Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene

The objective of this study was to determine the safety and antitumor activ ity of an autologous GM-CSF-secreting melanoma cell vaccine that was engine ered ex vivo with recombinant replication-incompetent adenovirus harboring a human GM-CSF gene (Adv/hGM-CSF). Melanoma samples were surgically obtaine d from 30 patients (15 female and 15 male, ages ranging from 23 to 87) and were processed for vaccine preparation. Due to stringent eligibility criter ia, 9 out of 30 patients were enrolled in the phase I clinical trial (FDA I ND7677). Melanoma cell lines established from surgical specimens of 9 patie nts were transduced with Adv/hGM-CSF (MOI of 100) and subsequently irradiat ed at 35 Gy. These cell lines secreted human GM-CSF in vitro at an average rate of 80-424 ng/10(6) cells/24 h. All patients were intradermally and sub cutaneously injected at several sites with irradiated autologous melanoma c ells (2x10(6)-1x10(7) in 300 mul saline), 2-10 times, at intervals of 4-8 w eeks. None of the patients vaccinated showed any serious adverse systemic r esponse. Three patients (nos.1, 6 and 7) demonstrated local reaction (eryth ema) to the vaccination. Tumor-specific CTL assays performed in the absence of K562 cells showed that the levels of CTLs in peripheral blood of 5 pati ents increased following vaccination, whereas those in one patient declined . Levels of CTLs assayed in the presence of K562 cells were considerably lo wer than those assayed in the absence of K562 cells, but were also found to increase following vaccination in the peripheral blood of 6 patients. A pa tient who had been vaccinated 10 times (patient 1) responded to the vaccina tion by apparent reduction in size of metastatic tumor in the lung. Immunoh istochemical examination of the vaccination sites of patient 1, biopsied af ter the 3rd and 4th vaccination, showed that the vaccination sites responde d with infiltration of inflammatory cells, such as T cells (CD3(+), CD8(+)) , macrophages and dendritic cells (CD83(+)), for a period up to about 8 day s. These data suggest that repeated vaccinations with irradiated autologous GMCSF-producing tumor cells were well tolerated by patients and led to the activation of an antitumor immune response in some patients.