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HER2-Specific T-Cell Immune Responses in Patients Vaccinated with Truncated HER2 Protein Complexed with Nanogels of Cholesteryl Pullulan

Authors' Affiliations: Departments of ¹ Medical Oncology and Immunology, ² Immuno-Gene Therapy, ³ Cancer Vaccine, and ⁴ Pathology, Mie University Graduate School of Medicine; ⁵ Blood Transfusion Service and ⁶ Department of Hematology, Mie University Hospital, Tsu, Mie, Japan; ⁷ Department of Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; ⁸ Kyoto University Graduate School of Engineering, Kyoto, Japan; ⁹ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan; ¹⁰ Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia; and ¹¹ Ludwig Institute for Cancer Research, New York, New York

Requests for reprints: Hiroshi Shiku, Department of Cancer Vaccine, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan. Phone: 81-59-231-5187; Fax: 81-59-231-5276; E-mail: shiku{at}clin.medic.mie-u.ac.jp.

Purpose: We developed a complex of tumor antigen protein with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4⁺ T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers.

Experimental Design: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 µg of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4⁺ T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the vaccine protein.

Results: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8⁺ and/or CD4⁺ T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8⁺ T-cell responses, two patients reacted to previously identified HER2_63-71 peptide and the other two reacted only to 146HER2 mRNA-transduced cells.

Conclusions: CHP-HER2 vaccine was safe and induced HER2-specific CD8⁺ and/or CD4⁺ T-cell immune responses.

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