's serum contains IgG antibodies (i.e., antibodies not removed by heat or DTT) to T-cells, infusion with the mononuclear infusate is precluded because of the possibility of serious side effects. This procedure is critical to determining the safety of the repetitive haplotype and cross-matched lymphocyte infusions from the same or different donors.
  • the screened mononuclear infusate is not irradiated and is stored at room temperature without shaking and under conditions to prevent or minimize cell degradation until it is administered to the patient. Under current Food and Drug Administration policy, the mononuclear infusate cannot be stored longer than 24 hours prior to administration to patients.
  • the immune replacement therapy of the present invention requires the periodic administration of the immune serum globulin solution or hyperimmune solution, and the haplotype and cross-matched mononuclear infusate to the AIDS patient.
  • the immune serum globulin solution or hyperimmune solution is administered to the patient prior to the haplotype and cross-matched mononuclear infusate, within about one week, preferably within about 48 hours and most preferably, within 24 hours of the hyperimmune solution.
  • the immune serum globulin solution or hyperimmune solution provides protection of the later administered mononuclear cells from attack from HIV present in the AIDS patient.
  • This combined modality therapy is repeated approximately every 2 weeks to 6 weeks, preferably about once a month and most preferably every 28 days for about 6 months. After 6 months the patient is tested to determine whether the immune deficiency has been arrested or diminished.
  • the patient is monitored, for example, by removing a blood sample and testing quantitatively for appropriate markers, such as, for example, p24 antigen activity, anti-p24 antibody activity, frequencies of CD4+ T-cells and the peripheral blood stem cell population, CD4+ cell activity or combinations thereof as well as any return of .in vivo delayed hypersensitivity reactions to recall skin test antigens.
  • the immune replacement therapy is then continued to obtain and sustain improvement in immune deficiency.
  • Immune serum globulin solution or pooled HIV+ hyperimmune solution which is obtained and treated as described hereinabove is administered to the patient, preferably intravenously.
  • the patient is infused with an amount of immune serum globulin solution or hyperimmune solution containing approximately at least 15 mg/kg, preferably at least about 200 mg/kg immunoglobulin.
  • the immune serum globluin solution or hyperimmune solution is administered by any acceptable route, preferably intravenously.
  • the patient is infused with about 500cc pooled plasma containing approximately at least about 150 mg/kg and preferably, 200 mg/kg immunoglobulin containing high titer anti-HIV antibodies.
  • the patient is administered a hyperimmune solution containing immune serum globulin (IgG) obtained from pooled HIV+ hyperimmune plasma in an amount of at least about 200 mg/kg.
  • IgG immune serum globulin
  • the patient is administered an immune serum globulin (IVIG) solution obtained from pooled HIV negative plasma in an amount of at least 200 mg/kg.
  • IVIG immune serum globulin
  • the exact dosage of the immune serum globulin solution or hyperimmune solution may vary and a greater or lesser dosage may be given at monthly or more or less frequent intervals followed within about 1 week, preferably within 48 hours, and more preferably within 24 hours of each infusion by administration of a haplotype and cross-matched mononuclear infusate.
  • the patient's condition is monitored to determine the safety, tolerance and efficacy of the treatment.
  • the mononuclear infusate is administered after administration of the immune serum globulin solution or hyperimmune serum so that the antibodies in the immune serum globulin solution or hyperimmune solution can protect the mononuclear infusate from attack by HIV present in the patient.
  • the mononuclear infusate contains at least about 10 8 PBLs and, preferably an amount of PBLs in the range of from about 10 9 to about 10 10 .
  • the mononuclear infusate may contain contaminating red blood cells without requiring further treatment to remove the red blood cells.
  • red blood cells may be present if the donor's and patient's blood is haplotype and cross-matched, however, preferably no more than 5% of contaminating red blood cells are present and most preferably the mononuclear infusate contains no more than 2% red blood cells.
  • Patients receiving the herein described immune replacement therapy should also be treated with anti ⁇ retroviral drug therapy and may also be treated with antimicrobial drug therapy, therapy for opportunistic infections, or other therapy, or combinations thereof, prior to, during and/or after the immune replacement therapy.
  • Drugs such as, for example, acetaminophen, demerol, diphenhydramine and steroids can be administered to the patient.
  • Prophylaxis treatment for opportunistic infections includes administration of drugs such as, for example, Bactrim, pentamidine or dapsone, or an ifungal drugs such as, for example, diflucan.
  • Prophylaxic treatment for Mycobacterium Avian Complex (MAC) and CMV may also be administered during the immune replacement therapy.
  • MAC Mycobacterium Avian Complex
  • antiretroviral therapy should be simultaneously administered (including, e.g. DDI, DDC an D4T) .
  • These prophylactic or other therapies may be administered following generally accepted and conventional dosages, etc., except in the instance of antiretroviral therapies which may be utilized at increased doses for the week after lymphocyte infusion.
  • the following examples illustrate practice of the invention but are in no way meant to be limiting.
  • Plasma donations were obtained from HIV+ donors who are hepatitis negative and who were shown to be free of clinically evident disease including any viral syndrome and hepatitis for a period of not less than one week prior to plasmapheresis.
  • Donors were shown to be serum- positive for HIV.
  • the donors had a red blood cell hematocrit equal to or greater than 38%, a peripheral blood CD4+ lymphocyte count greater than 500 cells/mm 3 and a relative CD4+ lymphocyte frequency greater than 28%.
  • the total Ig value of each donor was greater than 2 g/dl.
  • the donors tested negative for HBS Ag and HBC antibody by ELISA assay were RPR and FTA negative, p24 antigen was not detectable and the level of p24 antibody titer as a marker in donor plasma was greater than 1:125.
  • a negative urine for CMV as shown by ELISA assay was obtained for each donor.
  • Plasma donations obtained according to Example 1 were subjected to further treatment to obtain an intravenously injectable immune serum globulin (IgG) according to standard immunochemical techniques (Michell and Shiigi. Selected Methods in Cellular Immunology, 1980, 278-284).
  • the obtained IgG exhibited an antibody titer to HIV of about 1:125 as measured by ELISA.
  • the IgG level was at least 2 g/dl as determined by nephelometry.
  • EXAMPLE 3 Donors of mononuclear infusates were screened for suitability by HLA typing. Subjects and donors were screened for HLA Class I and . Class II histocompatibility antigens by standard marrow cross-matching techniques. Donors who matched at least one of the patient's HLA haplotypes at each major locus were selected and further screened as follows.
  • the presence in matched patient's sera of autoantibodies to B- or T-cells was ascertained by obtaining purified B- and T-cells from samples of the above-obtained donor cells and screening with sera obtained from the patient prior to apheresis.
  • the mononuclear infusates were stored at room temperature without shaking for up to 24 hours before infusing matched patients.
  • a second generation treatment protocol was initiated three months after the first generation protocol was halted. End-stage AIDS patients who had previously been enrolled in the treatment protocol described above were eligible for continued therapy.
  • the second clinical protocol includes an infusion of 15 to 20 grams of Immune Globulin Intravenous (Human), U.S.P., followed within 24 hours with at least about 1 x 10 9 haplotype-matched peripheral blood lymphocytes.
  • the new treatment protocol calls for the use of IVIG whereas HIV-hyper-immune plasma, inactivated with beta-propiolactone, was used for the initial protocol. Seven patients, previously enrolled in the initial protocol, were eligible for participation in the second treatment protocol.
  • the seven eligible individuals, #'s 1-7, enrolled in the above discussed first generation immune replacement therapy were enrolled to receive treatment under the revised protocol. There was a three month lapse of time between the end of the first clinical trial and the beginning of the trial utilizing the revised protocol.
  • One eligible patient (#1, AR) who requested enrollment into the second treatment program, expired prior to enrollment.
  • a second individual (#2, HQ) expired several days after receipt of the first infusion of IVIG followed by transfusion of lymphocytes.
  • the patient expired with diagnosis of primary central nervous system lymphoma secondary to AIDS. This diagnosis was confirmed at autopsy. The cause of death was found to be a highly malignant brain tumor, which most likely was present before the patient enrolled in the study that utilized the revised protocol.
  • a third patient (#7, RL) was found to have had pre-existing lesions in his chest and the investigational treatment has been postponed until the patient stabilizes or a diagnosis is confirmed.
  • the four patients are patient #3 (KK) , #4 (MT) , #5 (JMag) and #6 (JMar) listed in Table 1.
  • patient #3 (KK) lost 12 pounds and reported loss of appetite.
  • KK was only mildly symptomatic but able to work about 12 to 14 hours each day.
  • Patient #4 (MT) reported feeling well in the interim between cessation of the first trial and entry into the second trial.
  • Patient #6 (JMar) , a hemophiliac, did not receive treatment for approximately six months, between the end of the first seven rounds of treatment and entry into the second trial. In the interim, he developed a hemarthrosis of his left knee, which was refractory to treatment with factor IX, and which was subsequently shown to be infected with staphylococci. He responded well to a six-week course of IV antibiotics. Ten days prior to entry into the second trial, JMar had and was treated for an upper and lower respiratory infection. JMar remained essentially stable after the first round of treatment in the revised protocol trial.

