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WO2004026337A1 - Polytherapie contre le cancer dans laquelle un vaccin contre le cancer et un medicament chimiotherapeutique sont utilises - Google Patents

Polytherapie contre le cancer dans laquelle un vaccin contre le cancer et un medicament chimiotherapeutique sont utilises Download PDF

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Publication number
WO2004026337A1
WO2004026337A1 PCT/GB2003/003977 GB0303977W WO2004026337A1 WO 2004026337 A1 WO2004026337 A1 WO 2004026337A1 GB 0303977 W GB0303977 W GB 0303977W WO 2004026337 A1 WO2004026337 A1 WO 2004026337A1
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WIPO (PCT)
Prior art keywords
cancer
tumour
administration
drug
ctx
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PCT/GB2003/003977
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English (en)
Inventor
Vincenzo Cerundolo
Ian Francis Hermans
Michael Joachim Palmowski
Adrian Lewellyn Harris
Tsung Wen Cheng
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Isis Innovation Limited
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Priority to CA002499628A priority Critical patent/CA2499628A1/fr
Priority to AU2003269133A priority patent/AU2003269133A1/en
Priority to EP03750915A priority patent/EP1545592A1/fr
Publication of WO2004026337A1 publication Critical patent/WO2004026337A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/19—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/46—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5258—Virus-like particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/57—Skin; melanoma

Definitions

  • the present invention relates to the treatment of cancer and in particular to treatments based on a combination of chemotherapy and immunotherapy.
  • Cytotoxic T lymphocytes directed at tumour cells presenting unique peptide on MHC class I molecules constitute a potentially powerful effector arm of host immunity to tumours.
  • Immunisation strategies that aim to induce or restimulate tumour-specific CTL may therefore provide an effective and practical approach to cancer treatment (Rosenberg, Nature 2001; 411:380-4). While the utility of such immunotherapy has been shown in many preclinical studies, it is unlikely that this treatment modality alone will be sufficient to cure patients with significant metastatic disease, and hence high tumour burdens. This is because tumours may mutate such that they no longer present the unique peptide. In fact, immunotherapy may hold most promise as an adjunct to conventional strategies aimed at cytoreduction, such as chemotherapy (Greenberg, Adv Immunol 1991; 49:281-355).
  • the present inventors have assessed the efficacy of anti-tumour responses generated by a combination of metronomic dosing of cyclophosphamide (CTX) with an immunisation strategy aimed at eliciting tumour-specific CTL.
  • CTL cyclophosphamide
  • CTX cyclophosphamide
  • the present invention provides the use of an agent for stimulating an immune response against a cancer, and a chemotherapeutic drug in the manufacture of a medicament for the treatment of said cancer wherein said drug is for administration in a metronomic schedule.
  • the invention provides a product containing an agent for stimulating an immune response against a cancer; and a chemotherapeutic drug as a combined preparation for simultaneous, sequential or separate use in treating said cancer, the drug being for administration in a metronomic schedule.
  • the invention provides a method of treating a patient suffering from cancer, comprising administering to the patient: an agent for stimulating an immune response against said cancer; and a chemotherapeutic drug; wherein said drug is administered in a metronomic schedule.
  • chemotherapeutic anti- tumour drugs administered using the MTD regime might prevent or severely retard an immune response
  • such drugs administered in an metronomic schedule retain an anti- tumour effect but do not have such severe immune suppression effects. Accordingly, they can be administered in combination with treatments which cause an immune response to be raised against the tumour, resulting in an unexpectedly effective anti- tumour therapy.
  • a "metronomic schedule" means the administration of the chemotherapeutic drug at doses lower than the MTD which are nevertheless effective to prevent or delay growth of the cancer, preferably at frequent intervals and without extended rest periods.
  • the metronomic schedule may be such that 80% or less (and preferably 70%, 60%, 50%, 40%, 30%, 20% or less) of the drug is administered than would have been administered using the MTD regime.
  • the drug may be administered in a range from continuous fusion to weekly or 1-3 times a week.
