Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment

overall survival rate

Overall survival rate

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Summary

Surgery combined with chemotherapy is considered the best standard treatment for advanced colorectal cancer patients. This study evaluates the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment. The results show that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy.

Patients characteristics

142 patients were pathologically diagnosed with colorectal cancer at stages III–IV according to the International Union Against Cancer. All patients received standard first-line treatment including surgical resection, adjuvant chemotherapy, and/or radiotherapy.All patients are divided into 2 groups: 71 patients in DC-CIK group and 71 patients in control group.

Methodology

First-line treatment
All enrolled CRC patients underwent primary tumor resection and postoperative FOLFIRI chemotherapy with or without radiotherapy. The FOLFIRI [irinotecan (CPT- 11), leucovorin (LV), and 5-FU] regimen consisted of CPT-11 intravenous infusion (80 mg/m2) on day 1, intravenous LV infusion (400 mg/m2) on day 1, and intravenous bolus injection (0.4 g/m2) and 46-h infusion (2.4 g/m2) of 5-FU on day 1 and day 2. This regimen was repeated every 2 weeks.
DC-CIK generation
Peripheral blood mononuclear cells (PBMCs) were separated from a 50-mL peripheral blood sample from each patient in the “DC-CIK” group by Ficoll-Paque density gradient centrifugation. PBMCs (1 × 107 cells/mL) were plated onto six-well dishes. Non-adherent cells were collected after 2 hours of incubation at 37 °C under 5% CO2. Adherent cells were cultured in GT-T551 medium containing granulocyte- macrophage colony-stimulating factor (GM-CSF) and interleukin- 4 (IL-4). The medium was replaced every 2 days. WT1 antigen was then added to the medium at day 5 to a final concentration of 100 g/mL and cocultured with DCs for an additional 24 hours. Non-adherent cells were collected for CIK cell preparation. Cells were resuspended at a concentration of 5 × 106 cells/mL with GT-T551 medium containing interferon- gamma (IFN-γ) and cultured in 75-cm2 culture flasks at 37 °C under 5% CO2.
Cells were treated with 1000 U/mL IL-2 and 50 ng/mL anti-CD3 monoclonal antibody after 24 hours. Cell density was readjusted to 5 × 106 cells/mL by using fresh medium containing 500 U/mL IL-2 from day 2 to day 10. Matured DCs were harvested and mixed with CIK cells at a ratio of 1:10 at day 7.

Treatment

DC-CIK cell-based treatment was combined with first- line treatments. All 71 patients received at least two cycles of DC-CIK cells.DC-CIK cells were then harvested and resuspended in normal salt solution and administered via intravenous infusion during intervals of chemotherapy twice a day for 4 days. Four transfusions were defined as one cycle. Patients received a total of 1–2 × 1010 cells at each cycle. The interval of every cycle was at least 2 weeks.

Results

Side effects
During and after DC-CIK cell transfusion, six patients (8%) suffered from mild fever, chills, and fatigue; three also developed a headache; and one developed chest tightness and hypotension. All of them recovered after symptomatic treatment. There were no adverse reactions such as anaphylaxis. No patients presented with abnormal liver function tests (LFTs) or kidney function.
QoL assessment
Quality of life in DC-CIK-treated patients had the KPS score of 76.48 ± 8.53 compared to that of the control of 67.74 ± 7.82.
Clinical outcome
In the median 76-month follow-up period of time, the median survival time of the patients in the DC-CIK group and non-DC-CIK group was 32 months (95%CI 18.89–45.41 months) and 17 months (95%CI 15.18– 18.82 months), respectively.
Then subsequently analyzed the 1, 3, and 5-year progression-free survival rates, which were 85.3, 64.1, and 57.4%, respectively, in the DC-CIK group, whereas in the non-DC-CIK group were 65.0, 44.3, and 33.6%, respectively (p=0.017). Furthermore, the 1, 3, and 5-year overall survival rates were 84.5, 46.0, and 41.3%, respectively, in the DC-CIK group compared to 65.7, 23.4, and 19.4%, respectively, in the non-DC-CIK group (p = 0.001).

Conclusion

In summary, DC-CIK cell adjuvant transfusion resulted in significantly prolonged 5-year OS rates compared to that of the control group. Secondly, the 5-year PFS rates were significantly improved; the 1- and 3-year OS and PFS rates in the DC-CIK group were higher than those in the control group. These results suggested that DC- CIK cell treatment, combined with first-line therapy, is an effective therapeutic strategy for treatment of advanced colorectal cancer.

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Scientific article publishing date : 11/28/2017

Immucura identifier BSC21_190EN

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