WO2014196841A1 - Biological markers useful in cancer immunotherapy - Google Patents

Biological markers useful in cancer immunotherapy Download PDF

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WO2014196841A1
WO2014196841A1 PCT/KR2014/005031 KR2014005031W WO2014196841A1 WO 2014196841 A1 WO2014196841 A1 WO 2014196841A1 KR 2014005031 W KR2014005031 W KR 2014005031W WO 2014196841 A1 WO2014196841 A1 WO 2014196841A1
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treatment
crp
arm
eotaxin
serum
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PCT/KR2014/005031
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French (fr)
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Sang Jae Kim
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Kael-GemVax Co Ltd
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Kael-GemVax Co Ltd
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Priority to US14/896,358 priority Critical patent/US10383926B2/en
Priority to BR112015030627A priority patent/BR112015030627A2/en
Priority to KR1020147025258A priority patent/KR101552260B1/en
Priority to JP2016518278A priority patent/JP6059405B2/en
Priority to CN201480001504.3A priority patent/CN104508485B/en
Priority to EP22165760.4A priority patent/EP4063863A1/en
Priority to EP14808179.7A priority patent/EP3004883B1/en
Priority to AU2014275610A priority patent/AU2014275610B2/en
Priority to ES14808179T priority patent/ES2927473T3/en
Priority to CA2912557A priority patent/CA2912557A1/en
Application filed by Kael-GemVax Co Ltd filed Critical Kael-GemVax Co Ltd
Priority to RU2015149010A priority patent/RU2677277C2/en
Publication of WO2014196841A1 publication Critical patent/WO2014196841A1/en
Priority to PH12015502613A priority patent/PH12015502613A1/en
Anticipated expiration legal-status Critical
Priority to AU2018229511A priority patent/AU2018229511B2/en
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Definitions

  • the 16-mer peptide EARPALLTSRLRFIPK (SEQ ID NO: 1; also termed "GV1001") is a fragment of the human telomerase enzyme (WO 00/02581). GV1001 binds multiple HLA class II molecules and harbours putative HLA class I epitopes. The peptide has therefore been considered capable of eliciting combined CD4/CD8 T-cell responses, which in turn are important for initiation of tumour eradication and long-term memory. Clinical trials in advanced pancreatic and pulmonary cancer patients have demonstrated GV1001-specific T-cell responses in > 50% of subjects, without clinically important toxicity (Kyte JA (2009), Expert Opin Investig Drugs 18 (5):687-94.
  • Eotaxin-1, -2 and -3 are known chemokines known to recruit eosinophils and other leukocytes, and elicit their effects by binding to the cell surface chemokine receptors (e.g., CCR3).
  • CCR3 cell surface chemokine receptors
  • the trial recruited 1062 patients in 52 centres throughout the United Kingdom. While there was no significant difference in overall survival between the groups that received the vaccine and the control group receiving chemotherapy, the trial however also included an ambitious program of translational research. Initial results indicate that the vaccine resulted in a significant anti-inflammatory response that correlates well with new research being conducted by the parent company, Kael-GemVax. Additionally, 3 possible biomarkers - eotaxin, MIP1 ⁇ , and CRP - were identified in a subgroup of patients as indicators of an increased survival.
  • Fig. 1 Graphs showing levels of IL-4, IL-5, IL-7, IL-17, PDGF and VEGF in serum form baseline arm 2 and 3, arm 2 week 7 and arm 3 week 10 patients (p values uncorrected Kruskal-Wallis).
  • Fig. 2 Graphs showing the change in levels of IFN ⁇ , IL-10, IL-7, PDGF, RANTES, TNF ⁇ and VEGF for arms 2 and 3. Also shown are the numbers of positive (+ve) and negative (-ve) changes along with p values.
  • Fig. 4 Paired analysis of CRP in arm 2 patients (left) and 3 patients (right) at baseline and following treatment Also shown are the numbers of positive (+ve) and negative (-ve) changes along with p values.
  • Fig. 5 Survival curves for IL-8 dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
  • Fig. 6 Survival curves for Eotaxin dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
  • Fig. 7 Survival curves for MIP1 ⁇ dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
  • Fig. 8 Survival curves for MIP1 ⁇ dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
  • Fig. 9 Survival curves for VEGF dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
  • Fig. 10 Survival curves for CRP dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
  • Fig. 11. Survival curves for CRP dichotomised at the median for post treatment levels in arm 3.
  • Fig. 13 shows profile plots of baseline and post-treatment means of log cytokine data from serum for Arm 2.
  • BL and PT represent baseline and post treatment, respectively.
  • Fig. 14 shows baseline and post treatment means of log cytokine data from serum for Arm 3.
  • Fig. 15 shows a profile plot of the mean differences (post-treatment - baseline) for the cytokines in serum for each arm.Of note, 19 cytokines showed a statistically significant decrease between baseline and post-treatment in Arm 2 (PDGF, IL1 ⁇ , IL-1ra, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, IFN ⁇ , eotaxin, FGFb, MIP1 ⁇ , RANTES, TNF ⁇ , VEGF; but not CRP, IL-6, IL-8, IL-9, IL-15, GM-CSF, IP10, MCP1, MIP1 ⁇ ) and none in Arm3.
  • Arm 2 PDGF, IL1 ⁇ , IL-1ra, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, IFN ⁇ , eotaxin, FGFb, MIP
  • Fig. 16 shows the p-values obtained from a Wilcoxon signed-rank test used on each cytokine form serum for each arm to test for increase/decrease in values from baseline to post treatment. The significant differences (p ⁇ 0.05) as seen are in bold grey font. The decreases were larger in Arm2 than in Arm3, noting that there were 19 significant decreases in Arm2 but none in Arm3.
  • Fig. 17 shows the median difference of post-treatment minus baseline levels, for each cytokine in serum, for each arm of the study. Decreases are highlighted in light shadow and increases/no change are highlighted in dark shadow.
  • Fig. 18 shows Cox proportional hazards models on baseline data for each cytokine in serum for each arm of the study.
  • the table gives univariate analyses for the baseline data and shows hazard ratios with 95% confidence intervals and p-values.
  • CRP, IL-1ra, IL-2, IL-10, Eotaxin and IFN ⁇ are significant (p ⁇ 0.1) for Arm 2, while CRP, IL-1ra and Eotaxin are significant for Arm 3.
  • Figs. 22a and Fig. 22b show CRP in serum post treatment in Arm 2 and Arm 3.
  • Low levels of CRP give a median survival of 337 days for Arm 2 and a median survival of 450 days for Arm 3.
  • Figs. 23a and Fig. 23b show Eotaxin in serum post treatment in Arm 2 and Arm 3. High levels of Eotaxin give a median survival of 251 days for Arm 2 and a median survival of 364 days for Arm 3.
  • Figs. 24a and 24b show Proportional hazards models using dichotomized variables for the post-treatment data for serum CRP and serum Eotaxin combined.
  • Fig. 25 shows the vaccination schedule employed in the Examples.
  • GV1001 denotes the telomerase-derived peptide having SEQ ID NO: 1: EARPALLTSRLRFIPK
  • Epitaxin denotes the protein having any one of the amino acid sequences SEQ ID NO: 2-4 (or allelic or naturally occurring isoforms or variants thereof), which can be encoded by any one of the nucleic acid sequences SEQ ID NO: 5-7, respectively.
  • CRP is the protein having the amino acid sequence SEQ ID NO: 8 (or allelic or other naturally occurring isoforms or variants thereof), which can be encoded by the nucleic acid sequence SEQ ID NO: 9.
  • MIP1 ⁇ is the protein having the amino acid sequence SEQ ID NO: 10 (or allelic or other naturally occurring isoforms or variants thereof), which can be encoded by the nucleic acid sequence SEQ ID NO: 11.
  • the present invention provides a method for anti-cancer and/or anti-inflammatory treatment of an individual in need thereof by administering a therapeutically effective amount of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids (such as 8, 9, 10, 11, 12, 13, 14 or 15 amino acids), if said individual exhibits an increased serum level of eotaxin and/or MIP1 ⁇ when compared to population average or to a population of individuals suffering from the same cancer and/or inflammatory condition.
  • a polypeptide which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids (such as 8, 9, 10, 11, 12, 13, 14 or 15 amino acids)
  • a related embodiment relates to a method for determining whether to instigate anti-cancer and/or anti-inflammatory treatment of an individual in need thereof, wherein said anti-cancer treatment and/or anti-inflammatory treatment involves administration of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, comprising determining if said individual exhibits an increased serum level of eotaxin and/or MIP1 ⁇ when comparing to the population average or to a population of individuals suffering from the same cancer and/or inflammatory condition, a positive determination indicating that said treatment is justified.
  • a polypeptide which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids
  • the treatments of the present invention are preferably those where the patients subjected to the treatments are those who prior to treatment exhibit increased eotaxin and/or MIP-1 ⁇ serum levels in combination with decreased CRP levels - again the levels are determined either relative to the average (or median) in the general population or relative to the average or median in the relevant patient group.
  • the effective amount administered according to the various embodiments of the invention may vary. If the polypeptide is administered as a vaccine, the amounts typically range from 0.5 ⁇ g up to 500 mg, with preferred administration amounts ranging between 10 ⁇ g to 1000 ⁇ g, and in particular between 20 and 200 ⁇ g. These ranges are also relevant when the polypeptide is administered as an anti-inflammatory agent, but it may be relevant - for instance if the polypepide is administered intraveneously or intraarterially - to regulate the amounts administered on the basis of the individual's condition, body weight and age.
  • Increased levels of eotaxin and/or MIP1 ⁇ and/or CRP are in the relevant embodiments determined according to standardized assays generally known in the art - immune assays, for instance ELISAs, are preferred, but also assays that determine the activity of these cytokines on suitable target cells or suitable target molecules are relevant. If an assay is very sensitive and accurate, even small increases compared to standard values may be relevant, whereas less sensitive or accurate assays will require that larger deviations from standard values can be determined. As a rule, for a given assay for a particular cytokine there will exist a range of normal values and if the cytokine level is beyond these normal values, the level of eotaxin or MIP1 ⁇ will be considered to be increased.
  • the increased baseline level of eotaxin and/or MIP1 ⁇ is at least 10%, but higher increases in values may be relevant: at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, and even at least 100%.
  • Another embodiment of the invention relates to a method for anti-cancer and/or anti-inflammatory treatment of an individual in need thereof by administering a therapeutically effective amount of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, wherein said treatment is continued after an initial stage of said treatment if said individual exhibits a decrease of CRP level in serum after said initial stage of said treatment.
  • a polypeptide which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids
  • a method for determining the efficacy of therapeutic treatment of an individual with a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids comprising determining the serum level of CRP in said individual after an initial stage of said treatment and comparing with the serum level of CRP prior to said initial stage of treatment, where a decrease in said serum level indicates that said treatment is effective in terms of conferring an increase in survival time.
  • the anti-cancer and/or anti-inflammatory treatment involves concurrent treatment with at least one cytostatic or cytotoxic agent.
