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WO1991012813A1 - Procede du traitement du cancer par l'utilisation d'une combinaison de chimiotherapie et d'un modificateur de la reponse biologique - Google Patents

Procede du traitement du cancer par l'utilisation d'une combinaison de chimiotherapie et d'un modificateur de la reponse biologique Download PDF

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Publication number
WO1991012813A1
WO1991012813A1 PCT/US1991/001433 US9101433W WO9112813A1 WO 1991012813 A1 WO1991012813 A1 WO 1991012813A1 US 9101433 W US9101433 W US 9101433W WO 9112813 A1 WO9112813 A1 WO 9112813A1
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WIPO (PCT)
Prior art keywords
biological response
response modifier
brm
chemotherapeutic agent
ribosomes
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Ceased
Application number
PCT/US1991/001433
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English (en)
Inventor
Catherine Anne Mccall
Adel A. Yunis
Joaquin J. Jimenez
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/05—Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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 treatment of tumors in mammals. More particularly, the invention relates to a method for treating a tumor in a mammalian patient by administering a combination of a chemotherapeutic agent and a biological response modifier. In addition the invention relates to use of a chemotherapeutic agent and a biological response modifier in the manufacture of a medicament pack for use in the treatment of mammalian tumors.
  • chemotherapeutic agents have been demonstrated to be effective in the treatment of tumors in mammalian patients. In many cases, however, the result is merely a reduction in the tumor cell load. Upon cessation of chemotherapy, the tumor often resumes its growth. Since many types of chemotherapeutic agents can be tolerated by a patient for only a limited period of time, this presents a significant problem in treating many types of tumors.
  • Certain types of tumor cells respond to cytokines by differentiation to different types of mature cells.
  • the ability of cytokines to induce terminal differentiation of leukemia cells suggest the possibility that terminal differentiation of tumor cells may be achieved by administration of cytokines.
  • cytokines often demonstrate substantial toxic affects on mammalian patients. Thus far, such problems have limited the effectiveness of cytokines in treating tumors in vivo.
  • the administration of a biological . response modifier derived from the bacterium Serratia marcescens is capable of stimulating endogenous differentiation activity production in a mammalian host. Nevertheless, in many instances, the tumor burden may exceed the ability of endogenous differentiation activity to significantly deter further tumor growth. It is an object of the present invention to provide an improved method for treating tumors in mammalian patients. Another object of the invention is to provide an improved method for treating tumors in mammalian patients which is more effective than chemotherapeutic agents or biological response modifiers alone.
  • Still another object of the invention is to provide a method for enhancing the effectiveness of chemotherapy in treating mammalian tumors.
  • Still another object is to provide medicament packs for use in the treatment of mammalian tumors.
  • FIGURE 1 is a table illustrating DF and CSF production by stimulated monocytes.
  • FIGURE 2 is a table illustrating the differentiation inducing activity in vitro using one form of the method of the invention.
  • FIGURE 3 illustrates an experiment in connection with day old Fischer rats demonstrating the effectiveness of the method of the invention in connection with chloroleukemia.
  • the method of the invention comprises administering a chemotherapeutic agent in a therapeutically effective amount to stabilize or substantially reduce the tumor cell load in the mammalian patient.
  • a biological response modifier is administered in an amount sufficient to induce substantial terminal differentiation of the residual tumor cells.
  • a biological response modifier comprises natural membrane vesicles and ribosomes in a suspending buffer. The membrane vesicles and ribosomes are derived from a bacterial host.
  • the invention also comprises use of a chemotherapeutic agent and a biological response modifier in the manufacture of a medicament pack for use in the treatment of mammalian tumors.
  • Non-toxic means within a level of toxicity which is tolerable by the mammalian host receiving biological 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 non-toxic characteristic as defined herein.
  • Immuno 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 cells.
  • 'Tumor means a neoplasm or mass of new tissue which persists and grows independently of its surrounding structures, and which has no physiologic use. See Dorland's Illustrated Medical Dictionary, 24th Edition. Chemotherapy means treatment of tumors by chemical agents, and a chemotherapeutic agent means a chemical agent used in the treatment of tumors. See Dorland's Medical Dictionary, 24th Edition. An example of a chemotherapeutic agent is cytosine arabinoside (ARA-C).
  • ARA-C cytosine arabinoside
  • CIT-BRM shall mean the biological response modifier described 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 Adrninistration of the United States of America. Information relating to therapeutically effective amounts of CTI-BRM has been generated in those trials and some of this information is contained in PCT Application No. PCT/US87/01397, as well as in other published articles.
  • a therapeutically effective amount of CIT-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.