  • Such a schedule is to be contrasted with the maximum tolerated dose (MTD) regime normally used for chemotherapeutic drugs, where administration may consist of high dose(s) administered over short periods followed by a period (often 2-3 weeks) where no drug is administered in order to allow recovery of non-cancer cells which are killed by the high doses.
  • MTD maximum tolerated dose
  • the metronomic schedule may be such as to allow the drug to be anti-angiogenic, i.e. to cause apoptosis of vascular endothelial cells within the tumour, rather than to act directly on the tumour cells. Because the direct action of the drug on cancer cells is reduced, concomitant selection of drug resistant tumour cells is also avoided.
  • the anti-angiogenic effect of the schedule can be measured as described in Browder et al, Cancer Res 2000; 60: 1878-86.
  • the chemotherapeutic drug may be a small molecule cytotoxic agent, i.e. a compound with the ability to kill mammalian cells having a molecular weight of, for example, less than 700 daltons. Such compounds may contain toxic metals capable of having a cytotoxic effect. Furthermore, it is to be understood that these small molecule cytotoxic agents also include pro-drugs, i.e. compounds that decay or are converted under physiological conditions to release cytotoxic agents.
  • CTX cyclophosphamide
  • IL-1 cyclophosphamide
  • IL-2 an alkylating agent commonly used in chemotherapy.
  • CTX is known to have immuno- suppressive qualities, and indeed is commonly used as a suppressant in autoimmune conditions such as arthritis and lupus nephritis. It has also been shown to have immune-potentiating activity in some settings (Askenase et al, JExp Med 1975; 141:697-702; Maguire et al, J Invest Dermatol 1967; 48:39-43; Mitsuoka et al, Nature 1976; 262:77-8, Ehrke et al, Semin Oncol 1989; 16:230-53).
  • CTX has also been administered in combination with immunotherapy (Machiels et al, Cancer Res., 2001; 61: 3689-3697; Vierboom et al, Int. J. Cancer, 2000; 87:253-260) and been shown to enhance such immunotherapy in certain circumstances.
  • CTX administered in a metronomic schedule being administered in a single dose before immunotherapy.
  • Vierboom et al were not able to show any enhancement of immunotherapy when CTX was administered at a low dose. Therefore, prior to the present invention, it was not clear or predictable what effect CTX would have on the immune system when administered in a metronomic schedule.
  • the present inventors have found that the combination of CTX when administered in a metronomic schedule and immunotherapy is unexpectedly efficacious in killing tumour cells.
  • Metronomic dosing of CTX may comprise 130-250, 150-200, 160-180, 170-175 or 175 mg/kg of CTX injected or otherwise administered every 1-8, 3-7, 5 or 6 days (as compared to a typical MTD dosing of a 21 day cycle of 150 mg kg CTX administered every other day over 6 days (i.e. three injections) followed by 15 days rest), or may be as described in Browder et al, Cancer Res 2000; 60: 1878-86.
  • CTX may alternatively be administered as described in Man et al, Cancer Res. 200262:2731-2735, i.e. continuously in drinking water at a dose of 10-40 mg/kg/day.
  • This metronomic schedule sustains cytolytic activity against proliferating endothelial cells required for blood vessel growth, thereby starving developing tumours of oxygen.
  • vinblastine Another drug suitable for use in the invention is vinblastine, which may be administered at 0.5-5, 0.75-2, 0.85-1.5 or 1 mg/kg once, twice, three, four, five times or more every week, or as described in lement et al, J Clin Invest 2000; 105:R15-24.
  • drugs suitable for use in the invention include 5-fluorocil, 6-mercaptopurine, doxorubicin, taxol, cisplatinum, etopside, carboplatin, paclitaxel and topotecan.
  • 5- fluorocil and 6-mercaptopurine may be administered as a continuous fusion (preferably as described in Browder et al, Cancer Res 2000; 60: 1878-86).
  • Taxol and cisplatinum may be administered as described in Klement et al, Cancer Res.
  • etopside and carboplatin may be administered as described in Bello et al, Cancer Res, 2001; 61: 7501-7506 and topotecan may be administered as described in Soffer et al, J. Pediatr. Surg, 2001; 36:1781-1784.