  • the concurrent treatment may involve administration of GemCap as in the present examples, but depending on the cancer or inflammatory disease in question, the GV1001-derived peptide may according to the present invention be combined with the administration of cytostatic/cytotoxic agents particular relevant for the treatment of the disease in question.
  • inventions are those where the treatment is an anti-cancer treatment, and particularly preferred is treatment of pancreatic cancer.
  • treatment of other cancer forms are contemplated, and the cancer may be selected from the group consisting of an epithelial cancer, a non-epithelial cancer, and a mixed cancer.
  • the epithelial cancer may be both a carcinoma or an adenocarcinoma
  • the non-epithelial or mixed cancer is typically a liposarcoma, a fibrosarcoma, a chondrosarcoma, an osteosarcoma, a leiomyosarcoma, a rhabomyosarcoma, a glioma, a neuroblastoma, a medullablastoma, a malignant melanoma, a malignant meningioma, a neurofibrosarcoma, a leukemia, a myeloproleferative disorder, a lymphoma, a hemangiosarcoma, a Kaposi's sarcoma, a malignant teratoma, a dysgerminoma, a seminoma, or a choriosarcoma.
  • the anatomic location of the cancer can be anywhere in body. So the cancer may be a of the eye, the nose, the mouth, the tongue, the pharynx, the oesophagus, the stomach, the colon, the rectum, the bladder, the ureter, the urethra, the kidney, the liver, the pancreas, the thyroid gland, the adrenal gland, the breast, the skin, the central nervous system, the peripheral nervous system, the meninges, the vascular system, the testes, the ovaries, the uterus, the uterine cervix, the spleen, bone, or cartilage
  • polypeptide is administered typically parenterally, and when administered as a vaccine, the polypeptide will be normally be administered subcutaneously or intradermally. If the anti-inflammatory effect is most desired, also the intraveneous or intraarterial routes may be utilised.
  • Determination of serum levels of the above mentioned is performed in vitro. Typically, a serum sample is subjected to an ELISA in order to determine the amount of the serum levels of the cytokines.
  • the polypeptide can preferably be SEQ ID NO: 1 (i.e. the 16-mer peptide as such) or a fragment of at least 8 amino acids of SEQ ID NO: 1; that is, it is contemplated that it will not be necessary to include further amino acids in the GV1001-derived peptides.
  • eotaxin and/or MIP1 ⁇ and/or CRP as a prognostic marker in anticancer and/or anti-inflammatory treatment, in particular if said treatment involves administration of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids.
  • a polypeptide which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids.
  • the typical use will be as an agent captured/determined in an appropriate assay, so this aspect of the invention also covers use of antibodies and other agents that specifically bind to any one of the three cytokines.
  • An interesting embodiment relates to a method for modulation of the activity of eotaxin and/or MIP1 ⁇ and/or CRP in an individual in need thereof, said method comprising administering a therapeutically effective amount of a polypeptide as defined herein -such a method will be able to address the negative impact caused by abnormal levels of these cytokines in an individual. Consequently, this embodiment relates to the use of these polypeptides as modulators of eotaxin and/or MIP1 ⁇ and/or CRP.
  • the TeloVac trial recruited 1062 patients in 52 centres throughout the UK. There was no significant difference in overall survival between the groups that received the vaccine and the control group receiving chemotherapy (GemCap therapy, cf. below), but included an increasingly program of translational research, which is still undergoing evaluation. However, results show that the vaccine resulted in a significant anti-inflammatory response, and that simultaneous vaccination with chemotherapy provides an effective method for generating both an immune response and also promoting an anti-inflammatory effect. Importantly, biomarkers for an increased survival in response to the vaccine were identified in a subgroup of patients.
  • the TeloVac trial was initiated in January 2007 comparing combination therapy with Gemcitabine and Capecitabine (GemCap) therapy with concurrent and sequential chemo-immunotherapy using GV1001 in locally advanced and metastatic pancreatic cancer.
  • Fig. 25 shows the vaccination schedule employed: GV1001 intradermal injections were given three times (preferably Monday, Wednesday and Friday) in the first week (week 1), and once a week in weeks 2, 3, 4, and 6. After this, GV1001 was administered once monthly. GM-CSF was administered separately as an intradermal injection 10-15 minutes before all GV1001 injections at the approximately same site.
  • Serum samples (Arm3 only) from week1 (baseline) and week10 (Gemcitabine + Capecitabine + GV1001) were analyzed by Luminex multiplex cytokine analysis. A total of 26 cytokines were analyzed, and the CRP level was analyzed by ELISA.
  • Arm 1 patients received GemCap only, i.e. a currently accepted standard chemotherapeutic treatment regimen for pancreatic cancer patients utilising a combination of Gem citabine (administered iv weekly) and Cap ecitabine (adminstered as tablets twice daily).
  • Arm 2 patients received GemCap therapy followed by gv1001 at week 7.
  • Arm 3 patients received concurrent GemCap and GV1001 during the entire treatment period.
  • GemCap treatment resulted in decreased levels of a number of cytokines (pre-treatment compared to post treatment) in the serum fraction of blood (but not in plasma); this decrease was not evident in the presence of GV1001 (Table 3 and Fig. 2).
  • Table 1 shows Kruskal-Wallis comparison of Arms 2 and 3 baseline, Arm 2 week 7 (GemCap) with Arm 3 week 10 (GemCap and GV1001) serum.
  • Graphs showing the paired analysis for both arm 2 and arm 3 patients for a selection of cytokines are shown in Fig. 2.
  • the figure also includes the number of positive and negative changes seen in the patient samples from baseline to post treatment.
  • the cytokines analysed decrease from baseline to week 7, i.e. during GemCap treatment. This is in contrast with the arm 3 results, where the numbers of positive and negative changes are relatively evenly distributed.
  • Fig. 3 shows the levels of CRP in serum from patients in arms 2 and 3 at baseline and following treatment.
  • the data shows that there is no significant difference in CRP levels at baseline, however the post treatment analysis shows that there is a significant difference, with the levels in patients receiving GV1001/GemCap being significantly lower than in patients receiving GemCap only.
  • Table 4 shows the summary statistics for the CRP data split by arm and baseline post treatment.
  • Fig. 13 shows profile plots of baseline and post-treatment means of log serum cytokine data for Arm 2.
  • Fig. 14 shows baseline and post-treatment means of log serum cytokine data for Arm 3. .
  • Fig. 18 shows Cox proportional hazards models on baseline data for each cytokine in serum for each arm of the study.
  • the table provides univariate analyses for the baseline data and shows hazard ratios with 95% confidence intervals and p-values.
  • CRP, IL-1ra, IL-2, IL-10, Eotaxin and IFN ⁇ are significant (p ⁇ 0.1) for Arm 2, while CRP, IL-1ra and Eotaxin are significant for Arm 3.
  • Figs. 19a and 19b show serum levels of CRP at baseline in Arm 2 and Arm 3.
  • Low levels of CRP gave a median survival of 337 days for Arm 2 and a median survival of 373 days for Arm 3.
  • Figs. 22a and 22b show serum CRP post treatment in Arm 2 and Arm 3.
  • Low serum levels of CRP give a median survival of 337 days for Arm 2 and a median survival of 450 days for Arm 3.
  • Figs. 23a and 23b show serum Eotaxin post treatment in Arm 2 and Arm 3. High levels of serum Eotaxin give a median survival of 251 days for Arm 2 and a median survival of 364 days for Arm 3.
  • Figs. 24a and 24b show Proportional hazards models using dichotomized variables for the post-treatment data for serum CRP and serum Eotaxin combined.
  • Eotaxin(Eotaxin1) CCL11 chemokine (C-C motif) ligand 11
  • Protein UniProt ID: P51671; Length: 97 amino acids, MW: 10.732 kDa:MKVSAALLWLLLIAAAFSPQGLAGPASVPTTCCFNLANRKIPLQRLESYRRITSGKCPQKAVIFKTKLAKDICADPKKKWVQDSMKYLDQKSPTPKP
  • SEQ ID NO: 4 Human eotaxin 3 (CCL26); Protein; UniProt ID: Q9Y258; Length: 94 amino acids, MW: 10.648 kDa:MMGLSLASAVLLASLLSLHLGTATRGSDISKTCCFQYSHKPLPWTWVRSYEFTSNSCSQRAVIFTTKRGKKVCTHPRKKWVQKYISLLKTPKQL
  • Eotaxin(Eotaxin1) (CCL11 chemokine (C-C motif) ligand 11); nucleic acid; NCBI GeneBank ID: NM_002986.2:ATGGGCAAAGGCTTCCCTGGAATCTCCCACACTGTCTGCTCCCTATAAAAGGCAGGCAGATGGGCCAGAGGAGCAGAGAGGCTGAGACCAACCCAGAAACCACCACCTCTCACGCCAAAGCTCACACCTTCAGCCTCCAACATGAAGGTCTCCGCAGCACTTCTGTGGCTGCTGCTCATAGCAGCTGCCTTCAGCCCCCAGGGGCTCGCTGGGCCAGCTTCTGTCCCAACCACCTGCTGCTTTAACCTGGCCAATAGGAAGATACCCCTTCAGCGACTAGAGAGCTACAGGAGAATCACCAGTGGCAAATGTCCCCAGAAAGCTGTGATCTTCAAGACCAAACTGGCCAAGGATATCTGTGCCGACCCCAAGAAGAAGTGGGTGCAGGATTCCATGAAGTATCTGGACCAA
  • SEQ ID NO: 6 Human eotaxin 2 (CCL24); nucleic acid; NCBI GeneBank ID: NM_002991.2:ATGGCAGGCCTGATGACCATAGTAACCAGCCTTCTGTTCCTTGGTGTCTGTGCCCACCACATCATCCCTACGGGCTCTGTGGTCATCCCCTCTCCCTGCTGCATGTTCTTTGTTTCCAAGAGAATTCCTGAGAACCGAGTGGTCAGCTACCAGCTGTCCAGCAGGAGCACATGCCTCAAGGCAGGAGTGATCTTCACCACCAAGAAGGGCCAGCAGTTCTGTGGCGACCCCAAGCAGGAGTGGGTCCAGAGGTACATGAAGAACCTGGACGCCAAGCAGAAGAAGGCTTCCCCTAGGGCCAGGGCAGTGGCTGTCCAGAGATATCCTGGCAACCAAACCACCTGCTAAACCTGCTAAACCTGCTAAACCTGCTAA
  • SEQ ID NO: 8 Human CRP (C-reactive protein); Protein; UniProt ID: Q5VVP7; Length: 102 amino acids, MW: 11.632 kDa:MEKLLCFLVLTSLSHAFGQTDMSRKAFVFPKESDTSYVSLKAPLTKPLKAFTVCLHFYTELSSTHEINTIYLGGPFSPNVLNWRALKYEVQGEVFTKPQLWP
  • SEQ ID NO: 10 Human MIP1 ⁇ (CCL3 chemokine (C-C motif) ligand 3); Protein; UniProt ID: P10147; Length: 92 amino acids, MW: 10.085 kDa:MQVSTAALAVLLCTMALCNQFSASLAADTPTACCFSYTSRQIPQNFIADYFETSSQCSKPGVIFLTKRSRQVCADPSEEWVQKYVSDLELSA

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Abstract

Methods are disclosed that are based on the finding that serum and plasma levels of eotaxin, MIP1α, and CRP act as important biomarkers that are useful for determining the feasibility in instigating immunotherapeutic treatment of cancer when immunizing with the GV1001 peptide (EARPALLTSRLRFIPK; derived from human telomerase protein), optionally when combined with state of the art combination treatment with Gemcitabine and Capecitabine. In particular, the present invention provides methods for determining whether patients should be treated GV1001 and for determining whether instigated treatment should be continued.

