Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient

Kazuhide Tsuji, Toshitada Hamada, Akiko Uenaka, Hisashi Wada, Eiichi Sato, Midori Isobe, Kenji Asagoe, Osamu Yamasaki, Hiroshi Shiku, Gerd Ritter, Roger Murphy, Eric W. Hoffman, Lloyd J. Old, Eiichi Nakayama, Keiji Iwatsuki

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: NY-ESO-1 is a cancer/testis antigen highly immunogenic in cancer patients. Cholesterol-bearing hydrophobized pullulan (CHP) is a nanoparticle-forming antigen-delivery vehicle and CHP complexed with NY-ESO-1 protein (CHP-NY-ESO-1) efficiently activates CD4 and CD8 T cells in vitro. Aim: In this study we report on a 50-year-old male melanoma patient with multiple skin and organ metastases (T4N3M1c) who was vaccinated with CHP-NY-ESO-1 at biweekly intervals and who had an unusual disease course. We characterized in this patient humoral and cellular immune responses, immune regulatory cells, and cytokine profiles in the peripheral blood and at local tumor sites. Results: Ten days after the second CHP-NY-ESO-1 vaccination (day 25), blisters appeared on the skin at the metastatic lesions associated with inflammatory changes. A skin biopsy showed the presence of many NY-ESO-1-expressing apoptotic melanoma cells as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) test. However, the tumors continued to grow, and the patient died of pulmonary failure due to multiple metastases on day 48. Serum antibody responses were detected after the second CHP-NY-ESO-1 vaccination and antibody titer increased with subsequent vaccinations. Th1 dependent IgG1 was the predominant immunoglobulin subtype. Both, NY-ESO-1-specific CD4 and CD8 T cell responses were detected in PBMC by IFN-γ secretion assays. After CHP-NY-ESO-1 vaccination a slight decrease in CD4+CD25+Foxp3+ Tregs was observed in PBMC but significantly increased numbers of CD4+CD25+Foxp3 + Tregs and CD68+ immunoregulatory macrophages were detected at the local tumor sites. CD4+CD25+Foxp3 + Tregs were also increased in the blister fluid. Cytokines in the serum suggested a polarization towards a Th1 pattern in the PBMC and those in the blister fluid suggested a Th2-type response at the tumor site. Conclusions: Our observations indicate induction of specific humoral and cellular immune responses against NY-ESO-1 after CHP-NY-ESO-1 vaccination in a melanoma patient. The concomitant appearance of regulatory T cells and of immune regulatory macrophages and cytokines at the local tumor sites in this patient may explain immune escape.

Original languageEnglish
Pages (from-to)1429-1437
Number of pages9
JournalCancer Immunology, Immunotherapy
Volume57
Issue number10
DOIs
Publication statusPublished - Oct 2008

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Melanoma
Vaccination
Cholesterol
Blister
Neoplasms
Humoral Immunity
Cytokines
Cellular Immunity
Skin
Macrophages
Neoplasm Metastasis
T-Lymphocytes
Antigens
DNA Nucleotidylexotransferase
pullulan
Testicular Neoplasms
Regulatory T-Lymphocytes
Serum
Nanoparticles
Antibody Formation

Keywords

  • A complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein
  • Cancer vaccine
  • Melanoma
  • Tumor immunity

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

Cite this

Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient. / Tsuji, Kazuhide; Hamada, Toshitada; Uenaka, Akiko; Wada, Hisashi; Sato, Eiichi; Isobe, Midori; Asagoe, Kenji; Yamasaki, Osamu; Shiku, Hiroshi; Ritter, Gerd; Murphy, Roger; Hoffman, Eric W.; Old, Lloyd J.; Nakayama, Eiichi; Iwatsuki, Keiji.

In: Cancer Immunology, Immunotherapy, Vol. 57, No. 10, 10.2008, p. 1429-1437.

