Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)

Satoshi Takeuchi; Tadahiro Shoji; Masahiro Kagabu; Tatsuya Honda Tatsuya Honda; Tadayuki Nagasawa; Yukari Nitta; Toru Sugiyama; Sachiko Yoshimura; Yusuke Nakamura

doi:doi:10.11648/j.crj.20190703.15

Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)

Satoshi Takeuchi, Tadahiro Shoji, Masahiro Kagabu, Tatsuya Honda Tatsuya Honda, Tadayuki Nagasawa, Yukari Nitta, Toru Sugiyama, Sachiko Yoshimura, Yusuke Nakamura

Published in Cancer Research Journal (Volume 7, Issue 3)

Received: 1 August 2019 Accepted: 11 September 2019 Published: 24 September 2019

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Abstract

Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.

Published in	Cancer Research Journal (Volume 7, Issue 3)
DOI	10.11648/j.crj.20190703.15
Page(s)	106-116
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2019. Published by Science Publishing Group

Keywords

Immunotherapy, Cancer Vaccination, Epitope Peptide, Ovarian Cancer, Cervical Cancer, HLA, Chemotherapy Resistance, Persistent Disease

References

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Satoshi Takeuchi, Tadahiro Shoji, Masahiro Kagabu, Tatsuya Honda Tatsuya Honda, Tadayuki Nagasawa, et al. (2019). Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies). Cancer Research Journal, 7(3), 106-116. https://doi.org/10.11648/j.crj.20190703.15

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Satoshi Takeuchi; Tadahiro Shoji; Masahiro Kagabu; Tatsuya Honda Tatsuya Honda; Tadayuki Nagasawa, et al. Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies). Cancer Res. J. 2019, 7(3), 106-116. doi: 10.11648/j.crj.20190703.15

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Satoshi Takeuchi, Tadahiro Shoji, Masahiro Kagabu, Tatsuya Honda Tatsuya Honda, Tadayuki Nagasawa, et al. Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies). Cancer Res J. 2019;7(3):106-116. doi: 10.11648/j.crj.20190703.15

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@article{10.11648/j.crj.20190703.15,
  author = {Satoshi Takeuchi and Tadahiro Shoji and Masahiro Kagabu and Tatsuya Honda Tatsuya Honda and Tadayuki Nagasawa and Yukari Nitta and Toru Sugiyama and Sachiko Yoshimura and Yusuke Nakamura},
  title = {Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)},
  journal = {Cancer Research Journal},
  volume = {7},
  number = {3},
  pages = {106-116},
  doi = {10.11648/j.crj.20190703.15},
  url = {https://doi.org/10.11648/j.crj.20190703.15},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.crj.20190703.15},
  abstract = {Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.},
 year = {2019}
}

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TY  - JOUR
T1  - Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)
AU  - Satoshi Takeuchi
AU  - Tadahiro Shoji
AU  - Masahiro Kagabu
AU  - Tatsuya Honda Tatsuya Honda
AU  - Tadayuki Nagasawa
AU  - Yukari Nitta
AU  - Toru Sugiyama
AU  - Sachiko Yoshimura
AU  - Yusuke Nakamura
Y1  - 2019/09/24
PY  - 2019
N1  - https://doi.org/10.11648/j.crj.20190703.15
DO  - 10.11648/j.crj.20190703.15
T2  - Cancer Research Journal
JF  - Cancer Research Journal
JO  - Cancer Research Journal
SP  - 106
EP  - 116
PB  - Science Publishing Group
SN  - 2330-8214
UR  - https://doi.org/10.11648/j.crj.20190703.15
AB  - Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.
VL  - 7
IS  - 3
ER  -

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Author Information

Satoshi Takeuchi

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Tadahiro Shoji

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Masahiro Kagabu

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Tatsuya Honda Tatsuya Honda

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Tadayuki Nagasawa

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Yukari Nitta

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Toru Sugiyama

Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine Morioka, Iwate, Japan
Sachiko Yoshimura

Department of Cancer, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Yusuke Nakamura

Department of Cancer, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

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Satoshi Takeuchi, Tadahiro Shoji, Masahiro Kagabu, Tatsuya Honda Tatsuya Honda, Tadayuki Nagasawa, et al. (2019). Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies). Cancer Research Journal, 7(3), 106-116. https://doi.org/10.11648/j.crj.20190703.15

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Satoshi Takeuchi; Tadahiro Shoji; Masahiro Kagabu; Tatsuya Honda Tatsuya Honda; Tadayuki Nagasawa, et al. Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies). Cancer Res. J. 2019, 7(3), 106-116. doi: 10.11648/j.crj.20190703.15

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AMA Style

Satoshi Takeuchi, Tadahiro Shoji, Masahiro Kagabu, Tatsuya Honda Tatsuya Honda, Tadayuki Nagasawa, et al. Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies). Cancer Res J. 2019;7(3):106-116. doi: 10.11648/j.crj.20190703.15

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@article{10.11648/j.crj.20190703.15,
  author = {Satoshi Takeuchi and Tadahiro Shoji and Masahiro Kagabu and Tatsuya Honda Tatsuya Honda and Tadayuki Nagasawa and Yukari Nitta and Toru Sugiyama and Sachiko Yoshimura and Yusuke Nakamura},
  title = {Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)},
  journal = {Cancer Research Journal},
  volume = {7},
  number = {3},
  pages = {106-116},
  doi = {10.11648/j.crj.20190703.15},
  url = {https://doi.org/10.11648/j.crj.20190703.15},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.crj.20190703.15},
  abstract = {Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.},
 year = {2019}
}

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TY  - JOUR
T1  - Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)
AU  - Satoshi Takeuchi
AU  - Tadahiro Shoji
AU  - Masahiro Kagabu
AU  - Tatsuya Honda Tatsuya Honda
AU  - Tadayuki Nagasawa
AU  - Yukari Nitta
AU  - Toru Sugiyama
AU  - Sachiko Yoshimura
AU  - Yusuke Nakamura
Y1  - 2019/09/24
PY  - 2019
N1  - https://doi.org/10.11648/j.crj.20190703.15
DO  - 10.11648/j.crj.20190703.15
T2  - Cancer Research Journal
JF  - Cancer Research Journal
JO  - Cancer Research Journal
SP  - 106
EP  - 116
PB  - Science Publishing Group
SN  - 2330-8214
UR  - https://doi.org/10.11648/j.crj.20190703.15
AB  - Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.
VL  - 7
IS  - 3
ER  -

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