Description

BIOLOGICAL MARKERS USEFUL IN CANCER IMMUNOTHERAPY
The present invention relates to the field of cancer immunotherapy and the field of anti-inflammatory drugs. In particular the present invention relates to methods and kits for use in therapy, where the diagnostic/predictive value of eotaxin and C-reactive protein are exploited.
The 16-mer peptide EARPALLTSRLRFIPK (SEQ ID NO: 1; also termed "GV1001") is a fragment of the human telomerase enzyme (WO 00/02581). GV1001 binds multiple HLA class II molecules and harbours putative HLA class I epitopes. The peptide has therefore been considered capable of eliciting combined CD4/CD8 T-cell responses, which in turn are important for initiation of tumour eradication and long-term memory. Clinical trials in advanced pancreatic and pulmonary cancer patients have demonstrated GV1001-specific T-cell responses in > 50% of subjects, without clinically important toxicity (Kyte JA (2009), Expert Opin Investig Drugs 18(5):687-94.
An on-line publication on chronic inflammation by the Life Extension foundation (www.lef.org; accessed 6 June 2013), focused on the long-term health effects of chronic, low-level inflammation, reviewed various markers and mediators of inflammation, among which tumour necrosis factor alpha (TNFα), nuclear factor kappa-B(NF-κB), interleukins, C-reactive protein (CRP), eicosanoids, cyclooxygenases (COX) and lipooxygenases (LOX) and various other inciting factors.
Guo et al. (J Immunol 2001;166:5208-5218) found that eotaxin mRNA and protein were upregulated during an inflammatory response in a rat model of acute inflammatory injury, and explored its role in neutrophile recruitment.
Eotaxin-1, -2 and -3 (also known as CCL11, CCL24 and CCL26) are known chemokines known to recruit eosinophils and other leukocytes, and elicit their effects by binding to the cell surface chemokine receptors (e.g., CCR3).
It is an object of embodiments of the invention to provide improved methods for predicting efficacy of medical treatment with GV1001-derived drugs as well as for predicting patient survival among individuals suffering from cancer, in particular pancraetic cancer.
TeloVac, a multi-centre Phase III trial of a GV1001 based vaccine in advanced and metastatic pancreatic cancer has recently been conducted through the Cancer Research UK Liverpool Clinical Trials Unit and supported by the GemVax AS, a subsidiary of KAEL-GemVax.
The trial recruited 1062 patients in 52 centres throughout the United Kingdom. While there was no significant difference in overall survival between the groups that received the vaccine and the control group receiving chemotherapy, the trial however also included an ambitious program of translational research. Initial results indicate that the vaccine resulted in a significant anti-inflammatory response that correlates well with new research being conducted by the parent company, Kael-GemVax. Additionally, 3 possible biomarkers - eotaxin, MIP1α, and CRP - were identified in a subgroup of patients as indicators of an increased survival.
So, in its broadest aspects, the invention relates to the use of eotaxin and/or MIP1α and/or CRP as prognostic tools useful in therapeutic treatment with GV1001-derived material.
Fig. 1: Graphs showing levels of IL-4, IL-5, IL-7, IL-17, PDGF and VEGF in serum form baseline arm 2 and 3, arm 2 week 7 and arm 3 week 10 patients (p values uncorrected Kruskal-Wallis).
Fig. 2: Graphs showing the change in levels of IFNγ, IL-10, IL-7, PDGF, RANTES, TNFα and VEGF for arms 2 and 3. Also shown are the numbers of positive (+ve) and negative (-ve) changes along with p values.
Fig.3: Levels of CRP in arm 2 and 3 patients at baseline and following treatment.
Fig. 4: Paired analysis of CRP in arm 2 patients (left) and 3 patients (right) at baseline and following treatment Also shown are the numbers of positive (+ve) and negative (-ve) changes along with p values.
Fig. 5: Survival curves for IL-8 dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
Fig. 6: Survival curves for Eotaxin dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
Fig. 7: Survival curves for MIP1α dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
Fig. 8: Survival curves for MIP1β dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
Fig. 9: Survival curves for VEGF dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
Fig. 10: Survival curves for CRP dichotomised at the median for baseline levels, post treatment levels and absolute change form baseline to post treatment.
Fig.: 11. Survival curves for CRP dichotomised at the median for post treatment levels in arm 3.
Fig. 12: (A) Survival curves for eotaxin (high: median survival 493 days, n=16; low:median survival 239 days, n=25). (B) Survival curves for CRP (high: median survival 222 days, n=20; low: median survival 486 days, n=21).
Fig. 13 shows profile plots of baseline and post-treatment means of log cytokine data from serum for Arm 2. BL and PT represent baseline and post treatment, respectively.
Fig. 14 shows baseline and post treatment means of log cytokine data from serum for Arm 3.
Fig. 15 shows a profile plot of the mean differences (post-treatment - baseline) for the cytokines in serum for each arm.Of note, 19 cytokines showed a statistically significant decrease between baseline and post-treatment in Arm 2 (PDGF, IL1β, IL-1ra, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, IFNγ, eotaxin, FGFb, MIP1β, RANTES, TNFα, VEGF; but not CRP, IL-6, IL-8, IL-9, IL-15, GM-CSF, IP10, MCP1, MIP1α) and none in Arm3.
Fig. 16 shows the p-values obtained from a Wilcoxon signed-rank test used on each cytokine form serum for each arm to test for increase/decrease in values from baseline to post treatment. The significant differences (p<0.05) as seen are in bold grey font.The decreases were larger in Arm2 than in Arm3, noting that there were 19 significant decreases in Arm2 but none in Arm3.
Fig. 17 shows the median difference of post-treatment minus baseline levels, for each cytokine in serum, for each arm of the study. Decreases are highlighted in light shadow and increases/no change are highlighted in dark shadow.
Fig. 18 shows Cox proportional hazards models on baseline data for each cytokine in serum for each arm of the study. The table gives univariate analyses for the baseline data and shows hazard ratios with 95% confidence intervals and p-values. CRP, IL-1ra, IL-2, IL-10, Eotaxin and IFNγ are significant (p<0.1) for Arm 2, while CRP, IL-1ra and Eotaxin are significant for Arm 3.
Figs. 19a and Fig. 19b show levels of CRP at baseline in Arm 2 and Arm 3. Low levels of CRP gave a median survival of 337 days for Arm 2 and a median survival of 373 days for Arm 3. Baseline CRP levels predicted median (95% CI) overall survival in Arm3 (high CRP=250 [132-451] days; low CRP=372.5 [229-517] days; p=0.0500) but not in Arm2 (high CRP=195 [140-262] days; low CRP=337 [167-366] days; p=0.2534)
Figs. 20a and Fig. 20b show levels of Eotaxin at baseline in Arm 2 and Arm 3. High levels of Eotaxin in serum give a median survival of 300 days for Arm 2 and a median survival of 451 days for Arm 3. Baseline eotaxin levels predicted median (95% CI) overall survival in Arm3 (high eotaxin=451 [308-623] days; low eotaxin=238.5 [178-344] days; p=0.0135) but not in Arm2 (high eotaxin=299.5 [167-358] days; low eotaxin=188 [102-320] days; p=0.1138)
Figs. 21a and Fig. 21b show Proportional hazards models using dichotomized variables for the baseline data for CRP and Eotaxin in serum combined. When variables were combined at baseline the longest overall survival was predicted by a combination of low levels of CRP plus high levels of Eotaxin in Arm 2 (median survival = 337 days) and similarly for Arm 3 (median survival = 450 days).
Figs. 22a and Fig. 22b show CRP in serum post treatment in Arm 2 and Arm 3. Low levels of CRP give a median survival of 337 days for Arm 2 and a median survival of 450 days for Arm 3.
Figs. 23a and Fig. 23b show Eotaxin in serum post treatment in Arm 2 and Arm 3. High levels of Eotaxin give a median survival of 251 days for Arm 2 and a median survival of 364 days for Arm 3.
Figs. 24a and 24b show Proportional hazards models using dichotomized variables for the post-treatment data for serum CRP and serum Eotaxin combined. When variables were combined the longest survival was predicted by a combination of low levels of CRP plus high levels of Eotaxin in Arm 2 (median survival = 355 days) and similarly for Arm 3 (median survival = 535 days). When variables were combined at post-treatment the longest survival was predicted by a combination of low levels of CRP plus high levels of Eotaxin in Arm 2 (median survival = 355 days) and similarly for Arm 3 (median survival = 535 days).
Fig. 25 shows the vaccination schedule employed in the Examples.
Definitions
"GV1001" denotes the telomerase-derived peptide having SEQ ID NO: 1: EARPALLTSRLRFIPK
"Eotaxin" denotes the protein having any one of the amino acid sequences SEQ ID NO: 2-4 (or allelic or naturally occurring isoforms or variants thereof), which can be encoded by any one of the nucleic acid sequences SEQ ID NO: 5-7, respectively.
"CRP" is the protein having the amino acid sequence SEQ ID NO: 8 (or allelic or other naturally occurring isoforms or variants thereof), which can be encoded by the nucleic acid sequence SEQ ID NO: 9.
"MIP1α" is the protein having the amino acid sequence SEQ ID NO: 10 (or allelic or other naturally occurring isoforms or variants thereof), which can be encoded by the nucleic acid sequence SEQ ID NO: 11.
Specific embodiments of the invention
In one embodiment, the present invention provides a method for anti-cancer and/or anti-inflammatory treatment of an individual in need thereof by administering a therapeutically effective amount of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids (such as 8, 9, 10, 11, 12, 13, 14 or 15 amino acids), if said individual exhibits an increased serum level of eotaxin and/or MIP1α when compared to population average or to a population of individuals suffering from the same cancer and/or inflammatory condition.
A related embodiment relates to a method for determining whether to instigate anti-cancer and/or anti-inflammatory treatment of an individual in need thereof, wherein said anti-cancer treatment and/or anti-inflammatory treatment involves administration of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, comprising determining if said individual exhibits an increased serum level of eotaxin and/or MIP1α when comparing to the population average or to a population of individuals suffering from the same cancer and/or inflammatory condition, a positive determination indicating that said treatment is justified.
As appears from the examples, it has been found by the present inventors that median survival of cancer patients receiving the medical treatments disclosed herein is at its highest when these patients exhibit a combined baseline serum level of high eotaxin and low CRP. Further, it is also found that patients that exhibit the same combination (high eotaxin, low CRP) post-treatment art those that have the highest median survival.
