Maintenance Therapy With Autologous Cytokine-induced Killer Cells in Patients With Advanced Epithelial Ovarian Cancer After First-line Treatment Jun Liu,*wzy Hui Li,*wz Shui Cao,wz8 Xinwei Zhang,wz8 Jinpu Yu,*wz Jing Qi,wz8 Xiumei An,wz8 Wenwen Yu,*wz Xiubao Ren,*wz8 and Xishan Hao*wz8 Summary: Cytokine-induced killer (CIK) cells have shown cytolytic ability against ovarian cancer cells in vitro and in vivo. This study was aimed to evaluate the clinical efficacy of maintenance therapy of CIK cells in patients with advanced epithelial ovarian cancer after first-line treatment. A paired study was performed in patients with stages IIB–IV epithelial ovarian cancer after cytoreductive surgery followed by 6–8 courses of carboplatin/paclitaxel chemo- therapy. A total of 92 patients who achieved complete remission after first-line treatment were enrolled in this study. Forty-six patients in the treatment group received CIK cells transfusion monthly, whereas the other 46 patients in the control group received observation with follow-up. Progression-free survival (PFS), overall survival (OS), and toxicity were evaluated. Our results showed that median PFS was 37.7 months in the treatment group and 22.2 months in the control group (P = 0.004). However, although median OS in the treatment group (61.5 mo) was longer than that in the control group (55.9 mo), there was no significant difference (P = 0.289). The subgroup analysis revealed that the survival advantage of PFS from immunotherapy was independent of the extent of debulking surgery and pathologic stage. After 2 courses of CIK cells transfusion, the proportion of CD4 + CD25 + CD127  regular T cells in the peripheral blood sig- nificantly decreased (P = 0.006). No grades III and IV adverse reaction were found during CIK cells infusion. Maintenance ther- apy with CIK cells improved the PFS in patients with advanced ovarian cancer after first-line treatment with slight side effects. However, the benefits with respect to OS are still pending. Key Words: advanced epithelial ovarian cancer, cytokine-induced killer cells, maintenance therapy, adoptive immunotherapy, prognosis (J Immunother 2014;37:115–122) E pithelial ovarian cancer is the most common form of ovarian tumor and is one of the main causes of death from gynecologic tumor worldwide, especially in developed countries. Given that its symptoms are vague, which can be misdiagnosed as other benign lesions, >70% of patients have been diagnosed at advanced stages 1 and <40% can be cured. 2 Maximal cytoreductive surgery has been recommended as the standard initial treatment for patients with advanced ovarian cancer. 3 Many clinical trials have shown that survival negatively correlates with the amount of residual tumor after surgery. 4–6 Thus, the objective of the surgery is to remove all tumors as possible; an optimal cytoreductive surgery is defined as no residual tumor >1 cm in diameter. Given that surgery alone cannot cure advanced ovarian cancer, adjuvant chemotherapy is required to treat residual cancer cells that cannot be removed by surgery or too small to be seen. To date, platinum combined with taxane remains the standard regime. Compared with the standard 2-drug chemotherapy, additional cytotoxic drugs cannot improve either pro- gression-free survival (PFS) or overall survival (OS) but increase the toxic effects. 7–9 Unfortunately, even for patients who have achieved complete clinical remission (defined as no objective evidence of disease, ie, negative physical examination, negative CA125 levels, and negative computed tomography with < 1 cm lymph nodes) after primary surgery and chemotherapy, the majority will ultimately relapse and succumb to the disease in months to years. Given that maintenance therapy improves the prog- nosis in several cancers, many efforts have been made to improve the survival of patients with advanced epithelial ovarian cancer. 10 However, the results are far more than satisfactory. To date, only prolonged administration of paclitaxel and bevacizumab (a VEGF antibody) has dem- onstrated prolongation of PFS; data on OS remain pend- ing. 11–13 Despite of the improvement in survival, prolonged administration of paclitaxel or bevacizumab is not an optimal selection for maintenance therapy because of toxic side effects. Thus, finding a practice with minimal side effects is needed. In recent years, adoptive cellular therapy has become an important treatment for malignant tumors, and several kinds of immune cells have shown efficacy to ovarian can- cer. 14–17 Among these cells, cytokine-induced killer (CIK) cells, a newly reported group of heterogenous lymphocytes, are the most promising treatment. Compared with tradi- tional immune cells, such as lymphokine activated killer (LAK) cells and tumor-infiltrating lymphocyte (TIL) cells, CIK cells can be proliferated rapidly in vitro and have enhanced antitumor activity and broader spectrum of tar- geted tumors. 18 The CD3 and CD56 double positive T lymphocytes, known as NK-like T lymphocytes, have been proven to be the main effectors of CIK cells. 19 CIK cells recognize target cells without depending on TCR and MHC molecules, 19,20 and can kill the residual tumor cells that may be resistant to chemotherapy. 21,22 CIK cells improve the prognosis in several solid cancers, such as gastric Received for publication September 21, 2013; accepted December 17, 2013. From the Departments of *Immunology; 8Biotherapy, Tianjin Medical University Cancer Institute and Hospital; wNational Clinical Research Center of Cancer; zKey Laboratory of Cancer Immu- nology and Biotherapy, Tianjin; and yDepartment of Chemo- therapy, The Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China. Reprints: Xishan Hao, Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Huanhu Xi Road, Hexi District, Tianjin 300060, China (e-mail: rwziyi@yahoo.com). Copyright r 2014 by Lippincott Williams & Wilkins CLINICAL STUDY J Immunother  Volume 37, Number 2, February/March 2014 www.immunotherapy-journal.com | 115