WO1992008448A1 - Procede de prevention de myelosuppression due a la radiation ou aux medicaments - Google Patents

Procede de prevention de myelosuppression due a la radiation ou aux medicaments Download PDF

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Publication number
WO1992008448A1
WO1992008448A1 PCT/US1991/008185 US9108185W WO9208448A1 WO 1992008448 A1 WO1992008448 A1 WO 1992008448A1 US 9108185 W US9108185 W US 9108185W WO 9208448 A1 WO9208448 A1 WO 9208448A1
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WO
WIPO (PCT)
Prior art keywords
response modifier
brm
cti
biological response
radiation
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Application number
PCT/US1991/008185
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English (en)
Inventor
Catherine Anne Mccall
Frederick C. Pearson
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Cell Technology, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cell Technology, Inc. filed Critical Cell Technology, Inc.
Publication of WO1992008448A1 publication Critical patent/WO1992008448A1/fr

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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
    • A61K35/74—Bacteria

Definitions

  • This invention relates to the prevention of myelosuppression in patients undergoing treatment with radiation or chemotherapeutic agents and the like. More particularly, the invention relates to the use of a non ⁇ specific biological response modifier for improving the ability of such patients to resist opportunistic infections.
  • Chemotherapy and radiotherapy are two of the most successful treatment modalities for cancer. However, both have effects on normal cells as well as malignant ones, and hence give rise to a variety of undesirable side effects.
  • the primary life threatening side effect is myelosuppression - a loss of production of the granulocytic and monocytic leukocyte cell lines. These cell lines act as the first line of defense against pathogens such as bacteria and viruses. Patients experiencing chemo or radiotherapy-induced myelosuppression are prone to infection with opportunistic microorganisms. These infections can be lethal, and are one of the most common dose-limiting toxicities of cancer therapy. This, in turn, lowers the efficacy of the therapy, in that the level of tumor cell kill is roughly proportional to the amount of radiation or drug administered.
  • Chemotherapeutic drugs and radiation produce both tumor cell kill and myelosuppression by interfering with cell division. This can occur by direct damage to DNA, by activation of DNA modifying enzymes or production of reactive molecules such as superoxide, which in turn damage DNA, or by interfering with the itotic spindle which mechanically separates chromosomal material during cell division. Tumors will be disproportionately affected, as their growth fraction will contain a high percentage of cells which are dividing, or are about to divide. However, normal tissues which have a high turnover rate, such as epithelium (skin and gut lining) and the hematopoetic system (blood components) are also adversely affected.
  • Blood leukocytes such as the polymorphonuclear cells mainly responsible for engulfing pathogens are very short-lived cells - their life span being measured in hours after they are produced in the bone marrow.
  • Chemotherapy and radiation kill the rapidly dividing precursors of these cells, and hence myelosuppression is evident shortly after treatment.
  • the mechanism for production of myelosuppression by chemo or radiotherapy is thus different to the mechanism operative in burns and trauma patients, where the myeloid precursors are not killed but rather downregulated in some as yet undefined fashion.
  • Radiation affects cells by the production of chemically active intermediates - free radicals - which damage DNA, thus rendering the cell unable to divide.
  • Different lineages of cells are different in their ability to withstand radiation damage.
  • Cells with a slow turnover rate e.g. muscle
  • cells with a high turnover rate e.g. epithelium
  • Some cells which are radio resistant have more effective DNA repair systems, or can 'scavenge' radiation induced reactive intermediates before they can damage DNA.
  • Chemotherapeutic agents can be divided into groups depending on their origin and mode of action. Examples of the various subgroups, all of which can be myelosuppressive, are given below: Antimetabolities;
  • Doxorubicin (Adriamycin) is an example of a very effective antitumor antibiotic drug derived from a fungus. The mechanism of action of this drug is unc but seems to involve direct binding to DNA or produc of DNA damaging free radicals.
  • Alkylatin ⁇ agents These agents chemically interact with DNA forming covalent bonds with the molecule itself. This cause both misreading of the DNA and fragmentation of the strands. Examples of effective alkylating drugs are cyclophospha ide and the nitrosoureas (BCNU) . Plant alkaloids:
  • BCG Bacillus Calmette Guerin
  • levamisole a new biologic response modifier (BRM) , manufactured by Cell Technology, Inc. (CTI) of Boulder, Colorado has been shown to be an effective immunomodulator for treating some types of cancers.
  • BRM biologic response modifier
