EP1173199A1 - IMPFSTOFFE BASIEREND AUF RAS ONKOGEN p21 PEPTIDEN - Google Patents

IMPFSTOFFE BASIEREND AUF RAS ONKOGEN p21 PEPTIDEN

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Publication number
EP1173199A1
EP1173199A1 EP00925746A EP00925746A EP1173199A1 EP 1173199 A1 EP1173199 A1 EP 1173199A1 EP 00925746 A EP00925746 A EP 00925746A EP 00925746 A EP00925746 A EP 00925746A EP 1173199 A1 EP1173199 A1 EP 1173199A1
Authority
EP
European Patent Office
Prior art keywords
peptides
cancer
cell
peptide
peptide mixture
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00925746A
Other languages
English (en)
French (fr)
Inventor
Jon Amund Eriksen
Gustav Gaudernack
Marianne Klemp Gjertsen
Mona Moller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Norsk Hydro ASA
Original Assignee
Norsk Hydro ASA
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 Norsk Hydro ASA filed Critical Norsk Hydro ASA
Publication of EP1173199A1 publication Critical patent/EP1173199A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001154—Enzymes
    • A61K39/001164—GTPases, e.g. Ras or Rho
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • 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

Definitions

  • This invention relates to use of synthetic peptide mixtures for prophylaxis and/or treatment of cancers.
  • Proto-oncogenes are normal genes of the cell which have the potential of becoming oncogenes. All oncogenes code for and function through a protein. In the majority of cases they have been shown to be components of signal transduction pathways. Oncogenes arise in nature from proto-oncogenes through point mutations or translocations, thereby resulting in a transformed state of the cell harbouring the mutation. Cancer develops through a multistep process involving several mutational events in oncogenes and tumour supressor genes.
  • a single base substitution in a proto-oncogene may cause the resulting gene product to differ in one amino acid.
  • tumour rejection antigens consisting of peptides differing in a single amino acid from the normal peptide.
  • MHC major histocompatibility
  • Antibodies typically recognise free antigen in native conformation and can potentially recognize almost any site exposed on the antigen surface.
  • T cells recognize antigens only in the context of MHC molecules, designated HLA (human leucocyte antigen) in humans, and only after appropriate antigen processing, usually consisting of proteolytic fragmentation of the protein, resulting in peptides that fit into the groove of the MHC molecules.
  • HLA human leucocyte antigen
  • This enables T cells to recognize also peptides derived from intracellular proteins. T cells can thus recognize aberrant peptides derived from anywhere in the tumour cell, in the context of MHC molecules on the surface of the tumour cell, and subsequently can be activated to eliminate the tumour cell harbouring the aberrant peptide.
  • the HLA molecules are encoded by the HLA region on the human chromosome No 6.
  • the class I molecules are encoded by the HLA A, B and C subloci
  • the class II molecules are encoded by the DR, DP and DQ subloci. All the gene products are highly polymorphic. Different individuals thus express distinct HLA molecules that differ from those of other individuals. This is the basis for the difficulties in finding HLA matched organ donors in transplantations.
  • the significance of the genetic variation of the HLA molecules in immunobiology is reflected by their role as immune-response genes. Through their peptide binding capacity, the presence or absence of certain HLA molecules governs the capacity of an individual to respond to peptide epi topes. As a consequence, HLA molecules determine resistance or susceptibility to disease.
  • T cells may control the development and growth of cancer by a variety of mechanisms. Cytotoxic T cells, both HLA class I restricted CD8+ and HLA Class II restricted CD4+, may directly kill tumour cells carrying the appropriate tumour antigens. CD4+ helper T cells are needed for induction and maintenance of cytotoxic T cell responses as well as for antibody responses, and for inducing macrophage and LAK cell killing.
  • WO 92/14756 is based on the idea that another possible approach for combating cancer is by using the body's own immune system through an activation and strengthening of the immune response from specific T cells.