Hence according to the present invention, the treatments of the present invention are preferably those where the patients subjected to the treatments are those who prior to treatment exhibit increased eotaxin and/or MIP-1α serum levels in combination with decreased CRP levels - again the levels are determined either relative to the average (or median) in the general population or relative to the average or median in the relevant patient group.
Depending on the exact route of administration, the effective amount administered according to the various embodiments of the invention may vary. If the polypeptide is administered as a vaccine, the amounts typically range from 0.5 μg up to 500 mg, with preferred administration amounts ranging between 10 μg to 1000 μg, and in particular between 20 and 200 μg. These ranges are also relevant when the polypeptide is administered as an anti-inflammatory agent, but it may be relevant - for instance if the polypepide is administered intraveneously or intraarterially - to regulate the amounts administered on the basis of the individual's condition, body weight and age.
Increased levels of eotaxin and/or MIP1α and/or CRP are in the relevant embodiments determined according to standardized assays generally known in the art - immune assays, for instance ELISAs, are preferred, but also assays that determine the activity of these cytokines on suitable target cells or suitable target molecules are relevant. If an assay is very sensitive and accurate, even small increases compared to standard values may be relevant, whereas less sensitive or accurate assays will require that larger deviations from standard values can be determined. As a rule, for a given assay for a particular cytokine there will exist a range of normal values and if the cytokine level is beyond these normal values, the level of eotaxin or MIP1α will be considered to be increased. Typically, the increased baseline level of eotaxin and/or MIP1α is at least 10%, but higher increases in values may be relevant: at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, and even at least 100%.
Another embodiment of the invention relates to a method for anti-cancer and/or anti-inflammatory treatment of an individual in need thereof by administering a therapeutically effective amount of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, wherein said treatment is continued after an initial stage of said treatment if said individual exhibits a decrease of CRP level in serum after said initial stage of said treatment. This is to mean, that the treatment has been instigated, but subsequently the measurement of CRP is used to gauge the efficacy of the treatment regimen. If serum CRP does not decrease or increases (cf. the remarks concerning assay sensitivity above), the findings of the present invention questions whether continued treatment with the GV1001-derived polypeptide is of value to the patient, meaning that it can be considered to terminate this part of the treatment and turn to possible alternatives or palliative treatment.
Related to this embodiment is a method for determining the efficacy of therapeutic treatment of an individual with a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, comprising determining the serum level of CRP in said individual after an initial stage of said treatment and comparing with the serum level of CRP prior to said initial stage of treatment, where a decrease in said serum level indicates that said treatment is effective in terms of conferring an increase in survival time.
Said decrease in the serum level of CRP should typically be at least 10%, but further decreases in values may be relevant: at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, and even at least 80%.
The above-described embodiments have focussed on the use of the GV1001-derived polypeptide, but in important embodiments of the invention, the anti-cancer and/or anti-inflammatory treatment involves concurrent treatment with at least one cytostatic or cytotoxic agent. For instance, the concurrent treatment may involve administration of GemCap as in the present examples, but depending on the cancer or inflammatory disease in question, the GV1001-derived peptide may according to the present invention be combined with the administration of cytostatic/cytotoxic agents particular relevant for the treatment of the disease in question.
Very important embodiments of the invention are those where the treatment is an anti-cancer treatment, and particularly preferred is treatment of pancreatic cancer. However, treatment of other cancer forms are contemplated, and the cancer may be selected from the group consisting of an epithelial cancer, a non-epithelial cancer, and a mixed cancer. The epithelial cancer may be both a carcinoma or an adenocarcinoma, and the non-epithelial or mixed cancer is typically a liposarcoma, a fibrosarcoma, a chondrosarcoma, an osteosarcoma, a leiomyosarcoma, a rhabomyosarcoma, a glioma, a neuroblastoma, a medullablastoma, a malignant melanoma, a malignant meningioma, a neurofibrosarcoma, a leukemia, a myeloproleferative disorder, a lymphoma, a hemangiosarcoma, a Kaposi's sarcoma, a malignant teratoma, a dysgerminoma, a seminoma, or a choriosarcoma.
Also, the anatomic location of the cancer can be anywhere in body. So the cancer may be a of the eye, the nose, the mouth, the tongue, the pharynx, the oesophagus, the stomach, the colon, the rectum, the bladder, the ureter, the urethra, the kidney, the liver, the pancreas, the thyroid gland, the adrenal gland, the breast, the skin, the central nervous system, the peripheral nervous system, the meninges, the vascular system, the testes, the ovaries, the uterus, the uterine cervix, the spleen, bone, or cartilage
The polypeptide is administered typically parenterally, and when administered as a vaccine, the polypeptide will be normally be administered subcutaneously or intradermally. If the anti-inflammatory effect is most desired, also the intraveneous or intraarterial routes may be utilised.
Determination of serum levels of the above mentioned is performed in vitro. Typically, a serum sample is subjected to an ELISA in order to determine the amount of the serum levels of the cytokines.
In all of the above discussed embodiments, the polypeptide can preferably be SEQ ID NO: 1 (i.e. the 16-mer peptide as such) or a fragment of at least 8 amino acids of SEQ ID NO: 1; that is, it is contemplated that it will not be necessary to include further amino acids in the GV1001-derived peptides.
In general embodiments are provided the use of eotaxin and/or MIP1α and/or CRP as a prognostic marker in anticancer and/or anti-inflammatory treatment, in particular if said treatment involves administration of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids. As mentioned above, the typical use will be as an agent captured/determined in an appropriate assay, so this aspect of the invention also covers use of antibodies and other agents that specifically bind to any one of the three cytokines.
An interesting embodiment relates to a method for modulation of the activity of eotaxin and/or MIP1α and/or CRP in an individual in need thereof, said method comprising administering a therapeutically effective amount of a polypeptide as defined herein -such a method will be able to address the negative impact caused by abnormal levels of these cytokines in an individual. Consequently, this embodiment relates to the use of these polypeptides as modulators of eotaxin and/or MIP1α and/or CRP.
Finally, a separate embodiment of the invention relates to a kit comprisinga) a pharmaceutical composition comprising a GV1001-derived polypeptide discussed above, andb) means for determining the serum concentration of eotaxin and/or means for determining the serum concentration of MIP1α and/or means for determining the serum concentration of CRP. These means may e.g. be in the form of a suitable immune assay.
Example
The TeloVac trial recruited 1062 patients in 52 centres throughout the UK. There was no significant difference in overall survival between the groups that received the vaccine and the control group receiving chemotherapy (GemCap therapy, cf. below), but included an ambitious program of translational research, which is still undergoing evaluation. However, results show that the vaccine resulted in a significant anti-inflammatory response, and that simultaneous vaccination with chemotherapy provides an effective method for generating both an immune response and also promoting an anti-inflammatory effect. Importantly, biomarkers for an increased survival in response to the vaccine were identified in a subgroup of patients.
Materials and methods
The TeloVac trial, was initiated in January 2007 comparing combination therapy with Gemcitabine and Capecitabine (GemCap) therapy with concurrent and sequential chemo-immunotherapy using GV1001 in locally advanced and metastatic pancreatic cancer.
Vaccination Schedule
Fig. 25 shows the vaccination schedule employed: GV1001 intradermal injections were given three times (preferably Monday, Wednesday and Friday) in the first week (week 1), and once a week in weeks 2, 3, 4, and 6. After this, GV1001 was administered once monthly. GM-CSF was administered separately as an intradermal injection 10-15 minutes before all GV1001 injections at the approximately same site.
Patients with advanced pancreatic cancer have a short life expectancy and their immune system deteriorates rapidly. The window available for induction of immune response is hence limited. It is therefore important to use a frequent vaccination regimen in order to induce an efficient immune response as fast as possible. The vaccination regimen used for GV1001, with aggressive vaccination during the first six weeks of the treatment, was based on a similar regimen used for another peptide vaccine which has proven to be efficient for induction of immune response in patients with advanced pancreatic cancer.
Inflammatory cytokine analysis
Serum samples (Arm3 only) from week1 (baseline) and week10 (Gemcitabine + Capecitabine + GV1001) were analyzed by Luminex multiplex cytokine analysis. A total of 26 cytokines were analyzed, and the CRP level was analyzed by ELISA.
Overview of Samples analysed:
Figure PCTKR2014005031-appb-I000001
Grey shading: Plasma analysed
Italic letters: Serum analysed
Arm 1: patients received GemCap only, i.e. a currently accepted standard chemotherapeutic treatment regimen for pancreatic cancer patients utilising a combination of Gemcitabine (administered iv weekly) and Capecitabine (adminstered as tablets twice daily). Arm 2: patients received GemCap therapy followed by gv1001 at week 7. Arm 3: patients received concurrent GemCap and GV1001 during the entire treatment period.
Cytokines
Grouping of some of the cytokines tested for:
Factors associated with immune stimulatory functions
INF-γ Immune stimulatory
IL-12 (p70) Immune stimulatory
IL-1β Immune stimulatory
IL-6 Immune stimulatory
TNF-α Immune stimulatory
Factors associated with immune suppressive functions :
IL-10 Immune suppressive
IL-1Ra Immune suppressive
IL-4 Immune suppressive
VEGF Immune suppressive
Factors associated with chemotactic functions :
Eotaxin Chemotactic
IL-8 Chemotactic
IP-10 Chemotactic
MCP-1 Chemotactic
MIP-1α Chemotactic
MIP-1β Chemotactic
RANTES Chemotactic
Factors associated with vascular remodelling functions :
FGF basic Vascular remodelling
PDGF-BB Vascular remodelling
VEGF Vascular remodelling
Analysis of patient sera
Cytokine Results: The Kruskal-Wallis comparison of Arm 2 and Arm 3 baseline (i.e. before treament) with arm 2 week 7 (GemCap) with Arm 3 week 10 (GemCap and GV1001) serum samples are shown in table 1 below. Kruskal-Wallis testing identifies 18 cytokines with significantly different levels; following Bonferroni-Holm correction, 8 of these cytokines are still significant.
Results
The results are shown in Tables 1-6 and Figs. 1-24.
There were 7 cytokines (IL-4, IL-5, IL-7, IL-17, PDGF, VEGF and RANTES) that were at significantly higher levels after treatment with GV1001/GemCap compared to GemCap treatment alone. Using crude uncorrected 2-tailed Mann-Whitney PDGF (p<0.0001) and RANTES (p=0.002) were most significant. Following Bonferroni Holm correction both of these remained significant (Table 2 and Fig. 1).
GemCap treatment resulted in decreased levels of a number of cytokines (pre-treatment compared to post treatment) in the serum fraction of blood (but not in plasma); this decrease was not evident in the presence of GV1001 (Table 3 and Fig. 2).
C-Reactive Protein levels were significantly lower in serum from patients receiving GV1001/GemCap compared to patients receiving GemCap alone (see Fig. 3). There was no significant difference in CRP from baseline (before treatment) to post GemCap (n=38) or from baseline (before treatment) to post GemCap with GV1001 (n=41) (Fig. 4).