  • Another object of the invention is to provide an improved treatment for patients undergoing drug or radiation therapy to enhance resistance to opportunistic infections.
  • a further object of the invention is to provide an improved non-specific biological response modifier for improving the ability of certain immune-compromised patients to resist opportunistic infections.
  • Figure 1 is a set of graphs illustrating the effects of various doses of a cytotoxic agent (cyclophospha ide) with or without CTI-BRM, on spleen white blood cell progenitors in the mouse.
  • a cytotoxic agent cyclophospha ide
  • FIG 2 is a bar graph illustrating total white blood eel (WCC) and granulocyte levels in rats treated with a cytotoxic agent (cytosine-arabinoside, ARA-C) and CTI-BRM.
  • Figure 3 illustrates white blood cell counts in dogs treated with a cytotoxic agent (adriamycin) and different dosages of CTI-BRM.
  • the invention comprises a method for treating a patient, undergoing therapy by radiation or by a drug which induces myelosuppression, in order to enhance the ability of the patient's immune system to resist opportunistic infection.
  • a therapeutically effective amount of a non-specific biological response modifier is administered to the patient.
  • the biological response modifier comprises natural membrane vesicles and ribosomes, in a suspending buffer.
  • the ribosomes and vesicles are both derived from the bacterium Serratia marcescens.
  • Non-toxic means within a level of toxicity which is tolerable by the mammalian host receiving biologic response modifier therapy.
  • Non-immunogenic means evoking a sufficiently low immunogenic response, or no response at all, such that undesired, chronic inflammatory and hypersensitivity responses are not elicited, significantly, in the mammalian host.
  • Mean diameter means the mean diameter of MSD Particle Size Distribution Analysis as measured on a BI- 90 (Brookhaven Instrument Corp.) particle sizer. The measurement involves an intensity weighting of the size averaging process and is explained more fully in the Operator's Manual for the instrument, Chapter 6, incorporated herein by reference.
  • Substantially non-pathogenic in humans means not or rarely associated with disease in humans of normal health. Since most microorganisms are capable of causing opportunistic infections under the right circumstances, such as in persons whose immune system has been compromised, this definition excludes only those organism which typically cause non-opportunistic infections. "Tolerable level of endotoxin, cell walls, and cell membrane fragments” means that any such fractions, if present, have a low enough level of biologic activity to maintain a relatively non-toxic characteristic as defined herein. "Immune suppressing response” means an immune response which so attenuates the effect of the desired immune response as to be unacceptable for medical purposes.
  • Natural membrane vesicles means membrane vesicles prepared from membranes which are derived from living or dead natural cells.
  • CTI-BRM shall mean the biological response modifier described and claimed in the foregoing application.
  • CTI-BRM is, at the time of filing this application, undergoing Phase II Clinical Trials for cancer pursuant to regulations of the Food and Drug Administration of the United States of America.
  • a therapeutically effective amount of CTI-BRM is considered to be substantially equivalent to the amount found to be therapeutically effective in connection with cancer, as set out in the above-mentioned PCT patent application and other publications.
  • additional variants of therapeutically effective amounts may be readily determinable by the treating physician through observation, and from the information provided herein. Such are intended to be encompassed within the scope of term "therapeutically effective amount" as used herein and in the appended claims.
  • CTI-BRM comprises natural membrane vesicles and ribosomes in a suspending buffer.
  • the vesicles are comprised of cellular membrane material and are endogenous to a selected organism.
  • the ribosomes are also endogenous to the selected organism.
  • the biologic response modifier is substantially free of intact cells, cell walls, and cell membrane fragments.
  • the selected organism is one which does not evoke an immune suppressing response, is non-pathogenic in humans, and is one from which membrane vesicles are capable of being formed from cell membrane material and which vesicles are readily endocytosed by the monocyte macrophage cell line.
  • the vesicle population of the CTI-BRM exhibits a mean diameter of at least 180nm on particle size analysis.
  • CTI-BRM Further description of the CTI-BRM is provided in the aforementioned published PCT application. Such description, and the method of preparation, are set forth with particularity in that application and are incorporated herein by reference. The ability of CTI-BRM to alter the levels of various white blood count and neutrophil levels in cancer patients is described in the aforementioned PCT published application.
  • Dosage regimens described in the aforementioned published PCT patent application included dosage levels ranging from .25 to 10 milligrams administered from 3 to 6 times spaced at 7 day intervals and administered subcutaneously. Toxicity trials indicated no significant toxicity problems with those dosage regimens and further indicated that the product was well tolerated by the human patients. Adjuvant arthritis, granulomas, ulcerations, and similar effects of toxic components are minimized or eliminated by the use of the CTI-BRM.