Research output: Contribution to journalArticle

Tsuji, K, Hamada, T, Uenaka, A, Wada, H, Sato, E, Isobe, M, Asagoe, K, Yamasaki, O, Shiku, H, Ritter, G, Murphy, R, Hoffman, EW, Old, LJ, Nakayama, E & Iwatsuki, K 2008, 'Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient', Cancer Immunology, Immunotherapy, vol. 57, no. 10, pp. 1429-1437. https://doi.org/10.1007/s00262-008-0478-5
Tsuji, Kazuhide ; Hamada, Toshitada ; Uenaka, Akiko ; Wada, Hisashi ; Sato, Eiichi ; Isobe, Midori ; Asagoe, Kenji ; Yamasaki, Osamu ; Shiku, Hiroshi ; Ritter, Gerd ; Murphy, Roger ; Hoffman, Eric W. ; Old, Lloyd J. ; Nakayama, Eiichi ; Iwatsuki, Keiji. / Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient. In: Cancer Immunology, Immunotherapy. 2008 ; Vol. 57, No. 10. pp. 1429-1437.
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abstract = "Background: NY-ESO-1 is a cancer/testis antigen highly immunogenic in cancer patients. Cholesterol-bearing hydrophobized pullulan (CHP) is a nanoparticle-forming antigen-delivery vehicle and CHP complexed with NY-ESO-1 protein (CHP-NY-ESO-1) efficiently activates CD4 and CD8 T cells in vitro. Aim: In this study we report on a 50-year-old male melanoma patient with multiple skin and organ metastases (T4N3M1c) who was vaccinated with CHP-NY-ESO-1 at biweekly intervals and who had an unusual disease course. We characterized in this patient humoral and cellular immune responses, immune regulatory cells, and cytokine profiles in the peripheral blood and at local tumor sites. Results: Ten days after the second CHP-NY-ESO-1 vaccination (day 25), blisters appeared on the skin at the metastatic lesions associated with inflammatory changes. A skin biopsy showed the presence of many NY-ESO-1-expressing apoptotic melanoma cells as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) test. However, the tumors continued to grow, and the patient died of pulmonary failure due to multiple metastases on day 48. Serum antibody responses were detected after the second CHP-NY-ESO-1 vaccination and antibody titer increased with subsequent vaccinations. Th1 dependent IgG1 was the predominant immunoglobulin subtype. Both, NY-ESO-1-specific CD4 and CD8 T cell responses were detected in PBMC by IFN-γ secretion assays. After CHP-NY-ESO-1 vaccination a slight decrease in CD4+CD25+Foxp3+ Tregs was observed in PBMC but significantly increased numbers of CD4+CD25+Foxp3 + Tregs and CD68+ immunoregulatory macrophages were detected at the local tumor sites. CD4+CD25+Foxp3 + Tregs were also increased in the blister fluid. Cytokines in the serum suggested a polarization towards a Th1 pattern in the PBMC and those in the blister fluid suggested a Th2-type response at the tumor site. Conclusions: Our observations indicate induction of specific humoral and cellular immune responses against NY-ESO-1 after CHP-NY-ESO-1 vaccination in a melanoma patient. The concomitant appearance of regulatory T cells and of immune regulatory macrophages and cytokines at the local tumor sites in this patient may explain immune escape.",
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T1 - Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient

AU - Tsuji, Kazuhide

AU - Hamada, Toshitada

AU - Uenaka, Akiko

AU - Wada, Hisashi

AU - Sato, Eiichi

AU - Isobe, Midori

AU - Asagoe, Kenji

AU - Yamasaki, Osamu

AU - Shiku, Hiroshi

AU - Ritter, Gerd

AU - Murphy, Roger

AU - Hoffman, Eric W.

AU - Old, Lloyd J.