  • a therapeutically effective amoimt would substantially reduce or would stabilize the tumor cell load in the patient.
  • Such amounts may vary from patient to patient depending on factors such as patient condition, tumor type, etc. 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.
  • CIT-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 biological 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 C I-BRM exhibits a mean diameter of at least about 180 nm on particle size analysis.
  • CIT-BRM Further description of the CIT-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 56 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 CIT- BRM.
  • a preferred source of the material for the CTI-BRM is the organism Serratia marcescens.
  • Serratia marcescens other organisms are suitable as source for the membrane vesicles and ribosomes utilized in the CTT-BRM.
  • Such microorganisms should be not a member of the microflora of the patient.
  • the microorganism's 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 chrysanthemi (pectobacterium) and Enterobacter aerogenes.
  • 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 nm.
  • the membrane vesicles and free ribosomes are separated from the remaining cellular material in the cellular lysate.
  • the membrane vesicles and free ribosomes are then re-suspended in an appropriate buffer.
  • CIT-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 CIT-BRM show significant rises in granulocyte counts 24 hours later. Co- culture of CTT-BRM with human peripheral blood mononuclear cells results in elevation of NK activity, increased T-cell mediated cytotoxicity, and augmented lymphocyte and monocyte antibody mediated cytotoxicity (ADCC). The enhancement of these cellular effector functions is most likely a result of a cascade of cytokine release which occurs after CIT-BRM stimulation.
  • CIT-BRM CIT-BRM stimulated human peripheral blood mononuclear cells contain TLrl, TL-2, interferons alpha and gamma, TNF and GM-CSF.
  • Dulbecco's modified minimum essential medium was purchased from Flow Laboratories, McLean, VA; horse serum nd fetal calf serum (FCS) were purchased from the University of Miami Comprehensive Cancer
  • Bacto agar was purchased from Falcon Plastics, Oxnard, CA. Tissue culture dishes were from Corning Glass Works, Corning, NY. Fischer rats were obtained from Charles River Laboratories, Wilmington, MA. Cytosine arabinoside (ARA-C) was purchased from Jackson Memorial Hospital pharmacy, Miami, FL.
  • ARA-C Cytosine arabinoside
  • Mia C51 is a well characterized cell line established from rat myelogenous leukemia by Yunis, et al See Yunis, AA., Arimura, G.K., Haines, H.G., Ratzan, R.J. and Gross, M.A, Characteristics of rat chloroma in culture. Cancer Res. 35:337-345, 1975. It is maintained in DMEM/10 FCS in a humidified incubator at 37 ⁇ C and 5% C0 2 .
  • Rat peritoneal monocyte conditioned media was prepared as described in Jimenez, J J. and Yunis, A.A. Treatment with monocyte-derived partially purified GM-CSF but not G-CSF aborts the development of transplanted chloroleukemia in rats. Blood 72:1077-1080, 1988. Fischer rats were sacrificed and the peritoneal cavity was lavaged with serum free (SF) DMEM. The cell suspension at a concentration of 1 x 10 6 monocytes/ml w.as placed in a tissue culture dish that was placed in a humidified incubator at 37 ⁇ C and 5% C0 2 for 24 hours.
  • SF serum free
  • DA differentiation activity
  • CSF colony stimulating factor
  • ARA-C had a dose dependent inhibitory effect on C51 colony formation with maximal inhibition (80% ⁇ 1.5) at 0.06 ⁇ g/ml. This inhibition was not associated with differentiation. However, when ARA-C (o.06 ⁇ g/ml) was added with IMCM there was a 15% increase of C51 colony differentiation, as compared to IMCM alone (FIGURE 2).
  • Group HI received CIT-BRM 25 ⁇ g/ml IP.
  • Group IV received ARA-C, 20 mg/kg/day and CIT-BRM 25 ⁇ g/day, both TP. All rats were treated 6 hours after MIA C51 injection for a total of 7 consecutive days. In Group I all rats were dead of chloroleukemia by day 18. In Group ⁇ , 2 of 23 (9%) and in Group in 9 of 10 (45%) remained disease-free. In contrast in Group TV 18 of 20 (90%) remained disease-free (FIGURE 3). In Groups IL m and TV, 2(9%), 9(45%), and 18(90%) rats remained disease-free.
  • the clinical premise is that patients (PTS) with tumors containing endogenous effector cells which are capable of responding to BRM challenge by producing TCSC are more likely to respond to BRM therapy than are PTS whose tumors do not contain such functionally-active effector cells.
  • Differential cell counts performed on 125 solid tumor (ST) SPEC prior to culture showed a medium effector (macrophages + lymphocytes): tumor cell (E:T) ratio 0.5 30% of SPEC lacked discernible lymphocytes, 10% lacked macrophages 35% had an E:T ratio > 1.04% had an E:T ratio > 10.0.
  • E:T ratios of ST biopsies versus effusions There was no relationship between the activity of any BRM and the E:T ratio (corr. coeff, range 0.02 - 0.18), except for no activity in established cell lines or in fresh tumor SPEC totally devoid of effector cells.
  • IL2 (TND ⁇ 166 U/ml); BR 2/22-IND, 3/24 AVG; CO 0/18-IND, 0/20 AVG; LC 1/22-TND, 1/23-AVG; MEL 4/20-IND, 5/21-AVG, OV 4/21-TND, 2/23-AVG; B Cell 0/17-TND, 0/20- AVG.
  • the invention provides an improved method for treating a tumor in a mammalian patient.
  • a synergistic effect between chemotherapeutic agents and CTI-BRM is noted. It is clear that the method of the invention results in a marked increase in differentiation activity, although the specific nature of such activity is at present not fully understood. Such activity could represent the summation and/or interaction of a number of cytokines. Nevertheless, it is clear that the combination of chemotherapeutic agent and CTI-BRM offers a substantial benefit over each agent alone in the treatment of tumors.