  • synthetic peptides and fragments of oncogene protein products which elicit T cellular immunity, and cancer vaccines and compositions for anti-cancer treatment comprising said peptides or peptide fragments are disclosed.
  • cancer vaccines and compositions for anti-cancer treatment comprising said peptides or peptide fragments.
  • the rational basis for the feedback based augmentation effect is that the number of T cells that have the potential to recognize all the peptides in the mixture greatly outnumbers the number of T cells specific for a single peptide. In concert the activation of more T cells specific for individual peptides present in the peptide mixture will increase the magnitude of the response also against single peptides in the mixture.
  • ras peptides in the administered cocktails that do not correspond to the ras mutation actually existing in the tumour of the patient, also did generate T cells that were clinically relevant due to cross-reactivity with peptides corresponding to the actual mutation.
  • the effect of using a ras peptide mixture is therefore twofold, it creates an amplification of the T cells specific for a single peptide and adds a second component consisting of T cell clones that are specific for another peptide, but which cross reacts with the tumour relevant mutation.
  • T cell clones are otherwise not elicited by single peptide vaccination, since they were not observed in patients treated with a single peptide vaccination.
  • Another object of the invention is to provide a therapeutic agent, vaccine and pharmaceutical composition that induces immune responses and activation of T cells.
  • WO 92/14756 constitute the peptides used in the peptide mixtures in this invention. Thus, reference is made to the specification of WO/92/14756.
  • Fig. 1 In figure 1 the results from two clinical trials with vaccination of colorectal cancer patients with position 12 and/or position 13 mutant RAS peptides are compared.
  • Figure 3 shows different response patterns of four patients with colorectal adenocarcinoma that had received vaccination with a cocktail of five different position 12 and 13 mutant ras peptides, sequence id. no. 2, 3, 4, 6 and 7.
  • Figure 4 shows different T cell responses against individual mutant ras peptides for two responding patients.
  • Figure 5 shows the reactivity of peripheral T cells obtained after vaccination of a patient with colorectal adenocarcinoma.
  • FIG. 6 shows the reactivity of tumour infiltrating lymphocytes (TILs) obtained after vaccination of a patient with advanced pancreatic cancer.
  • TILs tumour infiltrating lymphocytes
  • Fig. 7 The extensive cross reactivity with different ras mutations, of ras specific T cells generated by vaccination with a mixture of ras peptides, was also demonstrated at a clonal level. This is shown in figure 7.
  • Fig. 8 The extensive cross reactivity with different ras mutations, of ras specific T cells generated by vaccination with a mixture of ras peptides, was also demonstrated at a clonal level. This is shown in figure 7.
  • Fig. 8 The extensive cross reactivity with different ras mutations, of ras specific T cells generated by vaccination with a mixture of ras peptides, was also demonstrated at a clonal level. This is shown in figure 7.
  • Fig. 8 The extensive cross reactivity with different ras mutations, of ras specific T cells generated by vaccination with a mixture of ras peptides, was also demonstrated at a clonal level. This is shown in figure 7.
  • Figure 8 shows the specificity of T cell clones obtained from vaccination of patients with melanoma cancer with a cocktail of four different position 61 mutant RAS peptides, sequence id. no. 9,10, 11 and 10.
  • the peptides were synthesised by using solid phase peptide synthesis.
  • N-a-Fmoc-amino acids with appropriate side chain protection Ser(tBu), Thr(tBu), Lys(Boc), His(Trt), Arg(Pmc), Cys(Trt), Asp(O-tBu), Glu(O-tBu) ) were used.
  • the Fmoc-amino acids were activated by TBTU prior to coupling. 20% piperidine in DMF was used for selective removal of Fmoc after each coupling. Detachment from the resin and final removal of
  • Vaccination with a cocktail of ras peptides instead of single peptides increases the efficacy of vaccination.
