The presented study aimed to determine the effect of a combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with colorectal cancer. The data indicates that CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, specially for patients with highrisk T4 stage and insufficient chemotherapy duration.
122 patients with CRC were retrospectively analyzed; 78 (63.9%) were men and 44 (36.1%) were women. The median age was 54 years (range, 30–81 years). Patients were undergone complete resection of histologically proven high- risk stage II or stage III CRC or they have had their resectable stage IV disease underwent radical resection.
60 patients received sequential CIK cell treatment (CIK group), while the other 62 patients diagnosed at the same or near day but without CIK cell treatment were used as the control group for comparisons.
CIK cell preparation
Peripheral blood mononuclear cells were separated using Ficoll-Hypaque density centrifugation, rinsed twice using saline solution, and then suspended in X-VIVO 15 serum-free medium. After culturing for 1 hour in the atmosphere with 5% CO2 at 37°C, the non-adherent cells were removed by aspiration and the cell density was adjusted to 2 × 106 cells/ ml using X-VIVO 15 medium supplemented with 1,000 U/mL recombinant human IFN-γ for the first 24 hours. Subsequently, 1,000 U/mL IL-2, 100 ng/mL mouse anti- human CD3 monoclonal antibody, and 100 U/mL IL- 1α were added to the medium. Fresh medium containing IL-2 was added periodically according to the cell growth and the CIK cells were harvested at 14 days.
All patients in the control group and CIK group received adjuvant chemotherapy with FOLFOX (bolus and infused fluorouracil with oxaliplatin), CAPOX (oxaliplatin and capecitabine), or single- agent capecitabine regimen. For patients receiving FOLFOX, treatment was given every 2 weeks with the intention of delivering twelve cycles to patients assigned 24 weeks of therapy. For patients receiving CAPOX or single- agent capecitabine, treatment was given every 3 weeks with an intention of delivering eight cycles to patients assigned 24 weeks of therapy.
For patients treated with sequential adjuvant chemotherapy plus CIK cell immunotherapy, the CIK cells transfusions were started 4 weeks after last chemotherapy. In general, patients would receive at least 4 cycles of CIK cell infusion with 1-week intervals between each cycle, and then another 4 cycles of treatment would be given at an interval of two weeks.
No significant induction of toxicity was observed in the patients who received CIK cell treatment. Across all processes of CIK cell immunotherapy in the CIK group, only 10 patients experienced adverse events, including 6 cases of self- limiting fever, 1 case of transient hypertension, 1 case of pruritus, and 2 cases of fatigue. All the adverse events were grade 1 or 2 and some of the patients recovered by symptomatic treatment. There were no immediate adverse reactions to the CIK cells treatment.
The median follow-up period for all patients was 54.5 months (range, 6.5–129.5 months). By the end of follow-up, 19.7% (24/122) of the patients died. The 1-, 3-, and 5-year OS rates for the whole study population after postoperative adjuvant chemotherapy were 98.3%, 90.2%, and 80.3%, respectively; while the 1-, 3-, and 5-year DFS rate for these patients were 91.7%, 65.7%, and 58.8%, respectively.
In the CIK group the 1-, 2-, 3-, 4-, and 5-year disease-free survival (DFS) rates were 98.3%, 85.8%, 80.2%, 73.6%, and 70.7%, respectively, and 85.5%, 61.0%, 52.4%, 48.3%, and 48.3%, in the control group.
In the CIK group, the 1-, 2-, 3-, 4-, and 5-year overall survival (OS) rates were 98.3%, 98.3%, 96.5%, 92.0%, and 88.7%, respectively and 98.4%, 93.4%, 84.2%, 75.0%, and 72.4%, respectively, in the control group.
In conclusion, these data indicate that sequential adjuvant CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, particularly for patients with high- risk T4 stage and insufficient chemotherapy duration.