  • the agent for stimulating an immune response against said cancer may be a tumour- specific antigen, preferably recognised by cytotoxic T cells (although antigens recognised by antibodies and such are included within the present invention), and/or nucleic acid encoding such an antigen.
  • tumour-specific antigen preferably recognised by cytotoxic T cells (although antigens recognised by antibodies and such are included within the present invention
  • nucleic acid encoding such an antigen examples include melanoma epitopes (e.g. MAGE-1 HLA-A1 restricted epitope) and other cancer-specific epitopes (e.g. the renal cell carcinoma associated antigen G250 restricted by HLA-A2).
  • cancer- associated antigens are listed in the HLA Factbook (Barclay (Ed) Academic Press), and many others have been and are being identified.
  • the agent for stimulating an immune response may comprise a plurality of different tumour-specific antigens and/or nucleic acid encoding such antigens.
  • subsequent rounds of treatment may involve the re- stimulation of T cells recognising one or a combination of the plurality of antigens. In such embodiments, it is preferred if there is a delay between administration of the agent and the drug.
  • the antigen may be administered by means of dendritic cells loaded with the antigen (Mayordomo et al. Nat Med. 1995 Dec; 1(12): 1297-302; Hsu et al. Nat Med. 1996 Jan; 2(l):52-8).
  • Other methods for administration of such antigens are known to those of skill in the art and include administration of the naked peptide, of liposomes containing the peptide, etc.
  • the agent for stimulating an immune response against said cancer may be a T cell specific for the tumour, which may be administered by adoptive transfer (Cheever et al, JExp Med 1986 May 1; 163(5): 1100-12; Vierboom et al, IntJ. Cancer, 2000; 87:253-260; Greenberg, / Immunol. 1986 Mar 1; 136(5): 1917-22.).
  • Nucleic acid encoding a tumour specific antigen may be administered in a suitable vector.
  • two different vectors are used to administer the nucleic acid, thereby focussing immune responses to the recombinant antigen shared by the vectors.
  • One of the vectors may be a replication- impaired pox virus, such as modified vaccinia virus (MVA).
  • MVA modified vaccinia virus
  • Nucleic acid may be administered using various types of recombinant viruses as vehicles for DNA inoculation or by techniques that use "naked" DNA.
  • the tumour- specific antigen may be administered such that it is expressed in the subject to be treated for example in the form of a recombinant DNA molecule comprising a polynucleotide encoding the antigen operatively linked to a nucleic acid sequence which controls expression, such as in an expression vector.
  • a vector will thus include appropriate transcriptional control signals including a promoter region capable of expressing the coding sequence, said promoter being operable in the subject to be treated.
  • the promoter which term includes not only the sequence necessary to direct RNA polymerase to the transcriptional start site, but also, if appropriate, other operating or controlling sequences including enhancers, is preferably a human promoter sequence from a human gene, or from a gene which is typically expressed in humans, such as the promoter from human cytomegalovirus (CMV).
  • CMV cytomegalovirus
  • eukaryotic promoters suitable in this regard are the CMV immediate early promoter, the HSV thymidine kinase promoter, the early and late SV40 promoters, the promoters of retroviral LTRs, such as those of the Rous sarcoma virus ("RSV"), and metallothionein promoters, such as the mouse metallothionein-I promoter.
  • a polynucleotide sequence and transcriptional control sequence may be provided cloned into a replicable plasmid vector, based on commercially available plasmids, such as pBR322, or may be constructed from available plasmids by routine application of well known, published procedures.
  • the expression vectors may also include selectable markers, such as for antibiotic resistance, which enable the vectors to be propagated.
  • Expression vectors capable in situ of synthesising antigen may be introduced directly by physical methods. Examples of these include topical application of the 'naked' nucleic acid vector in an appropriate vehicle for example in solution in a pharmaceutically acceptable excipient such as phosphate buffered saline (PBS). Other physical methods of administering the DNA directly to the recipient include ultrasound, electrical stimulation, electroporation and microseeding.
  • PBS phosphate buffered saline
  • vectors for expressing antigen for use in the invention comprise cis-acting control regions effective for expression in a host operatively linked to the polynucleotide to be expressed.