  • the single peptide was administered intradermally to Dukes B and C patients together with GM-CSF (30mg) in two series; first 4 injections of lOOmg peptide with one week between each dose was given, and then, four weeks after the last injection, 4 x 300mg was given, again one week between each 300mg dose.
  • the five peptide cocktail was administered to Dukes C and D patients together with GM-CSF (30mg) as four injections of 500 mg cocktail (lOOmg of each peptide) with one week between each injection in 15 of the patients, and as four injections of 2000mg cocktail (400mg of each peptide) in 12 of the patients.
  • the number of responding patients was 10 in the group receiving the low dose (67%) and 8 in the high dose group (67%).
  • the patient group receiving single peptide vaccinations predominantly contained patients that were in a better clinical condition (mainly resected cancer patients in Dukes stages B and C), whereas the group of patients receiving the vaccine cocktail mainly contained patients with advanced disease (Dukes stage D, with liver metastasis, that did not respond to chemotherapy/irradiation therapy). It is conceivable that the immune status of the patients in the latter group was lower than in the former group, since both prior treatment (cytostatics and irradiation) and large tumour burden may severely impair immune functions. It was therefore highly unexpected to us that the number of responders to the vaccine was higher in the group having advanced disease.
  • FIG 2 the results from two clinical trials with vaccination of pancreatic cancer patients with position 12 mutant RAS peptides are compared.
  • patients with resected pancreatic cancer (Whippel operation) were vaccinated with one single mutant RAS peptide, either sequence id. no. 2,3,4 or 6, and in the other trial, involving patients with inoperable (terminal) pancreatic cancer, a cocktail containing all four mutant RAs peptides was used for vaccination.
  • the patients with advanced disease given the vaccine cocktail were able to respond to the vaccine despite their deteriorating clinical condition and surprisingly that the number of responders were higher in this group of patients with non-resected tumour as compared to the tumour resected group that were given single peptide vaccine.
  • the single peptide was administered intradermally to tumour resected patients together with GM-CSF (30 ⁇ g) in six injections of lOO ⁇ g peptide with one week between first four doses, two weeks between dose four and five and four weeks between dose five and six.
  • the four peptide cocktail was administered to non resectable patients together with GM-CSF (30 ⁇ g) in six injections of 400 ⁇ g (lOO ⁇ g of each peptide) following the same schedule as for the single peptide administration.
  • Figure 3 shows different response patterns of four patients with colorectal adenocarcinoma that had received vaccination with a cocktail of five different position 12 and 13 mutant ras peptides, sequence id. no. 2, 3, 4, 6 and 7.
  • the peptide cocktail was administered intradermally to patients with colorectal adenocarcinoma together with GM-CSF (30 ⁇ g) in four weekly injections of 0,5 mg peptide cocktail.
  • the T cell responses were tested in pre- and post-vaccination samples after one in vitro stimulation. All four patients also showed development of a positive DTH reaction to the vaccine cocktail.
  • the results in figure 3 were obtained by using standard proliferation assays and peptides with sequence id. no. 2, 3, 4, 6, 7 and 8 (wild type).
  • FIG 4 the different T cell responses against individual mutant ras peptides for two non-resected pancreatic cancer patients are shown.
  • the patients were vaccinated with a cocktail containing four mutant ras peptides with sequence id. no. 2, 3, 4 and 6.
  • T cell responses were investigated in vitro in peripheral blood mononuclear cells (PBMC).
  • PBMCs from the two patients were tested against the 4 single mutant peptides (sequence id.no. 2, 3, 4 and 6) and the normal ras peptide (sequence id. no 8) after one stimulation in vitro.
  • PBMC peripheral blood mononuclear cells
  • Cultured cells (5 x 10 4 / well) were tested after 9 - 12 days for specific proliferating capacity against single mutant ras peptides/peptide mixture and normal ras peptide at 25 ⁇ M concentration, with or without IL-2 (1 U/ml), by using autologous, irradiated (30 Gy) PBMC (5 x 10 4 cells /well) as APCs. Proliferation was measured at day 3 after overnight incubation with 3 H-thymidine 3.7 x 10 4 Bq/well (Amersham). Values are given as mean counts per minute (cpm) from triplicates.
