Patients were randomly assigned to either the immunotherapy (n =77) or the control group (n=79).
Autologous DCs were generated from peripheral blood mononuclear cells (PBMC) obtained from the HCC patients through leukapheresis at each center 2 weeks before the first vaccination. Monocytes were separated from the patient PBMC and cultured with supplements of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 for 5 days. On day 5, immature DCs were harvested and pulsed with CTP24-fused human AFP, GPC-3, and MAGE-1 recombinant proteins, and then matured in the presence of a cytokine cocktail consisting of IL-6, IL-1b, tumor necrosis factor-a, prostaglandin E2, interferon (IFN)g, OK432, and poly I:C for 2 days. On day 7, the DCs were harvested, washed, and resuspended in cryopreserving solution. Finally, fully equipped DC vaccines were packed into a sterile glass vial, sealed with a snap-cap, and stored at an ultralow cryopreservation system.
Multiple TAA-pulsed DC vaccine (3 x 107 cells/injection) was injected subcutaneously into the thigh near the inguinal lymph nodes. Topical toll-like receptor-7 (TLR-7) agonist (Imiquimod) was applied around the injection site for two consecutive days before injection. Patients received DC vaccine six times over 14 weeks (four times every 2 week and then two times every 4 week). Vital signs were monitored during and after each vaccine injection.
Recurrence-free survival analysis
Among the 144 patients in the efficacy population, 69 experienced tumor recurrence or death by the time of data cut-off: 33 (47.8%) in the immunotherapy group and 35 (46.7%) in the control group. Among the subgroup of 62 patients who received surgical resection (30 immunotherapy and 32 control), the immunotherapy patients showed a trend toward prolonged RFS.
When assessed among the 56 surgically resected patients who completed the full treatment as per- protocol (PP) analysis, the RFS was significantly improved by immunotherapy. In a subgroup of 10 patients, who received TACE for HCC (5 immunotherapy and 5 control), none in immunotherapy group experienced tumor recurrence during the study period, compared with four of five controls.
Treatment-emergent adverse events (TEAEs) occurred in 108 patients (74.0%) in the safety population (n=146) and immunotherapy patients (69/70, 98.6%) experienced TEAEs more frequently than controls (39/76, 51.3%). However, the frequency of serious TEAEs between the two groups was comparable (14.2% immunotherapy vs. 17.1% control). Sixty-five immunotherapy patients (92.9%) experienced a total of 503 TEAEs counted related to study drug; 502 (99.8%) were mild to moderate (grade 1 or 2) and 1 (0.2%) was grade 3 (injection site ulcer), and there was no drug-related deaths.
In conclusion, this study demonstrated that active adjuvant immunotherapy using a TAA-pulsed DC vaccine can prolong RFS in patients with HCC who have achieved complete remission by treatment modalities other than RFA. The DC vaccine was associated with a higher frequency of TEAE, but not with severe TEAE.
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Scientific article publishing date: 6/28/2017
Immucura identifier BSC22_381EN