  • Appropriate trans-acting factors either are supplied by the host, supplied by a complementing vector or supplied by the vector itself upon introduction into the host.
  • the vectors provide for specific expression.
  • Such specific expression may be inducible expression or expression only in certain types of cells or both inducible and cell-specific.
  • vectors can be used to express antigen for use in the invention.
  • Such vectors include, among others, chromosomal, episomal and virus- derived vectors, e.g., vectors derived from bacterial plasmids, from bacteriophage, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, from viruses such as baculoviruses, papova viruses, such as SV40, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as those derived from plasmid and bacteriophage genetic elements, such as cosmids and phagemids.
  • any vector suitable to maintain, propagate or express polynucleotides to express a polypeptide in a host may be used for expression in this regard.
  • DNA sequence may be inserted into the vector by any of a variety of well-known and routine techniques, such as, for example, those set forth in Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1989).
  • tumour-mediated immune response to tumours can be initiated without prior knowledge of defined tumour antigens.
  • the agent for stimulating an immune response need not be a tumour-specific antigen.
  • irradiated or lysed tumour cells e.g. from biopsy tissue
  • tumour cells fused with dendritic cells e.g. from dendritic cells
  • heatshock proteins isolated from tumour tissue may be used.
  • Tumour tissue can also be modified to express gene sequences that enhance immune responses, (e.g. cytokine genes) before being irradiated and injected.
  • the agent for stimulating an immune response is preferably administered before the drug, although it is to be understood that the present invention includes treatments when the drug is administered before the agent for stimulating an immune response and when the respective treatments are administered simultaneously.
  • the time, if any, between the respective treatments may be varied widely. It is preferred if the drug is delivered after the peak CTL induction.
  • the drug may be administered from 3-100 days after the agent and preferably 10-30, 14-30 or 15-18 days after the agent.
  • an angiogenesis inhibitor may be administered. Suitable inhibitors are known to those of skill in the art and include TNP-470.
  • the present invention provides a) a method of treating a patient suffering from cancer, comprising administering to the patient: an agent for stimulating an immune response against said cancer; and a drug effective in preventing or delaying angiogenesis; b) the use of an agent for stimulating an immune response against a cancer, and a drug effective in preventing or delaying angiogenesis in the manufacture of a medicament for the treatment of said cancer; and c) a product containing an agent for stimulating an immune response against a cancer; and a drug effective in preventing or delaying angiogenesis as a combined preparation for simultaneous, sequential or separate use in treating said cancer.
  • Medicaments in accordance with the invention will usually be supplied as part of a sterile, pharmaceutical composition which will normally include a pharmaceutically acceptable carrier.
  • This pharmaceutical composition may be in any suitable form, (depending upon the desired method of administering it to a patient). It may be provided in unit dosage form, will generally be provided in a sealed container and may be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use. It may include a plurality of said unit dosage forms.
  • the pharmaceutical composition may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with the carrier(s) or excipient(s) under sterile conditions.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions).
  • Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof.
  • Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.
  • excipients which may be used include for example water, polyols and sugars.
  • suspensions oils e.g. vegetable oils
  • oil-in-water or water in oil suspensions may be used.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6):318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the compositions are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or enemas.
  • Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the active ingredient.
  • compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solution which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Excipients which may be used for injectable solutions include water, alcohols, polyols, glycerine and vegetable oils, for example.
  • compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carried, for example water for injections, immediately prior to use.
  • sterile liquid carried, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts (substances of the present invention may themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents or antioxidants. They may also contain therapeutically active agents in addition to the substance of the present invention. Preferred features of each aspect of the invention are as for each of the other aspects mutatis mutandis. The prior art documents mentioned herein are incorporated to the fullest extent permitted by law.
  • Figure 1 illustrates that the sequential immunisation with recombinant vectors encoding a tumour-specific antigen induces resistance to tumour challenge.
  • CTL responses in C57BL/6 mice were primed by i.m. injection of DNAmel3, and then boosted by i.v. injection with MVAmel3 14 days later.
  • B) Immunised animals were challenged with 3 x 10 5 B16mel3 cells 7 days after MVA boost, and tumour progression was compared with growth observed in unimmunised animals. Mean tumour size per group (n 5) ⁇ S.E. are shown.