  • FIG. 5 shows the reactivity of peripheral T cells obtained after vaccination of a patient with colorectal adenocarcinoma.
  • the patient received a vaccination with a cocktail consisting of seven different position 12 and 13 mutant ras peptides, sequence id. no.l, 2, 3, 4, 5, 6 and 7.
  • the peptide cocktail was administered intradermally to a patient with advanced colorectal cancer (Dukes D) together with GM-CSF (30 ⁇ g) in four weekly injections of 0,7 mg peptide cocktail at four different sites.
  • the results show T cells that react with five of the different ras mutations are generated, but there is no cross-reactivity with wild type ras.
  • T cell responses were investigated as mentioned above. Briefly, PBMC were tested after one in vitro stimulation in standard proliferation assays with peptides with sequence id. no. 1, 2, 3, 4, 5, 6, 7 and 8 (wild type).
  • FIG 6 shows the reactivity of tumour infiltrating lymphocytes (TILs) obtained after vaccination of a patient with advanced pancreatic cancer.
  • the patient received a vaccination with a cocktail consisting of four different position 12 mutant ras peptides, sequence id. no. 2, 3, 4 and 6.
  • the peptide cocktail was administered intradermally to a patient with advanced pancreatic cancer together with GM-CSF (30 ⁇ g) in six injections of 0,4 mg peptide cocktail with one week between the first four doses, two weeks dose four and five and four weeks between dose five and six.
  • the T cells were obtained from a tumour biopsy taken after the patient was successfully immunised by the peptide vaccination (positive DTH test).
  • the TIL's were expanded extensively in vitro by coculture in recombinant human interleukin 2 (rIL2) and were shown to be homogeneously expressing the same T cell receptor V ⁇ chain by analysis with monoclonal antibodies, indicating a monoclonal origin of the TIL cell line generated.
  • the results in figure 6 show that the TIL cell line cross-react with all four of the different mutant ras peptides contained in the vaccine cocktail.
  • TILs were tested in standard proliferation assays with peptides with sequence id. no. 2, 3, 4 and 6.
  • the peptide cocktail was administered as described for figure 6.
  • the T cell clones were obtained from blood samples from patients showing an immune response to the vaccine by a positive delayed type hypersensitivity test (DTH), by cloning under limiting dilution conditions.
  • DTH positive delayed type hypersensitivity test
  • the results in figure 7 were obtained using standard proliferation assays and peptides with sequence id. nos. 2,3,4,6 and 8 (wild type).
  • FIG. 8 shows the specificity of T cell clones obtained from peripheral blood after vaccination of patients with melanoma with a cocktail of four different position 61 mutant RAS peptides, sequence id. no. 9,10, 11 and 10.
  • the results show that both T cells that are strictly specific for single RAS mutations as well as T cells that are cross-reactive with two, three of four different RAS mutations RAS are generated by vaccination with this peptide cocktail. None of the T cell clones studied showed any evidence of cross-reactivity with wild type RAS.
  • the peptide cocktail was administered intradermally to tumour resected patients together with GM-CSF (30 ⁇ g) in six injections of 0.32 mg peptide cocktail with one week between the first four doses, two weeks between dose four and five and four weeks between dose five and six.
  • the T cell clones were obtained from blood samples from patients showing a immune response to the vaccine by a positive delayed type hypersensitivity test (DTH), after culturing of T cells under limiting dilution conditions.
  • DTH positive delayed type hypersensitivity test
  • the results in figure 8 were obtained using standard proliferation assays and peptides with sequence id. nos. 13, 14, 15, 16 and 17 (wild type).
  • cancer vaccines consisting of different mutant ras peptides can be used broadly in the clinical setting without the need for HLA-typing and prior determination of the ras mutation.
