Autologous Dendritic Cell-Cytokine Induced Killer Cell Immunotherapy Combined with S-1 Plus Cisplatin in Patients with Advanced Gastric Cancer: A Prospective Study

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Summary

This study investigates the combination of DC-CIK with S-1 plus cisplatin chemotherapy in patients with advanced gastric cancer (AGC). DC–CIK combined with S-1 plus cisplatin provided a favourable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities.

Patients characteristics

63 patients were age 18 to <80 years with advanced, unresectable or metastatic gastric adenocarcinoma. Patients with Eastern Cooperative Oncology Group performance status (ECOG) of 0–2; adequate organ function; and an expected survival of at least 3 months.

Methodology

Patient were divided into 4 treatment groups, S-1 alone (n=18), S-1 plus cisplatin (n=15), DC– CIK combined with S-1 (n=17) and DC–CIK combined with the S-1 plus cisplatin (n=13).
Generation of DC-CIK
Mononuclear cells were harvested from peripheral blood and expanded in vitro. For the induction of DC–CIKs, mobilization of PBMC was performed GM-CSF 5 mcg/kg sq per day to patients until the level of mononuclear cells reached 1.5 x 109/L. Then, PBMCs were separated by a COBE Spectra cell separator (COBE BCT) until CD34+ reaching ≥ 4.5 x 106/kg. Then, 40 mL of the apheresis product was co- cultured for 7 days with IL-4 (1,000 U/mL), TNF-a (20 ng/mL) and GM-CSF (800 U/mL) in vitro to generate autologous DCs. Mononuclear cells were separated by gradient centrifugation and activated in vitro with the recombinant cytokines IL-2 at 1,000 U/mL, IFNg at 1,000 U/mL and CD3 antibody at 1.7 mL/mL for 7 to 10 days. The proportion of CD80+ plus CD86+ cells reached greater than 80% among the cultured cells in the autologous DC-specific cultures. The cultured autologous DCs were then mixed with cultured CIKs at a proportion of 1:100, and then DC–CIK were harvested for administration.

Treatment

One cycle of DC/CIK immunotherapy included three cellular infusions after chemo- therapy. Patients received DC–CIK cell therapy at days 15, 17, and 19 for the first and repeatedly the second cycle was given after the second chemotherapy administrated. All patients in DC–CIK combined with chemotherapy arms of the study received 2 cycles of DC–CIK cell infusions. A median of 1.27 x 107 DC and 2.8 x 109 CIK cells were infused in the first cycle.

Results

Clinical outcome
The disease control rate (DCRs) was 5.6% in S-1 alone, 33.3% in S-1 plus cisplatin, 47.1% in DC- CIK with S-1 and 76.9% in DC-CIK with S-1 plus cisplatin.
Survival analysis
Median follow-up was 417 days [95% confidence interval (CI), 270–769]. For all the patients, the median progression-free survival (PFS) was 176 days, and the median overall survival (OS) was 400 days. The 1-year PFS and OS rates were 30.9% and 51.5%, respectively.
The 1-year OS rate for DC-CIK combined with S-1 plus cisplatin (87.5%) was significantly higher than that in the groups of patients who received DC-CIK combined with S-1 (59.9%), S-1 plus cisplatin (53.7%), and S-1 alone (22.2%). The 1-year PFS rate for DC-CIK combined with S-1 plus cisplatin (76.9%), S-1 plus cisplatin (31.9%) and S-1 alone (5.6%). DC–CIK combined with S-1 (33.9%).
Toxicity
The S-1 plus cisplatin group experienced more occurrences of leucopenia, neutropenia, anemia, and thrombocytopenia than the S-1 alone group, indicating that addition of cisplatin producing more toxic reactions. Among nonhematologic adverse events, there were no significant differences were shown in various groups. Moreover, there were no unanticipated significant differences in adverse events between the groups with and without treatment of DC– CIK cell immunotherapy. In particular, there were no immune mediated adverse events.

Conclusion

DC–CIK combined with S-1 plus cisplatin provided a favorable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities. Clinical efficacy correlated with decreases in ctDNA mutational profiles and restored TCR repertoire.

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Scientific article publishing date: 3/1/2019

Immucura identifier BSC22_378EN

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