Initial crude survival analysis of CRP levels showed that prior to treatment [at baseline] there was no evidence to show an association between overall survival and CRP levels (cut off 6 mg/l) in either arm 2 or arm 3. Further, after treatment in arm 2 there was no association between overall survival and CRP levels (cut off 9mg/ml). In contrast, after treatment in arm 3, a low CRP was associated with higher overall survival and median survival (486 days) compared to patients with a high CRP (median 222 days; p=0.0002) (Fig. 11). Without being bound to theory, patients responding to the vaccine with reduction of CRP appear to have significantly longer survival times than those that do not.
High baseline levels of eotaxin or MIP1α were associated with greatly increased survival in arm 3 (Figs. 6 and 7). As with CRP post initial treatment this will need to be confirmed by minimizing potential biases from other prognostic criteria, but the effect is remarkable. Somewhat surprisingly, it did not appear that treatment with GV1001 could regulate the serum levels of eotaxin or MIP1α, as is clear from the following data:
Figure PCTKR2014005031-appb-I000002
Serum analysis:
Table 1 shows Kruskal-Wallis comparison of Arms 2 and 3 baseline, Arm 2 week 7 (GemCap) with Arm 3 week 10 (GemCap and GV1001) serum.
The comparison of Arm 2 week 7 (GemCap) with Arm 3 week 10 (GemCap and GV1001) serum samples are shown in Table 2.
Mann Whitney analysis shows that there are significant increases in the levels of IL-17, IL-4, IL-5, IL-7, PDGF, RANTES and VEGF in serum samples from arm 3 week 10 patients that have received GemCap and GV1001 compared to serum samples from arm 2 week 7 patients that have received only GemCap. However, following Bonferroni-Holm correction only PDGF remains significant. Comparison graphs for IL-4, IL-5, IL7, IL-17, PDGF and VEGF cytokines in arms 2 and 3 at baseline and post treatment are shown in Fig. 1.
Paired analysis was carried out for:
■ Arm 2 patients at baseline and following 7 weeks of GemCap treatment.
■ Arm 3 patients at baseline and following 10 weeks of GemCap and GV1001 treatment. The overall P value results of these tests are shown in Table 3.
There was a clear difference in the p values from patients in arm 2 and arm 3. The paired Wilcoxon analysis indicated that there were significant differences in 19 cytokine levels between arm 2 baseline and post 7 weeks of GemCap treatment this decreases to 10 cytokines following Bonferroni Holm correction. However, in arm 3 only GM-CSF approached significance (p=0.052) between baseline and post 10 weeks of GV1001/GemCap treatment, this was no longer relevant following Bonferroni Holm correction.
Graphs showing the paired analysis for both arm 2 and arm 3 patients for a selection of cytokines are shown in Fig. 2. The figure also includes the number of positive and negative changes seen in the patient samples from baseline to post treatment. In the majority of arm 2 patients the cytokines analysed decrease from baseline to week 7, i.e. during GemCap treatment. This is in contrast with the arm 3 results, where the numbers of positive and negative changes are relatively evenly distributed.
C - Reactive Protein Results:
The levels of serum CRP was analysed. Fig. 3 shows the levels of CRP in serum from patients in arms 2 and 3 at baseline and following treatment. The data shows that there is no significant difference in CRP levels at baseline, however the post treatment analysis shows that there is a significant difference, with the levels in patients receiving GV1001/GemCap being significantly lower than in patients receiving GemCap only. Table 4 shows the summary statistics for the CRP data split by arm and baseline post treatment.
As with the cytokine data, paired analysis was carried out and is shown in Fig. 4. There were no significant differences in either arm 2 or 3 from baseline to post treatment.
Analysis of Plasma
Cytokine Results:
The comparison of arm 1 week 14 (GemCap) with arm 3 week 14 (GemCap and GV1001) plasma samples are shown in Table 4, there are no significant differences. The comparison of arm 1 week 26 (GemCap) with arm 3 week 26 (GemCap and GV1001) plasma samples are shown in table 5, there are no significant differences.
As with the serum analysis, plasma has been analysed with a paired Wilcoxon test, this has been carried out for the following comparisons with p values shown in Table 6:
■ Arm 1 patients at baseline and following 14 weeks of GemCap treatment.
■ Arm 3 patients at baseline and following 14 weeks of GemCap and GV1001 treatment.
■ Arm 1 patients at baseline and following 26 weeks of GemCap treatment.
■ Arm 3 patients at baseline and following 26 weeks of GemCap and GV1001 treatment.
It was noted that the decrease seen in cytokines in the serum following GemCap treatment was not seen in plasma. There was only one significant difference seen in RANTES for arm 3 week 14 patients, where levels decreased following GemCap and GV1001 treatment, however this was no longer significant following Bonferroni Holm correction.
Survival Analysis
Serum Cytokines:
Initial survival analyses of baseline, post treatment and absolute changes in cytokine levels revealed survival effects in one or both treatment arms with IL-8 (Fig. 5), Eotaxin (Fig. 6), MIP1α (Fig. 7), MIP1β (Fig. 8) and VEGF (Fig. 9).
CRP:
Although initial survival analysis has indicated an influence of baseline CRP on survival this did not reach significance. However, for arm 3 post treatment levels of CRP did appear to be significantly associated with a survival difference (median survival with high CRP 222 days, median survival with low CRP 486 days p=0.002, Fig. 11) this was not seen with arm 2 (Fig. 10).
Table 1. The Kruskal-Wallis comparison of Arms 2 and 3 baseline, Arm 2 week 7 (Gem-Cap) with Arm 3 week 10 (Gem-Cap and GV1001) serum
Figure PCTKR2014005031-appb-I000003
Table 2. The comparison of Arm 2 week 7 (Gem-Cap) with Arm 3 week 10 (Gem-Cap and GV1001) serum
Figure PCTKR2014005031-appb-I000004
Table 3. Shown are the p values for the paired comparison of arm 2 baseline versus week 7 and arm 3 baseline versus week 10
Figure PCTKR2014005031-appb-I000005
Table 4. Summary statistics for CRP data
Figure PCTKR2014005031-appb-I000006
Table 5A. The comparison of arm 1 week 14 (Gem-Cap) with arm 3 week 14 (Gem-Cap and GV1001) plasma
Figure PCTKR2014005031-appb-I000007
Table 5B. The comparison of arm 1 week 26 (Gem-Cap) with arm 3 week 26 (Gem-Cap and GV1001) plasma
Figure PCTKR2014005031-appb-I000008
Table 6. P values for the paired comparison of arm 1 baseline versus arm 1 week 14 and arm 3 baseline versus arm 3 week 14 (left) and arm 1 baseline versus arm 1 week 26 and arm 3 baseline
Figure PCTKR2014005031-appb-I000009
Further results of analyses
Fig. 13 shows profile plots of baseline and post-treatment means of log serum cytokine data for Arm 2.
Fig. 14 shows baseline and post-treatment means of log serum cytokine data for Arm 3. .
Fig. 15 shows a profile plot of the mean differences (post-treatment - baseline) for the cytokines in serum for each arm.
Of note, The analyses revealed that 19 cytokines showed a statistically significant decrease in serum between baseline and post-treatment in Arm 2 (PDGF, IL1β, IL-1ra, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-13, IL-17, G-CSF, IFNγ, eotaxin, FGFb, MIP1β, RANTES, TNFα, VEGF; but not CRP, IL-6, IL-8, IL-9, IL-15, GM-CSF, IP10, MCP1, MIP1α), whereas none showed a statistically significant decrease in Arm3. This appears from Fig. 16, which provides the p-values obtained from a Wilcoxon signed-rank test used on each cytokine for each arm to test for increase/decrease in values from baseline to post-treatment. The significant differences as seen are in bold grey font. The decreases were larger in Arm2 than in Arm3, noting that there were 19 significant decreases in Arm2 but none in Arm3.
Fig. 17 shows the median difference of post-treatment minus baseline levels in serum for each cytokine and for each arm of the study. Decreases are highlighted in light shadow and increases/no change are highlighted in dark shadow.
Fig. 18 shows Cox proportional hazards models on baseline data for each cytokine in serum for each arm of the study. The table provides univariate analyses for the baseline data and shows hazard ratios with 95% confidence intervals and p-values. CRP, IL-1ra, IL-2, IL-10, Eotaxin and IFNγ are significant (p<0.1) for Arm 2, while CRP, IL-1ra and Eotaxin are significant for Arm 3.
Figs. 19a and 19b show serum levels of CRP at baseline in Arm 2 and Arm 3. Low levels of CRP gave a median survival of 337 days for Arm 2 and a median survival of 373 days for Arm 3. Baseline CRP levels predicted median (95% CI) overall survival in Arm3 (high CRP=250 [132-451] days; low CRP=372.5 [229-517] days; p=0.0500) but not in Arm2 (high CRP=195 [140-262] days; low CRP=337 [167-366] days; p=0.2534)
Figs. 20a and 20b show levels of Eotaxin at baseline in Arm 2 and Arm 3. High levels of Eotaxin give a median survival of 300 days for Arm 2 and a median survival of 451 days for Arm 3. Baseline eotaxin levels predicted median (95% CI) overall survival in Arm3 (high eotaxin=451 [308-623] days; low eotaxin=238.5 [178-344] days; p=0.0135) but not in Arm2 (high eotaxin=299.5 [167-358] days; low eotaxin=188 [102-320] days; p=0.1138)
Fig. 21a and Fig. 21b shows Proportional hazards models using dichotomized variables for the baseline data for serum CRP and serum Eotaxin combined. When variables were combined at baseline the longest overall survival was predicted by a combination of low serum levels of CRP plus high serum levels of Eotaxin in Arm 2 (median survival = 337 days) and similarly for Arm 3 (median survival = 450 days).
Figs. 22a and 22b show serum CRP post treatment in Arm 2 and Arm 3. Low serum levels of CRP give a median survival of 337 days for Arm 2 and a median survival of 450 days for Arm 3.
Figs. 23a and 23b show serum Eotaxin post treatment in Arm 2 and Arm 3. High levels of serum Eotaxin give a median survival of 251 days for Arm 2 and a median survival of 364 days for Arm 3.
Figs. 24a and 24b show Proportional hazards models using dichotomized variables for the post-treatment data for serum CRP and serum Eotaxin combined. When variables were combined the longest survival was predicted by a combination of low levels of CRP plus high levels of Eotaxin in Arm 2 (median survival = 355 days) and similarly for Arm 3 (median survival = 535 days). When variables were combined at post-treatment the longest survival was predicted by a combination of low levels of CRP plus high levels of Eotaxin in Arm 2 (median survival = 355 days) and similarly for Arm 3 (median survival = 535 days).