  • Figure 2 illustrates that combining immunotherapy with metronomic dosing of CTX provides prolonged resistance to tumour challenge.
  • Figure 3 illustrates that activated CTL with a CD43 10 phenotype are resistant to metronomic CTX-mediated deletion, and retain potent restimulatory capacity.
  • A) CTL responses were initiated by immunization as in Figure 1, and then blood was taken for FACS analysis on the indicated days. CD43 expression was assessed on gated CD8 + Flu-NP 366-374 D b tetramer + cells.
  • B) CTL responses were monitored in the blood of immunized animals following metronomic CTX treatment initiated on the days indicated. The total number CD8 + Flu-NP 3 66-37 4 /D b tetramer + cells per mm 3 of blood was extrapolated from white blood cell counts.
  • Figure 4 illustrates that combining immunotherapy with metronomic dosing of vinblastine provides prolonged resistance to tumour challenge. Progression of B16 tumours was monitored in animals that were subjected to one of the following treatment schedules: O, no treatment; •, immunisation prior to challenge as outlined in Figure 1; 0, metronomic treatment with vinblastine (1 mg/kg twice weekly); ⁇ , a combination of prior immunisation and metronomic vinblastine.
  • Figure 5 illustrates that combining immunotherapy by way of dendritic cells dosed with tumour-specific antigen with metronomic dosing of CTX provides prolonged resistance to tumour challenge. Progression of B16 tumours was monitored in animals that were subjected to one of the following treatment schedules: O, dendritic cells only; •, dendritic cells only and CTX; ⁇ , dendritic cells and tumour-specific antigen; 0, a combination of dendritic cells and tumour-specific antigen and metronomic CTX (175 mg kg every 6 days).
  • mice C57BL/6 mice were from breeding pairs originally obtained from Jackson Laboratories, Bar Harbor, Maine. All mice were maintained at the Biomedical Services Unit of John Radcliffe Hospital by brother x sister mating; in vivo experimental protocols were performed according to institutional guidelines. In vitro culture media and reagents. All cultures were maintained in complete medium (CM) comprising of RPMI (Sigma- Aldrich , Dorset, England) with 2 mM glutamine, 1 % penicillin-streptomycin, 5 x 10 ⁇ 5 M 2-merca ⁇ to-ethanol (all Invitrogen Ltd, Paisley, UK) and 10 % fetal bovine serum (Globepharm, Guildford, England). Immunisation strategy.
  • CM complete medium
  • NP 366 - 37 -specific CTL responses by intramuscular injection of 50 ⁇ g of plasmid DNA encoding the mel3 polyepitope (DNA-mel3).
  • the mel3 construct consists of a string of five HLA-A2 and two HLA- Al melanoma epitopes, and an influenza nucleoprotein epitope restricted by H-2D (Palmowski et al, J Immunol 2002; 168:4391-8). Only the influenza epitope NP3 66 _ 37 (ASNENMDAM) is presented on a C57BL/6 background. Mice were boosted 14-60 days after DNA immunization by i.v.
  • mice were boosted a second time by i.v injection with 1 x 10 6 syngeneic splenocytes that had been infected with recombinant vaccinia encoding the melS polyepitope construct (Vacc-mel3).
  • Splenocytes (5 x 10 7 cells/ml) were infected with 10 8 PFU of Vacc- mel3 in PBS supplemented with 0.1 % BSA (Sigma- Aldrich) at 37°C for 2 h, washed, and injected i.v. into the lateral tail vein.
  • Cyclophosphamide dosing schedule CTX (ASTA Medica Ltd, Cambridge, UK) was reconstituted in sterile distilled H 2 O and administered by i.p. injection.
  • metronomic dosing consisted of 175 mg/kg of CTX injected every 6 days, and standard dosing consisted of a 21 day cycle of 150 mg/kg CTX administered every other day over 6 days (i.e. three injections) followed by 15 days rest.
  • Vinblastine dosing schedule Vinblastine sulphate (David Bull Laboroatories, Warwick, UK) was administered by i.p injection twice weekly at 1 mg/kg.
