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

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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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Acknowledgments

We thank Drs. Atsushi Fujita, Yayoi Tokuyama (Dermatology, Okayama University Hospital), Kazuhisa Yao, Kojiro Futagami, and Yutaka Gomita (Pharmacy and the Center for Clinical Research of New Drugs and Therapeutics, Okayama University Hospital). We also thank Y. Yamamoto and M. Nakano for excellent technical assistance, and J. Mizuuchi for preparation of the manuscript.

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Authors and Affiliations

  1. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Kazuhide Tsuji, Toshitada Hamada, Kenji Asagoe, Osamu Yamasaki & Keiji Iwatsuki

  2. Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Akiko Uenaka, Midori Isobe & Eiichi Nakayama

  3. Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

    Hisashi Wada

  4. Department of Pathology, Tokyo Medical University, Tokyo, Japan

    Eiichi Sato

  5. Department of Cancer Vaccine and Immuno-gene Therapy, Mie University Graduate School of Medicine, Tsu, Japan

    Hiroshi Shiku

  6. New York Branch at Memorial Sloan-Kettering Cancer Center, Ludwig Institute for Cancer Research, New York, USA

    Gerd Ritter & Lloyd J. Old

  7. Melbourne Centre for Clinical Sciences, Ludwig Institute for Cancer Research, Melbourne, Australia

    Roger Murphy

  8. Office of Clinical Trials Management, Ludwig Institute for Cancer Research, New York, USA

    Eric W. Hoffman

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  1. Kazuhide Tsuji
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  2. Toshitada Hamada
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  11. Roger Murphy
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  13. Lloyd J. Old
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  14. Eiichi Nakayama
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Correspondence to Kazuhide Tsuji.

Additional information

Supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Cancer Vaccine Collaborative of the Cancer Research Institute and the Ludwig Institute for Cancer Research.

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Tsuji, K., Hamada, T., Uenaka, A. et al. Induction of immune response against NY-ESO-1 by CHP-NY-ESO-1 vaccination and immune regulation in a melanoma patient. Cancer Immunol Immunother 57, 1429–1437 (2008). https://doi.org/10.1007/s00262-008-0478-5

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