Biologic sequence data
SEQ ID NO: 1; GV1001 amino acid sequence:EARPALLTSRLRFIPK
SEQ ID NO: 2; Human Eotaxin(Eotaxin1) (CCL11 chemokine (C-C motif) ligand 11); Protein; UniProt ID: P51671; Length: 97 amino acids, MW: 10.732 kDa:MKVSAALLWLLLIAAAFSPQGLAGPASVPTTCCFNLANRKIPLQRLESYRRITSGKCPQKAVIFKTKLAKDICADPKKKWVQDSMKYLDQKSPTPKP
SEQ ID NO: 3; Human eotaxin 2 (CCL24); Protein; UniProt ID: O00175; Length: 119 amino acids, MW: 13.134 kDa:MAGLMTIVTSLLFLGVCAHHIIPTGSVVIPSPCCMFFVSKRIPENRVVSYQLSSRSTCLKAGVIFTTKKGQQFCGDPKQEWVQRYMKNLDAKQKKASPRARAVAVKGPVQRYPGNQTTC
SEQ ID NO: 4; Human eotaxin 3 (CCL26); Protein; UniProt ID: Q9Y258; Length: 94 amino acids, MW: 10.648 kDa:MMGLSLASAVLLASLLSLHLGTATRGSDISKTCCFQYSHKPLPWTWVRSYEFTSNSCSQRAVIFTTKRGKKVCTHPRKKWVQKYISLLKTPKQL
SEQ ID NO: 5; Human Eotaxin(Eotaxin1) (CCL11 chemokine (C-C motif) ligand 11); nucleic acid; NCBI GeneBank ID: NM_002986.2:ATGGGCAAAGGCTTCCCTGGAATCTCCCACACTGTCTGCTCCCTATAAAAGGCAGGCAGATGGGCCAGAGGAGCAGAGAGGCTGAGACCAACCCAGAAACCACCACCTCTCACGCCAAAGCTCACACCTTCAGCCTCCAACATGAAGGTCTCCGCAGCACTTCTGTGGCTGCTGCTCATAGCAGCTGCCTTCAGCCCCCAGGGGCTCGCTGGGCCAGCTTCTGTCCCAACCACCTGCTGCTTTAACCTGGCCAATAGGAAGATACCCCTTCAGCGACTAGAGAGCTACAGGAGAATCACCAGTGGCAAATGTCCCCAGAAAGCTGTGATCTTCAAGACCAAACTGGCCAAGGATATCTGTGCCGACCCCAAGAAGAAGTGGGTGCAGGATTCCATGAAGTATCTGGACCAAAAATCTCCAACTCCAAAGCCATAAATAATCACCATTTTTGAAACCAAACCAGAGCCTGAGTGTTGCCTAATTTGTTTTCCCTTCTTACAATGCATTCTGAGGTAACCTCATTATCAGTCCAAAGGGCATGGGTTTTATTATATATATATATTTTTTTTTTTAAAAAAAAAACGTATTGCATTTAATTTATTGAGGCTTTAAAACTTATCCTCCATGAATATCAGTTATTTTTAAACTGTAAAGCTTTGTGCAGATTCTTTACCCCCTGGGAGCCCCAATTCGATCCCCTGTCACGTGTGGGCAATGTTCCCCCTCTCCTCTCTTCCTCCCTGGAATCTTGTAAAGGTCCTGGCAAAGATGATCAGTATGAAAATGTCATTGTTCTTGTGAACCCAAAGTGTGACTCATTAAATGGAAGTAAATGTTGTTTTAGGAATACATAAAGTATGTGCATATTTTATTATAGTCACTAGTTGTAATTTTTTTGTGGGAAATCCACACTGAGCTGAGGGGG
SEQ ID NO: 6; Human eotaxin 2 (CCL24); nucleic acid; NCBI GeneBank ID: NM_002991.2:ATGGCAGGCCTGATGACCATAGTAACCAGCCTTCTGTTCCTTGGTGTCTGTGCCCACCACATCATCCCTACGGGCTCTGTGGTCATCCCCTCTCCCTGCTGCATGTTCTTTGTTTCCAAGAGAATTCCTGAGAACCGAGTGGTCAGCTACCAGCTGTCCAGCAGGAGCACATGCCTCAAGGCAGGAGTGATCTTCACCACCAAGAAGGGCCAGCAGTTCTGTGGCGACCCCAAGCAGGAGTGGGTCCAGAGGTACATGAAGAACCTGGACGCCAAGCAGAAGAAGGCTTCCCCTAGGGCCAGGGCAGTGGCTGTCAAGGGCCCTGTCCAGAGATATCCTGGCAACCAAACCACCTGCTAA
SEQ ID NO: 7; Human Eotaxin 3 (CCL26); nucleic acid; NCBI GeneBank ID: NM_006072.4:CTGGAATTGAGGCTGAGCCAAAGACCCCAGGGCCGTCTCAGTCTCATAAAAGGGGATCAGGCAGGAGGAGTTTGGGAGAAACCTGAGAAGGGCCTGATTTGCAGCATCATGATGGGCCTCTCCTTGGCCTCTGCTGTGCTCCTGGCCTCCCTCCTGAGTCTCCACCTTGGAACTGCCACACGTGGGAGTGACATATCCAAGACCTGCTGCTTCCAATACAGCCACAAGCCCCTTCCCTGGACCTGGGTGCGAAGCTATGAATTCACCAGTAACAGCTGCTCCCAGCGGGCTGTGATATTCACTACCAAAAGAGGCAAGAAAGTCTGTACCCATCCAAGGAAAAAATGGGTGCAAAAATACATTTCTTTACTGAAAACTCCGAAACAATTGTGACTCAGCTGAATTTTCATCCGAGGACGCTTGGACCCCGCTCTTGGCTCTGCAGCCCTCTGGGGAGCCTGCGGAATCTTTTCTGAAGGCTACATGGACCCGCTGGGGAGGAGAGGGTGTTTCCTCCCAGAGTTACTTTAATAAAGGTTGTTCATAGAGTTGACTTGTTCAT
SEQ ID NO: 8; Human CRP (C-reactive protein); Protein; UniProt ID: Q5VVP7; Length: 102 amino acids, MW: 11.632 kDa:MEKLLCFLVLTSLSHAFGQTDMSRKAFVFPKESDTSYVSLKAPLTKPLKAFTVCLHFYTELSSTHEINTIYLGGPFSPNVLNWRALKYEVQGEVFTKPQLWP
SEQ ID NO: 9; Human CRP (C-reactive protein); nucleic acid; NCBI GeneBank ID: AAAGAATCAGAATTTGAGGTGTTTTGTTTTCATTTTTATTTCAAGTTGGACAGATCTTGGAGATAATTTCTTACCTCACATAGATGAGAAAACTAACACCCAGAAAGGAGAAATGATGTTATAAAAAACTCATAAGGCAAGAGCTGAGAAGGAAGCGCTGATCTTCTATTTAATTCCCCACCCATGACCCCCAGAAAGCAGGAGGGCATTGCCCACATTCACAGGGCTCTTCAGTCTCAGAATCAGGACACTGGCCAGGTGTCTGGTTTGGGTCCAGAGTGCTCATCATCATGTCATAGAACTGCTGGGCCCAGGTCTCCTGAAATGGGAAGCCCAGCAATACCACGCAGTCCCTCCACTTTCTCAAAGCACACTGGAAAGGCCATTAGAATTGCCCCAGCAGAGCAGATCTGCTTTTTTTCCAGAGCAAAATGAAGCACTAGGTATAAATATGTTGTTACTGCCAAGAACTTAAATGACTGGTTTTTGTTTGCTTGCAGTGCTTTCTTAATTTTATGGCTCTTCTGGGAAACTCCTCCCCTTTTCCACACGAACCTTGTGGGGCTGTGAATTCTTTCTTCATCCCCGCATTCCCAATATACCCAGGCCACAAGAGTGGACGTGAACCACAGGGTGTCCTGTCAGAGGAGCCCATCTCCCATCTCCCCAGCTCCCTATCTGGAGGATAGTTGGATAGTTACGTGTTCCTAGCAGGACCAACTACAGTCTTCCCAAGGATTGAGTTATGGACTTTGGGAGTGAGACATCTTCTTGCTGCTGGATTTCCAAGCTGAGAGGACGTGAACCTGGGACCACCAGTAGCCATCTTGTTTGCCACATGGAGAGAGACTGTGAGGACAGAAGCCAAACTGGAAGTGGAGGAGCCAAGGGATTGACAAACAACAGAGCCTTGACCACGTGGAGTCTCTGAATCAGCCTTGTCTGGAACCAGATCTACACCTGGACTGCCCAGGTCTATAAGCCAATAAAGCCCCTGTTTACTTGAAAAAAAAAA
SEQ ID NO: 10; Human MIP1α (CCL3 chemokine (C-C motif) ligand 3); Protein; UniProt ID: P10147; Length: 92 amino acids, MW: 10.085 kDa:MQVSTAALAVLLCTMALCNQFSASLAADTPTACCFSYTSRQIPQNFIADYFETSSQCSKPGVIFLTKRSRQVCADPSEEWVQKYVSDLELSA
SEQ ID NO: 11; Human MIP1α (CCL3 chemokine (C-C motif) ligand 3); nucleic acid; NCBI GeneBank ID: NM_002983.2:AGCTGGTTTCAGACTTCAGAAGGACACGGGCAGCAGACAGTGGTCAGTCCTTTCTTGGCTCTGCTGACACTCGAGCCCACATTCCGTCACCTGCTCAGAATCATGCAGGTCTCCACTGCTGCCCTTGCTGTCCTCCTCTGCACCATGGCTCTCTGCAACCAGTTCTCTGCATCACTTGCTGCTGACACGCCGACCGCCTGCTGCTTCAGCTACACCTCCCGGCAGATTCCACAGAATTTCATAGCTGACTACTTTGAGACGAGCAGCCAGTGCTCCAAGCCCGGTGTCATCTTCCTAACCAAGCGAAGCCGGCAGGTCTGTGCTGACCCCAGTGAGGAGTGGGTCCAGAAATATGTCAGCGACCTGGAGCTGAGTGCCTGAGGGGTCCAGAAGCTTCGAGGCCCAGCGACCTCGGTGGGCCCAGTGGGGAGGAGCAGGAGCCTGAGCCTTGGGAACATGCGTGTGACCTCCACAGCTACCTCTTCTATGGACTGGTTGTTGCCAAACAGCCACACTGTGGGACTCTTCTTAACTTAAATTTTAATTTATTTATACTATTTAGTTTTTGTAATTTATTTTCGATTTCACAGTGTGTTTGTGATTGTTTGCTCTGAGAGTTCCCCTGTCCCCTCCCCCTTCCCTCACACCGCGTCTGGTGACAACCGAGTGGCTGTCATCAGCCTGTGTAGGCAGTCATGGCACCAAAGCCACCAGACTGACAAATGTGTATCGGATGCTTTTGTTCAGGGCTGTGATCGGCCTGGGGAAATAATAAAGATGCTCTTTTAAAAGGTAAAAAAAAAAAAAAAAAAA

Claims (19)

  1. A method for anti-cancer and/or anti-inflammatory treatment of an individual in need thereof by administering a therapeutically effective amount of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, if said individual exhibits an increased serum level of eotaxin and/or MIP1α when compared to population average or to a population of individuals suffering from the same cancer and/or inflammatory condition.