  • Tetrameric H-2 D / NP3 66 -3 7 peptide complexes were prepared as outlined in Altman et al, Science 1996; 274:94-6, and used to stain fresh PBL isolated from the lateral tail vein. Approximately 5 x 10 5 PBL were suspended in 20 ⁇ l CM and incubated with 0.5 ⁇ g of tetramer complexes at 37 °C for 20 min.
  • the cells were then incubated with anti-CD8 and anti-CD43 (BD Pharmingen, San Diego, CA) for 10 min at 4 °C, washed twice with PBS, and resuspended in PBS for FACS analysis. Cells were analysed with FACScan hardware and CellQuest software (BD Biosciences , Mountain View, CA). Blood was also collected to perform white blood cell counts so that total lymphocyte numbers per mm 3 of blood could be extrapolated. White blood cell counts were performed using a Micros ⁇ O blood counter (ABX-PARC Euromedecine, France).
  • B16-GP33 is a derivative of the B 16 (C57BL/6, H-2 b ) which has been modified to express a minigene encoding LCMV 33- 1 (Prevost-Blondel et al. J Immunol. 1998 161(5): 2187-94).
  • Example I Sequential immunisation of C57BL/6 mice with DNA and vaccinia vectors encoding a tumour-specific antigen can elicit CTL responses capable of resisting tumour challenge
  • H-2 b strains such as C57BL/6
  • CTL responses are induced solely to the Derestricted influenza nucleoprotein epitope (NP 366 - 37 4)-
  • the efficacy of sequential immunisation with DNA and vaccinia (Modified Vaccinia Ankara strain, MVA) (Carroll et al, Vaccine 1997; 15:387-94) vectors encoding mel3 to induce NP3 66-37 4-specific responses capable of resisting challenge with B16 melanoma cells also modified to express mel3 was assessed.
  • DNA DNA (DNA-mel3) was injected intramuscularly to prime NP 366 - 374 -s ⁇ ecific CTL, and then these responses were boosted several days later by i.v.
  • MVA-mel3 was injected intravenously 14 days after DNA immunisation, the NP 366-3 -specific cells were effectively boosted, proliferating to an average of 25.6 ⁇ 4.5 % of CD8 + lymphocytes 7 days later.
  • B16-mel3 melanoma cells were injected subcutaneously 7 days after MVA-mel3 boost. These cells had been transfected with the mel3 polyepitope construct together with a green fluorescent protein (GFP) sequence to monitor antigen expression.
  • GFP green fluorescent protein
  • Example 2 Metronomic dosing with cyclophosphamide enhances anti-tumour effects of CTL-mediated immunity.
  • the immunotherapy model described in Example 1 was utilised to investigate the feasibility of combining CTX treatment with anti-tumour immunotherapy (Fig. 2 A).
  • CTX treatment alone whether delivered by a standard MTD regimen or a metronomic low dose schedule, induced anti-tumour activity resulting in retarded tumour growth relative to untreated controls. Measurements were terminated for each group when the first animal developed a tumour in excess of 200 mm 2 . Thus, while measurements were terminated for the untreated group at day 21 after challenge, animals undergoing the MTD regime survived until day 34 after tumour challenge, and animals receiving the metronomic schedule until day 42 after challenge.
  • NP3 66 -3 74 -specific CTL (Fig 2 B).
  • CTX-induced loss of NP 366-374 -specific CTL was not as severe soon after tumour challenge (day 15) in animals that received metronomic dosing as opposed to the MTD regime.
  • the metronomic low dose schedule permits greater CTL activity, and hence provides a more efficacious combination with immunotherapy.
  • Example 3 Effects of timing of CTX therapy on anti-tumour response.
  • Example 2 CTX treatment (by either dosing regime) was initiated 10 days after tumour challenge, which was 17 days after MVA boost.
  • the combination therapy was not as potent as in the earlier experiment, although the combination therapy was still greatly enhanced over the other treatment groups.
  • the metronomic therapy had been initiated at a time when the CTL proliferation was likely to be peaking after MVA boost.
  • Example 4 Metronomic dosing with cyclophosphamide reduces numbers of proliferating 'effector' CTL but spares CTL with restimulatory capacity.