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Abstract

Un procédé de traitement immunologique d'un patient infecté par un agent provoquant une immunodéficience acquise repose sur des moadlités thérapeutiques combinées consistant à administrer audit patient une solution de globuline d'immun-sérum ou une solution hyperimmune renfermant un titre élevé d'anticorps dirigés contre l'agent infectieux, puis à administrer une solution intraveineuse mononucléaire contenant l'haplotype des lymphocytes du sang périphérique rendue compatible avec le patient. Les modalités sont répétées autant que nécessaire.
PCT/US1994/006248 1993-06-07 1994-06-07 Traitement adoptif de reconstitution immunitaire pour des patients atteints d'immunodeficiences acquises WO1994028934A1 (fr)

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AU70986/94A AU7098694A (en) 1993-06-07 1994-06-07 Adoptive immune reconstitution treatment for patients with acquired immunodeficiencies

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0853486A2 (fr) * 1995-09-25 1998-07-22 Samir Chachoua Utilisation therapeutique de serums d'animaux, en particulier du cheval, pour le traitement du sida, du cancer et d'autres maladies virales et bacteriennes
WO2007017859A1 (fr) * 2005-08-11 2007-02-15 Omrix Biopharmaceuticals Ltd. Composition d'immunoglobuline pour voie intraveineuse

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0853486A2 (fr) * 1995-09-25 1998-07-22 Samir Chachoua Utilisation therapeutique de serums d'animaux, en particulier du cheval, pour le traitement du sida, du cancer et d'autres maladies virales et bacteriennes
EP0853486A4 (fr) * 1995-09-25 2001-09-26 Samir Chachoua Utilisation therapeutique de serums d'animaux, en particulier du cheval, pour le traitement du sida, du cancer et d'autres maladies virales et bacteriennes
WO2007017859A1 (fr) * 2005-08-11 2007-02-15 Omrix Biopharmaceuticals Ltd. Composition d'immunoglobuline pour voie intraveineuse
US8354249B2 (en) 2005-08-11 2013-01-15 Omrix Biopharmaceuticals Ltd. Intravenous immunoglobulin composition
US9365635B2 (en) 2005-08-11 2016-06-14 Omrix Biopharmaceuticals Ltd. Intravenous immunoglobulin composition

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