  2. A method for determining whether to instigate anti-cancer and/or anti-inflammatory treatment of an individual in need thereof, wherein said anti-cancer treatment and/or anti-inflammatory treatment involves administration of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, comprising determining if said individual exhibits an increased serum level of eotaxin and/or MIP1α when comparing to the population average or to a population of individuals suffering from the same cancer and/or inflammatory condition, a positive determination indicating that said treatment is justified.
  3. The method according to claim 1 or 2, wherein the significantly increased level of eotaxin and/or MIP1α is at least 10%.
  4. The method according to any on of the preceding claims, wherein in addition the serum level of CRP in said individual is determined, and wherein a decreased level of CRP compared to population average or to a population of individuals suffering from the same cancer and/or inflammatory condition is a further indication that said treatment is justified.
  5. A method for anti-cancer and/or anti-inflammatory treatment of an individual in need thereof by administering a therapeutically effective amount of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, wherein said treatment is continued after an initial stage of said treatment if said individual exhibits a decrease of CRP level in serum after said initial stage of said treatment.
  6. A method for determining the efficacy of therapeutic treatment of an individual with a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids, comprising determining the serum level of CRP in said individual after an initial stage of said treatment and comparing with the serum level of CRP prior to said initial stage of treatment, where a decrease in said serum level indicates that said treatment is effective in terms of conferring an increase in survival time.
  7. The method according to claim 5 or 6, wherein said decrease in the serum level of CRP is at least 10%.
  8. The method according to any one of the preceding claims, wherein said anti-cancer and/or anti-inflammatory treatment involves concurrent treatment with at least one cytostatic or cytotoxic agent.
  9. The method according to claim 8, wherein said concurrent treatment involves administration of GemCap.
  10. The method according to any one of the preceding claims, wherein treatment is an anti-cancer treatment.
  11. The method according to any one of the preceding claims, wherein the treatment is treatment of pancreatic cancer.
  12. The method according to any one of the preceding claims, wherein said polypeptide is administered parenterally.
  13. The method according to any one of the preceding claims, wherein determination of serum levels is performed in vitro.
  14. The method according to any one of the preceding claims, wherein said polypeptide is SEQ ID NO: 1 or a fragment of at least 8 amino acids of SEQ ID NO: 1.
  15. Use of eotaxin and/or MIP1α and/or CRP as a prognostic marker in anticancer and/or anti-inflammatory treatment.
  16. The use according to claim 14, wherein the treatment involves administration of a polypeptide, which comprises SEQ ID NO: 1 or comprises a fragment of SEQ ID NO: 1 of at least 8 amino acids.
  17. A kit comprisinga) a pharmaceutical composition comprising a polypeptide as defined in any one of claims 1-14, andb) means for determining the serum concentration of eotaxin and/or means for determining the serum concentration of MIP1α and/or means for determining the serum concentration of CRP.
  18. A method for modulation of the activity of of eotaxin and/or MIP1α and/or CRP in an individual in need thereof, said method comprising administering a therapeutically effective amount of a polypeptide as defined in claim 1 or 14.
  19. Use of a polypeptide as defined in claim 1 or 14 as a modulator of eotaxin and/or MIP1α and/or CRP.
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EP2899201B1 (en) 2012-09-19 2019-09-11 Gemvax & Kael Co., Ltd. Cell penetrating peptide, conjugate comprising same, and composition comprising conjugate
EP3305802B1 (en) 2015-05-26 2021-05-12 Gemvax & Kael Co., Ltd. Anti-inflammatory, anti-fibrotic and wound-healing octapeptides and compositions containing the same
KR20180064434A (en) * 2015-11-03 2018-06-14 주식회사 젬백스앤카엘 Peptides having the effect of preventing and regenerating neuronal cells and compositions comprising the same
WO2025143530A1 (en) * 2023-12-28 2025-07-03 주식회사 젬백스앤카엘 Pharmaceutical composition for preventing or treating depression comprising gv1001
WO2026059284A1 (en) * 2024-09-11 2026-03-19 주식회사 젬백스앤카엘 Composition for preventing or treating side effects caused by anticancer chemotherapy, comprising gv1001 peptide as active ingredient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090136917A1 (en) * 2007-10-25 2009-05-28 Szalay Aladar A Systems and methods for viral therapy
KR20120087885A (en) * 2007-06-29 2012-08-07 안국약품 주식회사 Predictive markers for ovarian cancer

Family Cites Families (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US425360A (en) * 1890-04-08 Clothes-pounder
HU207799B (en) 1991-07-24 1993-06-28 Beres Export Import Rt Process for producing pharmaceutical composition for influencing the reticuloendothelial system, for treating chronic pain symptomes of degenerative locomotor disorders or tumors, and for treating mucoviscidosis
EP0930876B2 (en) 1996-07-22 2010-07-07 Renovo Limited Use of compounds that promote oestrogenic activity for acclerating the healing of skin wounds
US6610839B1 (en) 1997-08-14 2003-08-26 Geron Corporation Promoter for telomerase reverse transcriptase
WO1998051329A1 (en) 1997-05-15 1998-11-19 Chugai Seiyaku Kabushiki Kaisha Cachexia remedy
KR100581990B1 (en) 1997-07-01 2006-05-23 캄비아 바이오시스템즈 엘엘씨 Vertebrate Telomerase Genes and Proteins and Their Uses
US7030211B1 (en) 1998-07-08 2006-04-18 Gemvax As Antigenic peptides derived from telomerase
US6378526B1 (en) 1998-08-03 2002-04-30 Insite Vision, Incorporated Methods of ophthalmic administration
IL132406A0 (en) 1998-10-21 2001-03-19 Pfizer Prod Inc Treatment of bph with cgmp elevators
US20040127470A1 (en) * 1998-12-23 2004-07-01 Pharmacia Corporation Methods and compositions for the prevention or treatment of neoplasia comprising a Cox-2 inhibitor in combination with an epidermal growth factor receptor antagonist
US6815426B2 (en) 2001-02-16 2004-11-09 E. I. Du Pont De Nemours And Company Angiogenesis-inhibitory tripeptides, compositions and their methods of use
US6967211B2 (en) 2001-04-10 2005-11-22 Nippon Shinyaku Co. Ltd. Remedial agent for chronic articular rheumatism
BR0210904A (en) 2001-05-16 2005-08-16 Yeda Res & Dev Use of il-18 inhibitors for the treatment or prevention of sepsis.
US20030143228A1 (en) 2001-10-29 2003-07-31 Baylor College Of Medicine Human telomerase reverse transcriptase as a class-II restricted tumor-associated antigen
US7786084B2 (en) 2001-12-21 2010-08-31 Biotempt B.V. Treatment of burns
AU2003240754B2 (en) 2002-04-10 2009-02-26 Merck Serono Sa Use of osteoprotegerin for the prevention and/or treatment of fibrosis/sclerosis
KR20050020987A (en) 2002-06-12 2005-03-04 바이오겐 아이덱 엠에이 인코포레이티드 Method of treating ischemia reperfusion injury using adenosine receptor antagonists
JP2004137239A (en) * 2002-10-21 2004-05-13 Bio Oriented Technol Res Advancement Inst Soil disease control agent and soil disease control method
WO2005000227A2 (en) 2003-06-06 2005-01-06 Intermune, Inc. Methods of treating tnf-mediated disorders
EP1648490A2 (en) 2003-06-25 2006-04-26 Canbas Co., Ltd. Peptides and peptidomimetics having immune-modulating, anti-inflammatory, and anti-viral activity
KR20050040517A (en) 2003-10-29 2005-05-03 주식회사 오리엔트 Transgenic mouse possessing resistance for ischemia
ES2258694T3 (en) 2003-11-11 2006-09-01 Mattern, Udo ADMINISTRATION SYSTEM FOR CONTROLLED RELEASE OF SEX HORMONES FOR NASAL APPLICATIONS.
GB0426146D0 (en) 2004-11-29 2004-12-29 Bioxell Spa Therapeutic peptides and method
CA2646131C (en) 2005-03-21 2018-09-04 Vicus Therapeutics Spe 1, Llc Compositions and methods for ameliorating cachexia
WO2007061029A1 (en) 2005-11-25 2007-05-31 Keio University Therapeutic agent for prostate cancer
EP1968643A2 (en) 2005-12-16 2008-09-17 Diatos Cell penetrating peptide conjugates for delivering of nucleic acids into a cell
JP5295785B2 (en) 2006-02-20 2013-09-18 エファ・ユニバーシティ・インダストリー・コラボレイション・ファウンデイション Cell membrane permeable peptide
JP2009544688A (en) 2006-07-24 2009-12-17 フォーヒューマンテック カンパニー リミテッド Pharmaceutical composition for alleviation and treatment of ischemic disease and method for delivering it
EP2837636B1 (en) 2007-01-29 2018-04-11 Procell Therapeutics Inc. Novel macromolecule transduction domains and methods for identification and uses thereof
CA2695374A1 (en) 2007-08-15 2009-02-19 Amunix, Inc. Compositions and methods for modifying properties of biologically active polypeptides
GB2455539B (en) 2007-12-12 2012-01-18 Cambridge Entpr Ltd Anti-inflammatory compositions and combinations
US8828403B2 (en) 2008-06-16 2014-09-09 Mediolanum Farmaceutici S.P.A. Anti-tumor immunotherapy
KR101043747B1 (en) 2008-07-16 2011-06-27 주식회사 텔콘 Coaxial cable connector for phase adjustment of RF signal
ES2334315B1 (en) 2008-07-29 2011-02-28 Universitat Pompeu Fabra PEPTIDES WITH CAPACITY OF CELL PENETRATION AND ITS USES.
JP5337809B2 (en) 2008-09-22 2013-11-06 日清ファルマ株式会社 Anti-inflammatory peptide
WO2010128807A2 (en) 2009-05-07 2010-11-11 (주)문엔제이 Pharmaceutical composition for preventing or treating neuronal damage and neurological diseases
EP2251028A1 (en) 2009-05-12 2010-11-17 Biocompatibles Uk Ltd. Treatment of eye diseases using encapsulated cells encoding and secreting an anti-angiogenic factor and/or a neuroprotective factor
US7928067B2 (en) 2009-05-14 2011-04-19 Ischemix Llc Compositions and methods for treating ischemia and ischemia-reperfusion injury
AU2010250452B2 (en) 2009-05-20 2014-06-05 Toray Industries, Inc. Cell membrane-permeable peptides
KR20110057049A (en) 2009-11-23 2011-05-31 박의신 Functional Prostatitis Therapeutics
KR20110062943A (en) 2009-12-04 2011-06-10 주식회사종근당 Prostate hypertrophy prevention or treatment using quinazoline derivative as an active ingredient
NO2524039T3 (en) 2010-01-11 2018-04-28
RU2581800C2 (en) 2010-02-16 2016-04-20 Ультимовакс Ас Polypeptides
FR2960542B1 (en) 2010-05-27 2012-08-17 Esther Suzy Arlette Fellous PEPTIDE AS A DRUG, ESPECIALLY FOR THE TREATMENT OF CANCER
KR101263212B1 (en) 2010-05-28 2013-05-10 성신여자대학교 산학협력단 A new cell-permeable peptide and its use
WO2011150494A1 (en) 2010-05-30 2011-12-08 The Governing Council Of The University Of Toronto Mitochondrial penetrating peptides as carriers for anticancer compounds
KR101388372B1 (en) 2010-06-11 2014-04-23 한국화학연구원 Novel compound having hearing protection effects
KR101348284B1 (en) 2010-09-09 2014-01-03 주식회사 나이벡 Combination of Human derived Cell Permeable Peptide and Bioactive Peptide (TOPscovery) and Use Thereof
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
KR20120121196A (en) 2011-04-26 2012-11-05 주식회사 글루칸 Treatment agent for osteoarthritis
KR101284772B1 (en) 2011-05-24 2013-07-17 정종문 Functional food composition with the effects of anti-inflammation and pain-relieving
KR20120133661A (en) 2011-05-31 2012-12-11 주식회사 바이오포트코리아 Anti-inflammatory agent containing astaxanthin
KR101288053B1 (en) 2011-07-04 2013-07-23 동국대학교 산학협력단 Composition for Prevention or Treatment of inner ear damage Comprising an extract of Piper longum L.
