| BackgroundLung cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality. Although much progress has been made in treating lung cancer over the last 10 years, the 5-year overall survival is still less than 20%. Patients at the late stage often have a worse prognosis. Immunotherapy with autologous cells is an important means of tumor treatment for its low toxicity, high efficiency, and no immune rejection. Dendritic cells with cytokine-induced killer cells(DCs/CIKs) are a viable adoptive cellular immunotherapy with strong anti-tumor effect. It has a better effect on small tumor burden and some strong immune-derived tumor types such as renal cell carcinoma, melanoma, et al. However, there still lacks a systematic study on its application in advanced lung cancer patients and on how to combine with chemotherapy and radiotherapy. Meanwhile, we all know that resistance of cancer cells to chemotherapy and radiation is the main cause of failure in treating advanced lung cancer. Therefore, the transformation research which explores the molecule resistant to chemotherapy and radiation as a novel antitumor immune antigen has important clinical significance. Our previous studies showed that Livin as a member of inhibitor of apoptosis(IAP) played an important role in drug resistance and radiation resistance. When the expression of Livin was blocked, the sensitivity to chemotherapy and radiation was improved in lung cancer cells. Therefore, we infer that Livin peptide-loaded DCs/CIKs combined with chemotherapy or radiotherapy may promote the sensitivity to treatment and improve clinical efficacy. ObjectiveThis trial aimed to study the efficacy of synchronous DCs/CIKs transfusion combined with chemotherapy and radiotherapy in advanced non-small cell lung cancer(NSCLC), and to explore whether Livin peptide could be a new tumor antigen to load DCs/CIKs, and then activate the immunity.Methods1. NSCLC patients, admitted from September 2012 to September 2014, who met the inclusive criteria, were enrolled in the study. Those NSCLC patients who received DCs/CIKs combined with chemotherapy were assigned to the treatment group, and the patients treated with only chemotherapy to the control group. Comparison was made on the clinical effects, qualities of life and T cell subsets between the two groups. The primary endpoint was progression-free survival(PFS), and secondary endpoints were objective response rate(ORR), median overall survival(mOS) and disease control rate(DCR).2. NSCLC patients, admitted from January 2012 to June 2014, who met the inclusive criteria, were taken as research subjects. All the patients were divided into two groups: treatment group and control group. Patients received DCs/CIKs combined with thoracic radiotherapy(TRT) in the treatment group, but received TRT alone in the control group. Comparison was made on the clinical effects, qualities of life and immune parameters between the two groups. The primary endpoint was PFS, and secondary endpoints were ORR, DCR, mOS and so on. The immune parameters are exploratory in this study.3. HLA A2+ NSCLC patients, admitted from July 2014 to December 2014, who met the inclusive criteria, were taken as research subjects. Those patients who received DCs/CIKs loaded with Livin peptide combined with chemotherapy or radiotherapy were taken as Livin group. From the treatment group which used MUC-1 as tumor peptide-loaded DCs in the second and third parts of this paper, we chose patients with similar general information such as gender, age and diagnosis as MUC-1 group. Comparison was made on the clinical effects, qualities of life and immune index between the two groups. Results1. Each group had 40 patients, with the baseline level of general information consistent. The DCR in treatment group was higher than that in control group(90% vs. 72.5%, P<0.05). The median PFS in treatment group was also longer than that in control group(275 days vs. 212 days, P<0.05). However, there was no statistically significant difference in ORR and mOS between the two groups(P>0.05). The karnofsky performance status(KPS) was better in treatment group than in control group(P<0.05). No severe adverse effects were observed in both groups. The difference in T cell subsets between the two groups had no statistic significance(P >0.05).2. In total, 83 cases were enrolled with 21 cases in the treatment group 62 cases in the control group and. The gender, age, clinical stage and the total dose of radiotherapy between the two groups had no significant difference(P>0.05). Analysis of the raw data showed that ORR in the treatment and control groups was 55% and 30.7%, respectively(P<0.05). The median PFS was 309 days and 180 days in the treatment group and control group, respectively(P<0.05). However, there was no significant difference in DCR and mOS between the two groups(P>0.05). No Grade III/IV adverse events were observed in the two groups. Main toxic effects included Grade I/II fever, anaphylaxis, radiation pneumonia and fatigue with complete recovery. The T cell subsets had no statistically significant difference between the two groups(P >0.05).3. Each group had 16 patients. There was no significant difference in ORR and DCR between the two groups(P>0.05). Until now, the PFS and OS in Livin group can not be calculated. The T cell subsets in the two groups were similar in trend. Therefore, there was no significant difference in the T cell subsets between the two groups(P>0.05). The tetramer of Livin group showed a positive result. The value of tetramer before treatment is higher than that after treatment(2.15 ± 2.98 vs. 3.94 ± 3.43, P<0.05). The difference of Livin antibody in patients’ peripheral blood before and after treatment had no statistical significance(P>0.05). Conclusions1. DCs/CIKs combined with chemotherapy can enhance the DCR, prolong the mPFS, and improve the life qualities of patients with advanced NSCLC.2. The reported data suggest that DCs/CIKs combined with TRT can effectively enhance the ORR, prolong the mPFS, and improve the life qualities of patients with advanced NSCLC. And this kind of therapy may partially reverse the immunosuppression caused by TRT.3. Livin peptide-loaded DCs/CIKs combined with chemotherapy or radiotherapy has a similar clinical efficacy and T cell subset to MUC-1-loaded DCs/CIKs. Livin peptide-loaded DCs/CIKs can activate the T cell immunity and stimulate the specific cytotoxic lymphocyte(CTL) response.4. DCs/CIKs therapy plays an important role in the comprehensive therapy. DCs/CIKs combined with chemotherapy or radiotherapy will improve the efficacy. |
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