Clinical Observation And Research Of The Adoptive Cellular Immunotherapy Combined With Chemotherapy In Biliary Tract Cancer

?Background?Biliary tract cancer is a malignant tumor in bile duct,including intrahepatic cholangiocarcinoma,extrahepatic cholangiocarcinoma,gallbladder carcinoma and ampullar carcinoma.Because of the high degree of malignancy,only about 10% of the patients with which can have an opportunity for radical surgery,treatment for the patients with metastasis is limited,the prognosis is very poor.Otherwise,even if the patients who underwent radical resection,the recurrence rate is also very high.In recent years,the combination of gemcitabine and cisplatin has been recommended as the first-line chemotherapy,but in spite of this,the overall survival time in ABC-02 trial is still not more than one year.Although targeted drugs had been emerged in an endless stream,but results of the clinical research showed that the effect was also not satisfied.Nowerdays,immunotherapy has received great attention since Rosenberg SA first announced the clinical trial results of LAK combined with IL-2 in the treatment of malignant melanoma,and become the fourth treatment pattern juxtaposed with surgery,radiotherapy and chemotherapy.Traditional surgery,radiotherapy and chemotherapy can reduce the tumor burden,but doesn't kill all tumor cells,immunotherapy can mobilize and activate the body's own immune system by man-made factors,enhance the effect of antitumor immune,then control and kill tumor cells.Tumor cellular immunotherapy is the application of biotechnology and biological agents on mononuclear cells from patients with peripheral blood collected in vitro screening,the IL-2,anti-CD3 monoclonal antibody,specific peptide activator induction,activation and amplification,then reinjected to tumor patients,and supplemented by appropriate growth factor,to stimulate the body's own immune system,inspire and enhance the body's own immune function,prompting it to kill tumor cells in vivo or activated immune cells for long-term monitoring tumor metastasis and recurrence.Now the clinical application of immune cells mostly are LAK,TIL,CIK,DC and CTL.The mechanism of adoptive immunotherapy is relatively clear,with prominent clinical safety and can be effectively combined with surgery,radiotherapy and chemotherapy,showed a good prospect in clinical application.This topic is divided into two parts: first part is to observe the clinical efficacy of adoptive cellular immunotherapy combined with chemotherapy and chemotherapy alone in patients with biliary tract cancer and compare the overall survival(OS),progression-free survival(PFS),disease control rate,changes in the quality life,the changes in immune function and adverse reaction between the two groups,and provide a clinical basis for the biological immune treatment of biliary tumor;the second part is to review and summary the current status of immunization in biliary tract cancer.Part ? Clinical observation and research of the adoptive cellular immunotherapycombined with chemotherapy in biliary tract cancer?Objective?To observe and study the clinical efficacy of DC vaccine and adoptive immunotherapy CIK cells combined with chemotherapy in the treatment of biliary tract cancer,then study and compare with the data in literatures reviewed.?Method?Sixty-two patients with biliary tract cancer received DC-CIK combined with chemotherapy(combination grop)in the Biotherapy Department of Easten Hepatobiliary Surgical Hospital from January 2012 to October 2014 were enrolled.First,peripheral blood mononuclear cells(PBMCs)of patients were collected,then chemotherapy was underwent.The PBMCs were amplified and cultured,loading with multiple antigen.Then mature DC were harvested to make vaccine,which was injected by subcutaneous,simultaneously,adoptive immunotherapy CIK cells were transfused by venous.In addition,sixty-two patients(control group)treated with chemotherapy alone were collected.The overall survival,progression-free survival,disease control rate,quality of life changes,lymphocyte subsets in peripheral blood,regulatory T cell level and adverse reactions were observed in the two groups.?Results?The median overall survival and median progression-free survival of the combination group were significantly prolonged than that of the control group(16.3 vs 11.0 months;10.0 vs 7.0 months).The disease control rate of the combination group was higher than the control group(87.1% vs 77.4%).The quality of life in combination group were also improved than before treatment and control group(P < 0.05).Peripheral blood CD3+,CD3+CD4+,CD3+CD8+,CD3+CD56+ proportion and CD4+/CD8+ ratio in combination group were increased significantly compared with the previous,and Treg declined(P<0.05),there were significant differences compared with the control group.The adverse reaction of chemotherapy in combination group was significantly less than that of control group(P<0.05),and the adverse reaction of immunotherapy was rare,mainly was a low-grade fever,most of which do not need special treatment,can be recovered by itself.?Conclusion?Adoptive cellular immunotherapy combined with chemotherapy is an efficient treatment compared to chemotherapy alone in biliary tract cancer,which can significantly prolong overall survival and progression-free survival,promote disease control rate,improve the quality of life,enhance the immune status of the body,and reduce Treg level which is related with the immune tolerance.The adverse reaction is rare and clinical tolerance is good.But there is still lack of reasonable efficacy evaluation system for adoptive cellular immunotherapy,and the evaluation is not the same with traditional operation,radiotherapy and chemotherapy.So even if appeared to be tumor progression in the course of treatment,adoptive immunotherapy can still be continued,and is expected to benefit from it.Part ? Immunotherapeutic approaches in biliary tract carcinoma: Current statusand emerging strategiesFor biliary tract carcinoma(BTC),complete surgical resection of tumor is only feasible in a minority of patients,and the treatment options for patients with unresectable or metastatic disease are limited.Advances in cancer immunology have led to identification of tumor-in ltrating immune cells as indicators of prognosis and response to treatment in BTC.This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors.This includes peptide-and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumor-speci c antigens.Adoptive immunotherapy,which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction,and cytokine-based therapies have been developed in BTC.Clinical studies indicate that this type of therapy is generally well tolerated.Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential.Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC.Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease.Based on the above two points,the main conclusions of this study:Adoptive immunotherapy is an effective treatment for biliary tract caner,which is a supplement to surgery and chemotherapy effectively,and adverse reaction is rare,with good clinical tolerance.