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  • br Conflict of interest br Acknowledgments This research was


    Conflict of interest
    Acknowledgments This research was supported by the Grants from the National Natural Science Foundation of China (No. 31270820 and No. 81230061 to Wei-Dong Han, No. 81402567 to Ya-jing Zhang) and was partially supported by a Grant from the National Basic Science and Development Programme of China (no. 2012CB518103 to Wei-Dong Han).
    Introduction Small cell lung cancer (SCLC) is the most devastative type of human lung malignancies, with two-thirds of these patients presenting with extensive disease. Despite a high initial response rate to first-line chemotherapy, most patients die rapidly from drug-resistant relapse. The median survival for treated patients with extensive stage SCLC (ES-SCLC) is 8–13 months with modern chemotherapy, with 5% surviving to 2 years and only 1% of patients achieving a long-term disease-free survival [1]. Even with more advanced chemotherapeutic agents, the prognosis of this disease remains poor due to low treatment efficacy [2,3]. Maintenance therapy has recently become a treatment paradigm in advanced non-small cell lung cancer (NSCLC) [4]. However, a meta-analysis of published randomized clinical trials [5] showed that both maintenance and consolidation therapy failed to improve the outcomes of SCLC, and in some cases even caused severe side effects or death. Thus, there is no recommendation for maintenance therapy in current SCLC treatment guidelines. Given its high recurrence rate and mortality, new therapeutic strategies are urgently needed to improve the outcome of this disease. Immune escape plays an important role in cancer recurrence and neuraminidase inhibitor [6,7]. With an improved mechanistic understanding of immune response and immune escape, several immunotherapies were investigated for ES-SCLC. Some of them failed, such as the dendritic cell-based p53 vaccine [8]. Some of them were effective, such as phased ipilimumab (an antibody against cytotoxic T-lymphocyte antigen-4 [CTLA-4]) with paclitaxel/carboplatin, pembrolizumab and nivolumab (an antibody against programmed death-1 [PD-1]) for recurrent patients [9–11]. It indicated that immunotherapy combined with chemotherapy might have the potential to improve the prognosis of ES-SCLC. Therefore, increasing attention has been paid to the development of immunotherapy for ES-SCLC patients in recent years. SCLC patients have often been found to have functional deficiency in a variety of immunocytes [12–14], therefore cellular immunotherapy (CIT) with ex vivo-activated and expanded immunocytes may be feasible and effective in SCLC patients. Several immunotherapies to induce cytotoxic T lymphocyte (CTL) for SCLC have been tried. However few of them have lengthened survival, partly due to the complexity of the immune escape in this malignancy. Decreased expression of HLA-class I antigen has been reported in SCLC, which may be one of the mechanisms of SCLC cells to escape CTL attack [15]. Natural killer (NK) and γδT cells are effector cells of innate immunity, and both can exert anti-cancer effects in a non-MHC-restricted manner. Cytokine-induced killer (CIK) cells are ex vivo-activated lymphocytes, and represent a heterogeneous cell population, including CD3+CD56+, which show an NK-like, non-MHC-restricted cytolytic activity against cancer cells. CIT based on one of these cell types has proved to be effective against a variety of cancers [16–18], and NK, γδT and CIK cells demonstrated synergistic cell-killing effects when used in combination both in preclinical and clinical studies [19–21]. SCLC cells were also found to be susceptible to NK or γδT cell-mediated cytotoxicity in preclinical studies [15,22]. In our previous small study, CIT as maintenance therapy with the combination of NK, γδT and CIK cells improved the outcome of SCLC patients, especially in ES-SCLC patients with improved progression free survival (PFS) and overall survival (OS) [23]. We therefore conducted this study with more patients and longer follow-up time to confirm the efficacy and safety of combined NK, γδT, and CIK cells based CIT as maintenance therapy for ES-SCLC patients who responded to first-line therapy.