Efficacy of adjuvant chemotherapy combined with immunotherapy with cytokine-induced killer cells for gastric cancer after d2 gastrectomy

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Summary

This study investigates the effect of chemotherapy in combination with autologous CIK therapy after D2 gastrectomy compared with adjuvant chemotherapy alone after D2 gastrectomy in patients with gastric cancer. The findings suggest that the combined therapy can improve prognosis for gastric carcinoma patients after D2 gastrectomy.

Patients characteristics

226 patients with stage II-III gastric carcinoma diagnosed after surgery. All the patients had R0 gastrectomy with D2 lymphadenectomy. All patients were diagnosed and histologically confirmed with stages IIA, IIB, IIIA, IIIB, or IIIC disease. Eastern Cooperative Oncology Group performance status between 0 and 2 before adjuvant chemotherapy. All patients had received at least four cycles of adjuvant chemotherapy based on 5-fluorouracil (5-FU) or capecitabine doublet regimens. Adequate bone marrow, liver function and renal function. An expected survival period of > 3 months.

Methodology

Peripheral blood (50 ml) was drawn from patients using heparin as an anticoagulant. Mononuclear cells were isolated by Ficoll-Conray density gradient centrifugation and their viability assessed by try- pan blue exclusion. About 2.0 × 106/ml mononuclear cells were plated onto six-well dishes and cultured with Medium I containing RPMI 1640 plus 1.0 × 106 U/L human interferon gamma (IFN-γ), 5.0 × 105 U/L recombinant human interleukin-2 (IL-2), 10% heat inactivated human serum, 25 mM HEPES, 2 mM L- glutamine, 100 U/ml penicillin, and 100 μg/ ml streptomycin.
The cells were incubated in a humidified atmosphere with 5% CO2 at 37°C. After 24 hours, 100 μg/L of monoclonal antibody (MAb) against CD3 and 1.0 × 105 U/L IL-1α were added. After another 48 hours, the supernatant was aspirated and the cells were cultured in Medium II (Medium I in the absence of INF-γ). The medium was changed every three days. Cell viability was determined using trypan blue staining. The CIK cells were transfused back into the donors following eight days of culture.

Treatment

Adjuvant chemotherapy
All patients had received at least four cycles of adjuvant chemotherapy based on 5-fluorouracil (5-FU) or capecitabine doublet regimens, including Xelox (Capecitabine, 1,000 mg/m2 twice daily on days 1 to 14 of each cycle. Oxaliplatin, 130 mg/m2 on day 1 of each cycle), Folfox4 (Oxaliplatin, 85 mg/m2 on day 1, 5- florouracil, 2,400 mg/m2 46-hour infusion Leucovorin (400 mg/m2 on day 1 of each cycle), PF (Paclitaxel, 135 mg/m2 on day 1, 5-florouracil, 2,400 mg/m2 46-hour infusion, and Leucovorin, 400 mg/m2 on day 1 of each cycle).
CIK cells treatment
137 patients (control group) received adjuvant chemotherapy alone, and 89 patients (CIK group) received adjuvant chemotherapy combined with autologous CIK cell therapy. The patients in the CIK group received at least three cycles of CIK cell therapy, the first one of which was given within two weeks after surgery, and the others were given once per month starting within six weeks after adjuvant chemotherapy. For each cycle, patients were given an infusion of at least 1.0 × 1010 CIK cells.

Results

Disease-free survival (DFS) and overall survival (OS)
For the 226 patients, the median follow-up period was 44.1 months (95% CI = 41.9-46.3 months). By the end of follow-up 93 patients (41.2%) had died and 96 patients (42.5%) had been diagnosed with recurrence. The median DFS was 39.0 months (95% CI = 35.7-42.3 months) and median OS was 45.0 months (95% CI = 40.2-49.8 months) and the 3-year DFS rate and 3-year OS rate were 59.3% and 69.9%, respectively.
The median DFS and OS of patients in the CIK group were significantly longer than for those in the control group, DFS 41.0 months vs. 32.0 months, OS 45.0 months vs. 44.0 months.
Safety of CIK cell treatment
In the CIK group, autologous CIK cell treatment was generally well tolerated. CIK-treatment- related adverse events (Grade 1/2) were observed in 23.6% of patients, with the most common events being flu- like symptoms such as fever and fatigue (13 patients, 14.6%), rash (five patients, 5.6%), and diarrhea (three patients, 3.4%). No patient experienced adverse events consistent with grade 3/4 toxicity or an autoimmune reaction.

Conclusion

In conclusion, these results indicate that CIK cell therapy combined with adjuvant chemotherapy is associated with an improved prognosis for gastric carcinoma patients after D2 gastrectomy, especially for the patients with stage III disease. The side effects of this treatment are mild.

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Scientific article publishing date 30/5/2015

Immucura identifier BSC21_237EN

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