Feasibility study of DCs/CIKs combined with thoracic radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer

Cancer cytotherapy is a novel therapeutic approach with great potential [22–24]. Since the report of the first DCs-based cancer vaccine clinical trial in 1995 [25], a lot of trials have been designed and conducted [26, 27]. In 2010, Food and Drug Administration (FDA) approved the first DCs-based vaccine Provenge for the treatment of advanced prostate cancer [23, 28]. Additionally, the cytotoxic and regulatory anti-tumor effects of CIKs are also attractive and promising. The combination of DCs with CIKs is a viable adoptive cytotherapy with a strong anti-tumor effect [29, 30]. It was shown that irradiation enhanced MHC I expression, and changed the tumor microenvironment to boost greater infiltration of immune-effector cells [31–33]. Tumor cells killed by irradiation released tumor antigens which were presented by ectopic DCs [10]. Both preclinical and clinical researches proved that radiotherapy combined with cytotherapy elicited greater anti-tumor response [34, 35].

As for the clinical outcomes of our study, a longer mPFS was observed in treatment group than in control group (330 days vs 233 days, P??0.05), and ORR was higher in treatment group (47.6 % vs 24.6 %, P??0.05). Although there was no significant difference in DCR and mOS between the two groups (P??0.05), the positive results in mPFS and ORR were still encouraging. Thus, patients treated with DCs/CIKs combined with TRT had a better clinical benefit. In the present study, we started DCs/CIKs cytotherapy from the 6^th fraction of TRT to release enough tumor antigens. Our results validate the hypothesis that tumor antigens released by TRT could enhance tumor-specific killing via ectopic DCs/CIKs infusion.

For safety analysis, during the combination therapy of DCs/CIKs and TRT, a majority of side effects were mild, tolerant and similar to TRT alone. No new safety signals were identified, and no treatment-related deaths occurred. In addition, we found a significant PS increase after TRT in control group (P??0.05). Nevertheless, there was a minor PS increase in treatment group (P??0.05). It suggests that combined cytotherapy improves the PS for advanced patients receiving TRT. Thus, DCs/CIKs in combination with TRT shows a good safety profile.

Cancer patients often suffer from immune deficiency, including a decrease in CD4⁺/CD8⁺ T cell ratio, especially during a long period of systemic chemotherapy [36]. In the present study, we found that there was a tendency of a decrease in CD4⁺/CD8⁺ T cell ratio after TRT in control group (P?=?0.08) instead of in treatment group (Table 2). Thus, a reasonable explanation could be that radical TRT with conventional fractionation causes immune suppression in control group, and DCs/CIKs cytotherapy partially rescues immune suppression induced by TRT in treatment group.

Meanwhile, the current study detected other cytokines, such as IL-2 and IFN-? in peripheral blood, which were supposed to play critical roles in specific immunological effects and promoting innate and adaptive immune responses [37]. The serum levels of IL-2 and IFN-? did not change significantly after TRT in both groups (P??0.05). Since the immune response is very complex in DC/CIK combined with TRT, further research is needed to reveal cytokine activity in the future.

Given that irradiation-mediated immune responses alter the tumor micro-environment, more and more researches have explored that local radiation combined with CTLA-4 blockade [38] or PD-L1 blockade [39] could promote anti-tumor immunity. Our results also suggest that the combination of cytotherapy with TRT is a novel feasible application. It shows better clinical benefit, a good tolerance, minor PS change, and promotes the immunity to some extent. However, further studies are needed with larger sample sizes. In addition, due to the lack of randomization and thus possible bias (e.g. more wealth, better education, better supportive care in treatment group), activity needs to be further evaluated in a properly designed randomized trial. Standardized treatment schedule and detailed mechanism of DCs/CIKs combined with TRT should be elucidated in the ongoing research.