title: Clinical response in Japanese metastatic melanoma patients treated with peptide cocktail-pulsed dendritic cells.
abstract: BACKGROUND: Metastatic, chemotherapy-resistant melanoma is an intractable cancer with a very poor prognosis. As to immunotherapy targeting metastatic melanoma, HLA-A2+ patients were mainly enrolled in the study in Western countries. However, HLA-A24+ melanoma patients-oriented immunotherapy has not been fully investigated. In the present study, we investigated the effect of dendritic cell (DC)-based immunotherapy on metastatic melanoma patients with HLA-A2 or A24 genotype. METHODS: Nine cases of metastatic melanoma were enrolled into a phase I study of monocyte-derived dendritic cell (DC)-based immunotherapy. HLA-genotype analysis revealed 4 cases of HLA-A*0201, 1 of A*0206 and 4 of A*2402. Enriched monocytes were obtained using OptiPreptrade mark from leukapheresis products, and then incubated with GM-CSF and IL-4 in a closed serum-free system. After pulsing with a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-2, MAGE-3 and MART-1 or MAGE-1) restricted to HLA-A2 or A24 and KLH, cells were cryopreserved until used. Finally, thawed DCs were washed and injected subcutaneously (s.c.) into the inguinal region in a dose-escalation manner. RESULTS: The mean percentage of DCs rated as lin-HLA-DR+ in melanoma patients was 46.4 +/- 15.6 %. Most of DCs expressed high level of co-stimulatory molecules and type1 phenotype (CD11c+HLA-DR+), while a moderate number of mature DCs with CD83 and CCR7 positive were contained in DC products. DC injections were well tolerated except for transient liver dysfunction (elevation of transaminases, Grade I-II). All 6 evaluable cases except for early PD showed positive immunological responses to more than 2 melanoma peptides in an ELISPOT assay. Two representative responders demonstrated strong HLA-class I protein expression in the tumor and very high scores of ELISPOT that might correlate to the regression of metastatic tumors. Clinical response through DC injections was as follows : 1CR, 1 PR, 1SD and 6 PD. All 59 DC injections in the phase I study were tolerable in terms of safety, however, the maximal tolerable dose of DCs was not determined. CONCLUSIONS: These results suggested that peptide cocktail-treated DC-based immunotherapy had the potential for utilizing as one of therapeutic tools against metastatic melanoma in Japan.
authors.affiliation: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shimonagakubo, Nagaizumi-cho, Shizuoka, Japan. y.akiyama@scchr.jp.
authors.forename: Yasuto
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authors.lastname: Akiyama
authors.forename: Ryuji
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authors.lastname: Tanosaki
authors.forename: Naoki
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authors.lastname: Inoue
authors.forename: Makiko
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authors.lastname: Shimada
authors.forename: Yukie
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authors.lastname: Hotate
authors.forename: Akifumi
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authors.lastname: Yamamoto
authors.forename: Naoya
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authors.lastname: Yamazaki
authors.forename: Ichiro
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authors.lastname: Kawashima
authors.forename: Ikuei
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authors.lastname: Nukaya
authors.forename: Kazutoh
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authors.lastname: Takesako
authors.forename: Kouji
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authors.lastname: Maruyama
authors.forename: Yoichi
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authors.lastname: Takaue
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi