Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients

Abstract

Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-γ, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3-5 times in 2 weeks as one cycle with a total of 188.3 ± 79.8 × 10(6) DCs and 58.8 ± 22.3 × 10(8) CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-γ and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients.

Figure 1. Following up of DC/CIK therapy and control patients.

The prognoses of patients were recorded up to 98 months after the dates of surgery in both treatment and control groups.

Figure 2. The maturity of dendritic cells (A,C) and CIK cells (B, D) was determined by measuring the percentage of cells expressing DR and CD11c, CD83 (DC markers), and CD3/CD8, CD3/CD56 (CIK cell markers) in blood samples collected from treated gastric cancer patients.

Figure 3. The maturity of dendritic cells (A,C) and CIK cells (B, D) was determined by measuring the percentage of cells expressing DR and CD11c, CD83 (DC markers), and CD3/CD8, CD3/CD56 (CIK cell markers) in blood samples collected from treated colorectal cancer patients.

Figure 4. Serum levels of INF-γ, IL-2, IL-6, IL-10 and IL-12 measured from gastric (A) and colorectal (B) cancer patients before and after a 2-week cycle of treatment with DC/CIK cells (A, n = 14, B, n = 13, *p<0.05, **p<0.01).

Figure 5

(A) The overall survival rate of the gastric cancer patients. The 1-, 3-, and 5-year survival rates in the treatment group was 93%, 82%, and 66%, compared with the control 79%, 42%, and 34% respectively. B) Disease free survival rate of the gastric cancer patients. The 1-, 3-, and 5-year survival rates in the treatment groups (red box marked) were 86%, 73%, and 66%, compared with the control 79%, 42%, and 34% respectively. The cumulative survival curves in A and B were analyzed by the Kaplan-Meier method.

Figure 6

(A) The overall survival rate of the colorectal cancer patients. The 1-, 3-, and 5-year survival rates in the treatment group were 100%, 77%, and 75%, compared with the control 85%, 23%, and 15% respectively. (B) Disease free survival of the gastric cancer patients. The 1-, 3-, and 5-year survival rates in the treatment group were 100%, 69%, and 66%, compared with the control 69%, 15%, and 8% respectively. The cumulative survival curves in A and B were analyzed by the Kaplan-Meier method.