AU - Nakayama, Eiichi

AU - Iwatsuki, Keiji

PY - 2008/10

Y1 - 2008/10

N2 - Background: NY-ESO-1 is a cancer/testis antigen highly immunogenic in cancer patients. Cholesterol-bearing hydrophobized pullulan (CHP) is a nanoparticle-forming antigen-delivery vehicle and CHP complexed with NY-ESO-1 protein (CHP-NY-ESO-1) efficiently activates CD4 and CD8 T cells in vitro. Aim: In this study we report on a 50-year-old male melanoma patient with multiple skin and organ metastases (T4N3M1c) who was vaccinated with CHP-NY-ESO-1 at biweekly intervals and who had an unusual disease course. We characterized in this patient humoral and cellular immune responses, immune regulatory cells, and cytokine profiles in the peripheral blood and at local tumor sites. Results: Ten days after the second CHP-NY-ESO-1 vaccination (day 25), blisters appeared on the skin at the metastatic lesions associated with inflammatory changes. A skin biopsy showed the presence of many NY-ESO-1-expressing apoptotic melanoma cells as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) test. However, the tumors continued to grow, and the patient died of pulmonary failure due to multiple metastases on day 48. Serum antibody responses were detected after the second CHP-NY-ESO-1 vaccination and antibody titer increased with subsequent vaccinations. Th1 dependent IgG1 was the predominant immunoglobulin subtype. Both, NY-ESO-1-specific CD4 and CD8 T cell responses were detected in PBMC by IFN-γ secretion assays. After CHP-NY-ESO-1 vaccination a slight decrease in CD4+CD25+Foxp3+ Tregs was observed in PBMC but significantly increased numbers of CD4+CD25+Foxp3 + Tregs and CD68+ immunoregulatory macrophages were detected at the local tumor sites. CD4+CD25+Foxp3 + Tregs were also increased in the blister fluid. Cytokines in the serum suggested a polarization towards a Th1 pattern in the PBMC and those in the blister fluid suggested a Th2-type response at the tumor site. Conclusions: Our observations indicate induction of specific humoral and cellular immune responses against NY-ESO-1 after CHP-NY-ESO-1 vaccination in a melanoma patient. The concomitant appearance of regulatory T cells and of immune regulatory macrophages and cytokines at the local tumor sites in this patient may explain immune escape.

AB - Background: NY-ESO-1 is a cancer/testis antigen highly immunogenic in cancer patients. Cholesterol-bearing hydrophobized pullulan (CHP) is a nanoparticle-forming antigen-delivery vehicle and CHP complexed with NY-ESO-1 protein (CHP-NY-ESO-1) efficiently activates CD4 and CD8 T cells in vitro. Aim: In this study we report on a 50-year-old male melanoma patient with multiple skin and organ metastases (T4N3M1c) who was vaccinated with CHP-NY-ESO-1 at biweekly intervals and who had an unusual disease course. We characterized in this patient humoral and cellular immune responses, immune regulatory cells, and cytokine profiles in the peripheral blood and at local tumor sites. Results: Ten days after the second CHP-NY-ESO-1 vaccination (day 25), blisters appeared on the skin at the metastatic lesions associated with inflammatory changes. A skin biopsy showed the presence of many NY-ESO-1-expressing apoptotic melanoma cells as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) test. However, the tumors continued to grow, and the patient died of pulmonary failure due to multiple metastases on day 48. Serum antibody responses were detected after the second CHP-NY-ESO-1 vaccination and antibody titer increased with subsequent vaccinations. Th1 dependent IgG1 was the predominant immunoglobulin subtype. Both, NY-ESO-1-specific CD4 and CD8 T cell responses were detected in PBMC by IFN-γ secretion assays. After CHP-NY-ESO-1 vaccination a slight decrease in CD4+CD25+Foxp3+ Tregs was observed in PBMC but significantly increased numbers of CD4+CD25+Foxp3 + Tregs and CD68+ immunoregulatory macrophages were detected at the local tumor sites. CD4+CD25+Foxp3 + Tregs were also increased in the blister fluid. Cytokines in the serum suggested a polarization towards a Th1 pattern in the PBMC and those in the blister fluid suggested a Th2-type response at the tumor site. Conclusions: Our observations indicate induction of specific humoral and cellular immune responses against NY-ESO-1 after CHP-NY-ESO-1 vaccination in a melanoma patient. The concomitant appearance of regulatory T cells and of immune regulatory macrophages and cytokines at the local tumor sites in this patient may explain immune escape.

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