  • a preferred source of the material for the CTI- BRM is the organism Serratia marcescens.
  • Serratia marcescens other organisms are suitable as a source for the membrane vesicles and ribosomes utilized in the CTI-BRM.
  • Such microorganism should not be a member of the microflora of the patient.
  • the microorganisms common bacterial antigen must not react or at least must be poorly cross-reactive with organisms making up the normal microflora of the patient.
  • suitable microorganism sources other than Serratia marcescens are Erwinia chrvsanthemi (pectobacterium) and Enterobacter aeroqenes.
  • bacterial cells of a strain of microorganism which is not present in the microflora of the patient to be treated and which has a common bacterial antigen which does not cross react or is poorly cross reactive with organisms making up the normal microflora of the patient to be treated are cultivated.
  • the cultivated cells are harvested and cell membrane is disassociated with an appropriate detergent.
  • the cellular concentrate is subjected to disruption mechanically at a pressure in excess of 10,000 psi to produce membrane vesicles with a mean diameter not less than 180 n .
  • the membrane vesicles and free ribosomes are separated from the remaining cellular material in the cellular lysate.
  • CTI-BRM is a powerful immunomodulator: it is rapidly phagocytosed by monocytes/macrophages which then show increased phagocytic, bactericidal and tumoricidal activity.
  • Patients injected subcutaneously with CTI- BRM show significant rises in granulocyte counts 24 hours later.
  • stimulation of human peripheral blood mononuclear cells with CTI BRM results in elevation of NK activity (4) , increased T-cell mediated cytotoxicity, and aug ented lymphocyte and monocyte antibody mediated cytotoxicity (ADCC) (5) .
  • CTI-BRM This ability of CTI-BRM to stimulate endogenous production of cytokines, inducing proliferation, maturation or enhancement of function of macrophages and lymphocytes, suggests it may be useful for the treatment of radiation-induced or drug-induced myelosuppression.
  • myelosuppression is a unique mechanism, it is by no means predictable that administration of CTI-BRM will work.
  • CF-1 mice were treated with cyclophospha ide at two doses-a "low" dose of 150mg/kg amd a "high" dose of 300 mg/kg.
  • mice were given one dose of either lOug CTI-BRM (low dose) or lOOug CTI-BRM (high dose) intraperitoneally.
  • the spleen is the major site of hematopoiesis, particularly under conditions of stress. This differs from the situation in humans where bone marrow is the primary hematopoietic organ.
  • the degree of protection/rescue from immunosuppressive agents can be measured by the splenic CFUc (colony forming units) assay in soft agar. Spleens were harvested at days 1, 2, A , and 7 post CTI-BRM treatment and assayed for CFUc.
  • both high and low doses of cyclophosphamide suppress colony formation through days 3 and 4 post treatment with a rebound from treatment occurring by Day 6.
  • Low dose CTI-BRM stimulates CFUc formation as quickly as 24 hours post injection and maintains stimulation through day 4 with effects diminishing by day 6.
  • High dose CTI-BRM has a longer lasting stimulatory effect, through day 6.
  • lOOug CTI-BRM mice have twice the number of CFUs than the lOug dose animals.
  • Combination treatment of low dose cyclophosphamide and low dose CTI-BRM maintains CFUs at control values through day 3.
  • Low dose Cyclophosphamide/high dose CTI-BRM stimulates CFU formation as early as 24 hours and at day 6 CFUc,s are higher than can accurately be measured in the assay.
  • CTI-BRM can also mitigate the effects of high dose cyclophosphamide.
  • High dose CTI-BRM takes 4 days to overcome the effects of high dose cyclophosphamide, but low dose CTI-BRM requires 6 days to exert its effects.
  • CTI-BRM may be used to protect patients undergoing chemotherapy from infections resulting from low white cell counts, allowing higher, possibly more effective doses of chemotherapy to be given.
  • CTI-BRM also maintains peripheral blood leukocyte counts in two other animal models of drug-induced cytopenia: l. Cytosine arabinoside (ARA-C) treatment in rats (see FIGURE 2 ) .
  • ARA-C Cytosine arabinoside
  • CTI-BRM has been shown to mitigate myelosuppression caused by drugs from three classes of chemotherapeutic agents, namely ARA-C, cyclophosphamide, and adriamycin.
  • the mechanism of action of CTI-BRM in mitigating myelosuppression is not known, but probably is a result of production of endogenous cytokines and growth factors which speed division of remaining precursor cells and aid maturation of the myeloid cells.
  • Administration of the CTI-BRM pursuant to the method of the invention is capable of restoring the immune system in the case of patients suffering from myelosuppression caused by radiation or drugs.
  • the method of the invention is safe in that it is well tolerated by patients. Restoration of the immune system in such patients restores their ability to withstand opportunistic infection, thereby greatly enhancing their chances for recovery.

