Clinical response in Japanese metastatic melanoma patients treated with peptide cocktail-pulsed dendritic cells

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-orientated 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. 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.very high scores of ELISPOT that might correlate to the regression of metastatic tumors. Clinical response through DC injections was as follows : 1CR, 1PR, 1SD and 6PD. All 59 DC injections in the phase 1 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.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 HLAA* 0201, 1 of A*0206 and 4 of A*2402. Enriched monocytes were obtained using OptiPrep (TM) 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, 1PR, 1SD and 6PD. All 59 DC injections in the phase 1 study were tolerable in terms of safety, however. the maximal tolerable dose of DCs was not determined. Conclusion: These results suggested that peptide cocktail-treated DC-based immunotherapy had the potential for utilizing as one therapeutic tools against metastatic melanoma in Japan.