  • the effect of CTX on CTL proliferation and restimulatory capacity was studied in the context of the immunisation strategy outlined above, without tumour challenge.
  • CTX was administered by low dose metronomic schedule at different times relative to MVAmel3 boost in order to observe the effect of timing of CTX treatment on numbers of NP3 66-3 4 -specific cells detected in the blood (Fig 3).
  • each of the groups of animals above was subjected to a restimulation regime involving intravenous injection with syngeneic splenocytes that had been infected ex vivo with the recombinant vaccinia virus Vacc-mel3.
  • This strategy was used because the previous MVA infection would have generated antibodies capable of neutralising a second vaccinia virus infection.
  • these neutralising antibodies could be avoided temporarily, permitting presentation of the NP 366-3 4 peptide, and hence allowing CTL restimulation.
  • CTX treatment was terminated 6 days before injection of infected splenocytes.
  • Example 5 Combination of vinblastine and immunotherapy To establish whether the combination therapy was effective when a different chemotherapeutic agent was used, the mel3-mediated immunisation strategy described in the previous examples was adopted, but combined with vinblastine, another drug shown to have anti-angiogenic qualities when delivered in a low dose metronomic fashion (Klement et al. J. Clin. Invest 2000; 105:R15-24). DNA-mel3 immunisation and MVA-mel3 re-stimulation were performed as described in the above examples. B16-mel3 was administered one week after MVA-mel3 injection, and vinblastine therapy (1 mg/kg twice weekly) initiated on the same day. Once again, the combination of metronomic delivery of chemotherapeutic agent and immunotherapy induced the most powerful anti-tumour response (see Figure 4).
  • Example 6- Combination of CTX and administration of dendritic cells
  • DC dendritic cells
  • the LCMV GP33 -s ⁇ ecific immune response generated with the peptide-loaded DC provided significant protection against tumour challenge leading to a delay in tumour engraftment and growth.
  • the combination therapy was, once again, the most powerful anti-tumour strategy, with complete protection from tumour challenge observed over the period of the experiment (see Figure 5).
  • the efficacy of the combination therapy is a result of efficient CTL-mediated cytolysis in the first instance, which effectively reduces the tumour burden upon which the drug must act.
  • sustained CTX treatment is able to keep growth of the antigen-loss variants in check for a considerably enhanced period.
  • the CTX treatment whether by minimising angiogenesis, or by acting upon the tumour cells directly, may be preferentially removing proliferating tumour cells. The remaining cells, with a slower proliferative capacity, may take more time to provide antigen-loss variants that can avoid CTL-mediated deletion.
  • CTX can be administered constantly in drinking water, effectively lowering CTX dose while sustaining antiangiogenic capacity (Man et al. Cancer Res 2002; 62:2731-5). It is likely that such a strategy would result in less immune suppression, and less associated morbidity.
  • CTX is a well-recognised alkylating agent, with its activity directed at the DNA of dividing cells. It is not surprising therefore that CTL in a proliferating "effector" phase fall prone to the activity of this drug, while cells activated months earlier, and approaching quiescence, do not.
  • the treatment of the present invention may be used, for example, where primary treatment either through surgical extirpation or radiation therapy has not been curative, or where the risks of developing subsequent metastatic disease are high; combination treatment could be administered in an adjuvant setting.
  • Immunotherapy could be initiated before continuous metronomic low dose CTX or other chemotherapeutic administration to avoid the immunosuppressive properties of the drug. With the first signs of recurrent disease, immunotherapy by booster administration aimed at re-stimulating the tumour-specific memory compartment, can be effectively instituted during a temporary respite from metronomic dosing.
  • MTD chemotherapy could initially be at sufficiently high doses to debulk the tumour, followed by combination therapy as described.

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Abstract

L'invention concerne un procédé de traitement d'un patient souffrant d'un cancer. Dans ledit procédé, un agent de stimulation d'une réponse immunitaire contre le cancer et un médicament chimiothérapeutique sont administrés au patient. Ledit médicament est administré selon un plan métronomique afin de l'empêcher de supprimer la réponse immunitaire et l'efficacité de l'agent à stimuler une réponse immunitaire contre le cancer.
PCT/GB2003/003977 2002-09-17 2003-09-16 Polytherapie contre le cancer dans laquelle un vaccin contre le cancer et un medicament chimiotherapeutique sont utilises WO2004026337A1 (fr)

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AU2003269133A AU2003269133A1 (en) 2002-09-17 2003-09-16 Combination treatment of cancer using a cancer vaccine and a chemotherapeutic drug
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ITRM20110654A1 (it) * 2011-12-07 2013-06-08 Ist Superiore Sanita Combinazione di ciclofosfamide e cellule dendritiche per lo uso nel trattamento del carcinoma alla cervice uterina .
US9259406B2 (en) 2008-11-28 2016-02-16 Sanofi Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
US9314522B2 (en) 2010-12-10 2016-04-19 Sanofi Antitumors combinations containing antibodies recognizing specifically CD38 and bortezomib
US9399662B2 (en) 2005-11-02 2016-07-26 Duke University Concurrent chemotherapy and immunotherapy
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AU2006293659C1 (en) * 2005-09-21 2012-11-15 Oxford Biomedica (Uk) Limited Chemo-immunotherapy method
WO2007034188A3 (fr) * 2005-09-21 2007-06-14 Oxford Biomedica Ltd Methode de chimiotherapie et d'immunotherapie
US8133681B2 (en) 2005-09-21 2012-03-13 Oxford Biomedica (Uk) Limited Chemo-immunotherapy method
AU2006293659B2 (en) * 2005-09-21 2012-04-05 Oxford Biomedica (Uk) Limited Chemo-immunotherapy method
US9399662B2 (en) 2005-11-02 2016-07-26 Duke University Concurrent chemotherapy and immunotherapy
WO2008008541A3 (fr) * 2006-07-14 2008-03-27 Mannkind Corp Procédés destinés à susciter, améliorer et entretenir les réponses immunitaires contre des épitopes limités au cmh de classe i dans des buts prophylactiques ou thérapeutiques
EA026008B1 (ru) * 2008-11-28 2017-02-28 Санофи Фармацевтическая комбинация, содержащая специфически распознающее cd38 антитело и циклофосфамид, и способ лечения злокачественной опухоли
US9259406B2 (en) 2008-11-28 2016-02-16 Sanofi Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
WO2010061360A1 (fr) * 2008-11-28 2010-06-03 Sanofi-Aventis Associations antitumorales contenant des anticorps reconnaissant spécifiquement cd38 et du cyclophosphamide
EP2191843A1 (fr) * 2008-11-28 2010-06-02 Sanofi-Aventis Combinaisons antitumorales contenant des anticorps reconnaissant spécifiquement les CD38 et cyclophosphamide
US9314522B2 (en) 2010-12-10 2016-04-19 Sanofi Antitumors combinations containing antibodies recognizing specifically CD38 and bortezomib
ITRM20110654A1 (it) * 2011-12-07 2013-06-08 Ist Superiore Sanita Combinazione di ciclofosfamide e cellule dendritiche per lo uso nel trattamento del carcinoma alla cervice uterina .
WO2013084250A1 (fr) * 2011-12-07 2013-06-13 ISTITUTO SUPERIORE Dl SANITA' Combinaison de cyclophosphamide et de cellules dendritiques pour une utilisation dans le traitement du carcinome du col de l'utérus
WO2017060650A1 (fr) * 2015-10-08 2017-04-13 Jean-Marc Limacher Composition anti-tumorale
FR3042121A1 (fr) * 2015-10-08 2017-04-14 Jean-Marc Limacher Composition anti-tumorale
FR3042122A1 (fr) * 2015-10-08 2017-04-14 Jean-Marc Limacher Composition anti-tumorale
IL258430A (en) * 2015-10-08 2018-06-28 Jean Marc Limacher Anti-tumoral composition
CN108348587A (zh) * 2015-10-08 2018-07-31 让-马克·利马谢 抗肿瘤组合物
US10881730B2 (en) 2017-02-01 2021-01-05 Modernatx, Inc. Immunomodulatory therapeutic MRNA compositions encoding activating oncogene mutation peptides

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