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Abstract

On décrit un procédé de traitement d'un patient subissant une thérapie nécessitant l'utilisation de radiations ou d'un médicament qui provoque la myélosuppression. On administre au patient une quantité thérapeutiquement efficace d'un modificateur de réponse biologique compenant deux populations de particules majeures, l'une de ces populations comprenant des particules de moindre grosseur composées de ribosomes, et l'autre population se composant de vésicules membraneuses naturelles, dans un tampon de suspension. Les vésicules membraneuses et les ribosomes sont endogènes à un micro-organisme choisi qui est sensiblement non pathogène chez les humains. Le modificateur de réponse biologique est sensiblement dépourvu de cellules intactes et présente des niveaux tolérables d'endotoxine, de parois cellulaires et de fragments membraneux de cellules.
PCT/US1991/008185 1990-11-09 1991-11-04 Procede de prevention de myelosuppression due a la radiation ou aux medicaments WO1992008448A1 (fr)

Applications Claiming Priority (2)

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US61117090A 1990-11-09 1990-11-09
US611,170 1990-11-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7022315B2 (en) 2000-04-26 2006-04-04 Oregon Health & Science University Administration of a thiol-based chemoprotectant compound

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993754A (en) * 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
US4053585A (en) * 1974-06-25 1977-10-11 National Research Development Corporation Immunological preparations
US4372949A (en) * 1979-03-05 1983-02-08 Toyama Chemical Co., Ltd. Treatment of cancer with carcinostatic and immunostimulating agent containing lysophospholipid and phospholipid
JPS5849311A (ja) * 1981-09-18 1983-03-23 Eisai Co Ltd 安全なるリポソ−ムの製造法
US4663161A (en) * 1985-04-22 1987-05-05 Mannino Raphael J Liposome methods and compositions
US4873088A (en) * 1983-09-06 1989-10-10 Liposome Technology, Inc. Liposome drug delivery method and composition
US4873089A (en) * 1985-07-12 1989-10-10 Cornell Research Foundation Inc., Cornell University Proteoliposomes as drug carriers
US4971801A (en) * 1986-06-09 1990-11-20 Cell Technology, Inc. Biologic response modifier

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4053585A (en) * 1974-06-25 1977-10-11 National Research Development Corporation Immunological preparations
US3993754A (en) * 1974-10-09 1976-11-23 The United States Of America As Represented By The United States Energy Research And Development Administration Liposome-encapsulated actinomycin for cancer chemotherapy
US4372949A (en) * 1979-03-05 1983-02-08 Toyama Chemical Co., Ltd. Treatment of cancer with carcinostatic and immunostimulating agent containing lysophospholipid and phospholipid
JPS5849311A (ja) * 1981-09-18 1983-03-23 Eisai Co Ltd 安全なるリポソ−ムの製造法
US4873088A (en) * 1983-09-06 1989-10-10 Liposome Technology, Inc. Liposome drug delivery method and composition
US4663161A (en) * 1985-04-22 1987-05-05 Mannino Raphael J Liposome methods and compositions
US4873089A (en) * 1985-07-12 1989-10-10 Cornell Research Foundation Inc., Cornell University Proteoliposomes as drug carriers
US4971801A (en) * 1986-06-09 1990-11-20 Cell Technology, Inc. Biologic response modifier

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7022315B2 (en) 2000-04-26 2006-04-04 Oregon Health & Science University Administration of a thiol-based chemoprotectant compound

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