  • cross-reactive T cells that are clinically relevant will be generated in the patients.
  • the results in figure 6 showing anti mutant ras reactivity in tumour infiltrating lymphocytes that can be found in biopsy specimens post peptide vaccination, are of great importance because they demonstrates that cross-reactive T cells are capable of localising their target tumour area in situ.
  • the peptide mixture according to this invention can be administered to the patient as described in WO 92/14756.
  • the peptide mixtures of this invention can be administered in an amount in the range of 1 nanogram (1 ng) to 1 gram (lg) to an average human patient or individual to be vaccinated. It is preferred to use a dose in the rage of 1 microgram (1 mg) to 1 milligram (1 mg) for each administration.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP00925746A 1999-04-30 2000-04-28 IMPFSTOFFE BASIEREND AUF RAS ONKOGEN p21 PEPTIDEN Withdrawn EP1173199A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NO992102 1999-04-30
NO19992102A NO309798B1 (no) 1999-04-30 1999-04-30 Peptidblanding, samt farmasoytisk sammensetning og kreftvaksine som innbefatter peptidblandingen
PCT/NO2000/000142 WO2000066153A1 (en) 1999-04-30 2000-04-28 RAS ONCOGEN p21 PEPTIDE VACCINES

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Publication Number Publication Date
EP1173199A1 true EP1173199A1 (de) 2002-01-23

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EP (1) EP1173199A1 (de)
JP (1) JP2002543149A (de)
AR (1) AR023806A1 (de)
AU (1) AU4438900A (de)
CA (1) CA2372187A1 (de)
NO (1) NO309798B1 (de)
WO (1) WO2000066153A1 (de)

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KR20090008290A (ko) 2006-03-27 2009-01-21 글로브이뮨 Ｒａｓ 돌연변이와 그에 관련된 조성물 및 방법
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PE20161560A1 (es) * 2009-09-03 2017-01-11 Pfizer Vaccines Llc Vacuna de pcsk9
EP2569633B1 (de) 2010-05-14 2016-02-10 The General Hospital Corporation Zusammensetzungen und verfahren zur identifikation tumorspezifischer neoantigene
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WO2015077717A1 (en) 2013-11-25 2015-05-28 The Broad Institute Inc. Compositions and methods for diagnosing, evaluating and treating cancer by means of the dna methylation status
US11725237B2 (en) 2013-12-05 2023-08-15 The Broad Institute Inc. Polymorphic gene typing and somatic change detection using sequencing data
CA2933126A1 (en) * 2013-12-09 2015-06-18 Targovax Asa A peptide mixture
AU2014368898B2 (en) 2013-12-20 2020-06-11 Dana-Farber Cancer Institute, Inc. Combination therapy with neoantigen vaccine
JP2017514847A (ja) * 2014-05-06 2017-06-08 タルゴバックス エーエスエー 突然変異ｒａｓペプチド及び化学療法剤を含むペプチドワクチン
WO2016100975A1 (en) 2014-12-19 2016-06-23 Massachsetts Institute Ot Technology Molecular biomarkers for cancer immunotherapy
US10993997B2 (en) 2014-12-19 2021-05-04 The Broad Institute, Inc. Methods for profiling the t cell repertoire
EP3297660A2 (de) 2015-05-20 2018-03-28 The Broad Institute Inc. Gemeinsam genutzte neoantigene
CA2989373A1 (en) * 2015-06-16 2016-12-22 Targovax Asa Mutated fragments of the ras protein
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Publication number Publication date
AU4438900A (en) 2000-11-17
NO992102L (no) 2000-10-31
NO309798B1 (no) 2001-04-02
WO2000066153A1 (en) 2000-11-09
AR023806A1 (es) 2002-09-04
NO992102D0 (no) 1999-04-30
JP2002543149A (ja) 2002-12-17
CA2372187A1 (en) 2000-11-09

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