KR101361445B1 (en) 2011-12-26 2014-02-12 성균관대학교산학협력단 Composition comprising peptide, 5-fluorouracil, and mature dendritic cells for cancer treatment
SG11201404570WA (en) 2012-02-10 2014-11-27 Hakushinkouseikai Foundation Proliferating agent for monocyte, culture medium for proliferating monocyte, method for producing monocyte, method for producing dendritic cell, and method for producing dendritic cell vaccine
WO2013135266A1 (en) 2012-03-12 2013-09-19 Gemvax As Treatment of non-small cell lung carcinoma by active immunotherapy
CN104507961B (en) 2012-05-11 2018-08-14 珍白斯凯尔有限公司 Anti-inflammatory peptides and compositions comprising them
EP2875826B1 (en) 2012-05-11 2017-08-23 KAEL-GemVax Co.,Ltd Composition for preventing or treating sepsis
WO2014010971A1 (en) 2012-07-11 2014-01-16 주식회사 카엘젬백스 Cell-penetrating peptide, conjugate comprising same and composition comprising same
US20150125438A1 (en) 2012-07-20 2015-05-07 Sang Jae Kim Anti-Inflammatory Peptides and Composition Comprising the Same
EP2899201B1 (en) 2012-09-19 2019-09-11 Gemvax & Kael Co., Ltd. Cell penetrating peptide, conjugate comprising same, and composition comprising conjugate
KR102038487B1 (en) 2012-09-19 2019-10-30 주식회사 젬백스앤카엘 Antimicrobial or antifungal composition comprising telomerase peptide
EP2899199B1 (en) 2012-09-19 2019-07-03 Gemvax & Kael Co., Ltd. Cell penetrating peptide, conjugate comprising same, and composition comprising conjugate
EP3736282B1 (en) 2012-09-19 2023-06-21 Gemvax & Kael Co., Ltd. Cell penetrating peptide, conjugate comprising same, and composition comprising conjugate
KR102258864B1 (en) 2013-04-19 2021-06-01 주식회사 젬백스앤카엘 Composition for treating and preventing an ischemic injury
ES2808076T3 (en) 2013-06-21 2021-02-25 Gemvax & Kael Co Ltd Regulator of hormonal secretion, composition that contains it and procedure to control hormonal secretion through its use
ES2773296T3 (en) 2013-10-23 2020-07-10 Gemvax & Kael Co Ltd Composition to treat and prevent benign prostatic hyperplasia
KR102359396B1 (en) 2013-11-22 2022-02-08 주식회사 젬백스앤카엘 Peptide having angiogenesis inhibitory activity and composition containing same
JP6367950B2 (en) 2013-12-17 2018-08-01 ジェムバックス アンド カエル カンパニー，リミティド Prostate cancer treatment composition
ES2908096T3 (en) 2014-04-11 2022-04-27 Gemvax & Kael Co Ltd Peptide with inhibitory activity of fibrosis and composition containing it
WO2015167067A1 (en) 2014-04-30 2015-11-05 주식회사 카엘젬백스 Composition for organ, tissue, or cell transplantation, kit, and transplantation method
KR102413243B1 (en) 2014-12-23 2022-06-27 주식회사 젬백스앤카엘 Peptides for treating ophthalmopathy and the Composition Comprising the Same
US10835582B2 (en) 2015-02-27 2020-11-17 Gemvax & Kael Co. Ltd. Peptide for preventing hearing loss, and composition comprising same
KR20180064434A (en) 2015-11-03 2018-06-14 주식회사 젬백스앤카엘 Peptides having the effect of preventing and regenerating neuronal cells and compositions comprising the same
KR20170054310A (en) 2015-11-09 2017-05-17 주식회사 젬백스앤카엘 Dendritic Cell Therapeutic Agent and Immunotherapeutic Agent Comprising a Peptide Derived from Telomerase, and Method for Treatment Using the Same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20120087885A (en) * 2007-06-29 2012-08-07 안국약품 주식회사 Predictive markers for ovarian cancer
US20090136917A1 (en) * 2007-10-25 2009-05-28 Szalay Aladar A Systems and methods for viral therapy

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GUNTURU ET AL: "IMMUNOTHERAPY UPDATES IN PANCREATIC CANCER ARE WE THERE YET", THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, vol. 5, no. 1, 1 January 2013 (2013-01-01), pages 81 - 89, XP055300909, DOI: 10.1177/1758834012462463 *
INDERBERG-SUSO ET AL: "WIDESPREAD CD4+ T-CELL REACTIVITY TO NOVEL HTERT EPITOPES FOLLOWING VACCINATION OF CANCER PATIENTS WITH A SINGLE HTERT PEPTIDE GV1001", ONCOIMMUNOLOGY, vol. 1, no. 5, 1 January 2012 (2012-01-01), pages 670 - 686, XP055300919, DOI: 10.4161/ONCI.20426 *
KOKHAEI ET AL: "TELOMERASE(HTERT 611-626) SERVES AS ATUMOR ANTIGEN IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA AND GENERATES SPONTANEOUSLY ANTILEUKEMIC CYTOTOXIC T CELLS", EXPERIMENTAL HEMATOLOGY, vol. 35, no. 2, 1 February 2007 (2007-02-01), pages 297 - 304, XP005858089, DOI: 10.1016/J.EXPHEM.2006.10.006 *
SCHLAPBACH ET AL: "TELOMERASE-SPECIFIC GV1001 PEPTIDE VACCINATION FAILS TO INDUCE OBJECTIVE TUMOR RESPONSE IN PATIENTS WITH CUTANEOUS T CELL LYMPHOMA", JOURNAL OF DERMATOLOGICAL SCIENCE, vol. 62, no. 2, 1 May 2011 (2011-05-01), pages 75 - 83, XP028190948, DOI: 10.1016/J.JDERMSCI.2011.02.001 *
See also references of EP3004883A4 *
VENNELA B. ET AL: "CURRENT AND FUTURE STRATEGIES FOR THERAPY OD PANCRAETIC CANCER", INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY, vol. 2, no. 3, 1 January 2012 (2012-01-01), pages 728 - 740, XP055300623 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10960056B2 (en) 2012-05-11 2021-03-30 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US9540419B2 (en) 2012-05-11 2017-01-10 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US12168039B2 (en) 2012-05-11 2024-12-17 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US12156902B2 (en) 2012-05-11 2024-12-03 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US9730984B2 (en) 2012-05-11 2017-08-15 Gemvax & Kael Co., Ltd. Composition for preventing or treating rheumatoid arthritis
US9844584B2 (en) 2012-05-11 2017-12-19 Gemvax & Kael Co., Ltd. Composition for preventing or treating sepsis
US11857607B2 (en) 2012-05-11 2024-01-02 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US9907837B2 (en) 2012-05-11 2018-03-06 Gemvax & Kael Co., Ltd. Composition for preventing or treating cachexia
US11369665B2 (en) 2012-05-11 2022-06-28 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US10039811B2 (en) 2012-05-11 2018-08-07 Gemvax & Kael Co., Ltd. Anti-inflammatory peptides and composition comprising the same
US10967000B2 (en) 2012-07-11 2021-04-06 Gemvax & Kael Co., Ltd. Cell-penetrating peptide, conjugate comprising same and composition comprising same
US9907838B2 (en) 2013-04-19 2018-03-06 Gemvax & Kael Co., Ltd. Composition and methods for treating ischemic damage
US10561703B2 (en) 2013-06-21 2020-02-18 Gemvax & Kael Co., Ltd. Method of modulating sex hormone levels using a sex hormone secretion modulator
US9572858B2 (en) 2013-10-23 2017-02-21 Gemvax & Kael Co., Ltd. Composition for treating and preventing benign prostatic hyperplasia
US10034922B2 (en) 2013-11-22 2018-07-31 Gemvax & Kael Co., Ltd. Peptide having angiogenesis inhibitory activity and composition containing same
EP3085380A4 (en) * 2013-12-17 2017-06-14 Gemvax & Kael Co., Ltd. Composition for treating prostate cancer
US11058744B2 (en) 2013-12-17 2021-07-13 Gemvax & Kael Co., Ltd. Composition for treating prostate cancer
US9937240B2 (en) 2014-04-11 2018-04-10 Gemvax & Kael Co., Ltd. Peptide having fibrosis inhibitory activity and composition containing same
US10662223B2 (en) 2014-04-30 2020-05-26 Gemvax & Kael Co., Ltd. Composition for organ, tissue, or cell transplantation, kit, and transplantation method
US11077163B2 (en) 2014-12-23 2021-08-03 Gemvax & Kael Co., Ltd. Peptide for treating ocular diseases and composition for treating ocular diseases comprising same
WO2016105086A1 (en) * 2014-12-23 2016-06-30 주식회사 젬백스앤카엘 Peptide for treating ocular diseases and composition for treating ocular diseases comprising same
US10463708B2 (en) 2014-12-23 2019-11-05 Gemvax & Kael Co., Ltd. Peptide for treating ocular diseases and composition for treating ocular diseases comprising same
JP2018502095A (en) * 2014-12-23 2018-01-25 ジェムバックス アンド カエル カンパニー，リミティド Ophthalmic disease treatment peptide and ophthalmic disease treatment composition containing the same
US10835582B2 (en) 2015-02-27 2020-11-17 Gemvax & Kael Co. Ltd. Peptide for preventing hearing loss, and composition comprising same
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US10898540B2 (en) 2016-04-07 2021-01-26 Gem Vax & KAEL Co., Ltd. Peptide having effects of increasing telomerase activity and extending telomere, and composition containing same
WO2019166463A1 (en) * 2018-02-27 2019-09-06 Oslo Universitetssykehus Hf Specific binding molecules for htert
US12071467B2 (en) 2018-02-27 2024-08-27 Oslo Universitetssykehus Hf Specific binding molecules for hTERT
WO2020226498A1 (en) 2019-05-07 2020-11-12 Rijksuniversiteit Groningen Biomarker, kit and method for predicting clinical responsiveness to therapy with an agent that targets alpha4beta7 integrin.

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