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Abstract

L'invention concerne un procédé de traitement de tumeurs chez un patient mammifère par adminsitration d'une combinaison d'un agent chimiothérapeutique et d'un modificateur de la réponse biologique en des quantités thérapeutiquement efficaces pour stabiliser ou réduire sensiblement la charge de cellules tumorales chez le patient mammifère. Selon le procédé, une quantité thérapeutiquement efficace d'un agent chimiothérapeutique est administrée à un patient mammifère, à qui on administre par la suite le modificateur de la réponse biologique en une quantité suffisante pour induire une différenciation terminale substantielle des cellules tumorales résiduelles. Le modificateur de la réponse biologique comprend des ribosomes et des vésicules de membranes naturelles dans un tampon en suspension. Les ribosomes et les vésicules de membrane sont dérivés d'un hôte bactérien. L'invention consiste également en l'utilisation d'un agent chimiothérapeutique et d'un modificateur biologique pour la production d'un médicament combiné utilisé dans le traitement de tumeurs affectant des mammifères.
PCT/US1991/001433 1990-03-02 1991-03-01 Procede du traitement du cancer par l'utilisation d'une combinaison de chimiotherapie et d'un modificateur de la reponse biologique Ceased WO1991012813A1 (fr)

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US48874790A 1990-03-02 1990-03-02
US488,747 1990-03-02

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WO1991012813A1 true WO1991012813A1 (fr) 1991-09-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054790A1 (fr) * 1999-03-15 2000-09-21 Pierre Fabre Medicament Fractions membranaires bacteriennes immunostimulantes dans le traitement de cancers
EP2589391A4 (fr) * 2010-07-01 2014-03-05 Postech Acad Ind Found Méthode de diagnostic et de traitement du cancer par des microvésicules cellulaires

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007503A1 (fr) * 1986-06-09 1987-12-17 Cell Technology, Inc. Modificateur de reponse biologique
US4863969A (en) * 1985-06-28 1989-09-05 Hoffmann-La Roche Inc. Treatment of premalignant lesions and certain malignant tumors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4863969A (en) * 1985-06-28 1989-09-05 Hoffmann-La Roche Inc. Treatment of premalignant lesions and certain malignant tumors
WO1987007503A1 (fr) * 1986-06-09 1987-12-17 Cell Technology, Inc. Modificateur de reponse biologique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHARLES E. KUPCHELLA, "Dimensions of Cancer", Published in 1987, by WADSWORTH PUBLISHING COMPANY, (Belmont), see pages 311 and 315. *
JAY S. ROTH, "All About Cancer", Published in 1985, by GEORGE F. STICKLEY COMPANY, (Philadelphia), see pages 166 and 167. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000054790A1 (fr) * 1999-03-15 2000-09-21 Pierre Fabre Medicament Fractions membranaires bacteriennes immunostimulantes dans le traitement de cancers
EP2589391A4 (fr) * 2010-07-01 2014-03-05 Postech Acad Ind Found Méthode de diagnostic et de traitement du cancer par des microvésicules cellulaires
US9066971B2 (en) 2010-07-01 2015-06-30 Postech Academy-Industry Foundation Method for treating and diagnosing cancer by using cell-derived microvesicles
KR101752506B1 (ko) * 2010-07-01 2017-06-30 포항공과대학교 산학협력단 세균유래 마이크로베시클을 이용한 암치료 및 암진단 방법

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AU7477791A (en) 1991-09-18

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