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AIM: To explore the effects of dendritic cells (DC) and cytokine-induced killer cells (CIK) carrying melanoma-associated antigen gene A3 (MAGE-A3) on endometrial cancer tumor stem cells and malignant progression. METHODS: Human peripheral blood was collected to separate mono-nuclear cells, and DC and CIK cells were induced by cytokines, respectively. DCs were incubated with MAGE-A3 and then co-cultured with CIK, and the phenotypes of DC-CIK and MAGE-A3-DC-CIK were detected by flow cytometry; The CD133
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Objective:To investigate the effect of immunotherapy with dendritic cells and cytokine-induced killer cells combined with chemotherapy on apoptosis-related genes and immune function in patients with middle- and advanced-stage non-small cell lung cancer.Methods:A total of 100 patients with middle- and advanced-stage non-small cell lung cancer who received treatment in Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, China from February 2018 to May 2019 were included in this study. They were randomly divided into control and observation groups ( n = 50/group). The two groups were given chemotherapy with pemetrexed and cisplatin. The observation group was given immunotherapy with dendritic cells and cytokine-induced killer cells based on chemotherapy with pemetrexed and cisplatin. Changes in apoptosis-related genes [primary autosomal recessive microcephaly gene (MCPH1), ataxia-telangiectasia mutated (ATM), ataxia telangiectasia mutated and Rad3 related (ATR), transcription factor 21 (TCF21)] and immune function were monitored. Clinical efficacy of immunotherapy with dendritic cells and cytokine-induced killer cells combined with chemotherapy with pemetrexed and cisplatin in the treatment middle-and advanced-stage non-small cell lung cancer was assessed. Results:After treatment, expression of MCPH1, ATM, ATR and TCF21 in the observation group was 301.11 ± 41.12, 239.98 ± 30.15, 270.01 ± 36.01, 270.01 ± 34.02, respectively, which was significantly higher than that in the control group [101.32 ± 15.32, 103.00 ± 13.97, 101.12 ± 14.90, 100.20 ± 14.99, t = 32.194, 29.149, 30.644, 32.299, all P < 0.001]. The proportion of the number of Th1-positive cells in the number of CD +4 T cells in the observation group was significantly higher than that in the control group [(29.00 ± 3.41)% vs. (22.61 ± 3.22)%, t = 9.634, P < 0.001]. The proportion of the number of Th17-,Th2 and CD +4CD +25Treg-positive cells in the number of CD +4 T cells in the observation group were (0.89 ± 0.10)%, (12.01 ± 1.36)%, (11.02 ± 1.92)%, respectively, which were significantly lower than those in the control group [(1.70 ± 0.20)%, (17.61 ± 2.20)%, (18.70 ± 2.40%)%, t = 25.614, 15.310, 17.670, all P < 0.001]. Total effective rate in the observation group was significantly higher than that in the control group [52.0% (26/50) vs. 30.0% (15/50), χ2 = 5.002, P < 0.05]. Conclusion:Immunotherapy with dendritic cells and cytokine-induced killer cells combined with chemotherapy with pemetrexed and cisplatin can induce apoptosis and regulate immune function. The combined therapy exhibits better clinical efficacy in the treatment of non-small cell lung than chemotherapy alone.
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@#Objective To investigate the influence of programmed cell death protein-1 (PD-1) monoclonal antibody on the anti-lung cancer effect of cytokine-induced killer cells (CIK) which were programmed in vitro. Methods Peripheral blood mononuclear cells from 20 patients (8 males and 12 females with an average age of 56.45±5.89 years ranging from 42 to 65 years) diagnosed with advanced lung cancer from January to May 2019 at the Department of Oncology of Dalian Central Hospital were collected and induced to amplify into CIK cells in vitro. PD-1 monoclonal antibody combined with CIK cell culture group, individual cell culture group and PD-1 monoclonal antibody group were set up to detect the cell killing activity of CIK cells against lung cancer under different effective target ratio conditions, and the ratio of perforin and granzyme positive expression in PD-1 monoclonal antibody combined CIK cell culture group and individual CIK cell culture group was detected by flow cytometry. ELISA method was used to detect the interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) cytokine secretion levels in the two groups. Results The killing effect of CIK cells on A549 lung cancer cells increased with the increase of effective target ratio by CCK8, and PD-1 monoclonal antibody increased the killing effect of CIK cells on A549 lung cancer cells under different effective target ratio, E∶T=5∶1 (28.5%±1.9% vs. 20.3%±1.8%), 10∶1 (40.6%±2.4% vs. 31.7%±2.1%), 20∶1 (57.4%±3.5% vs. 44.7%±3.8%), 40∶1 (74.1%±8.3% vs. 60.8%±5.3%). The killing effect of PD-1 monoclonal antibody combined with CIK cells and CIK cells alone on A549 lung cancer cells was statistically different (P<0.05). The killing effect of cells in both groups on lung cancer A549 cells was stronger than that of the PD-1 monoclonal antibody group (P<0.01). The results of flow cytometry showed that PD-1 monoclonal antibody increased the positive ratio of perforin and granzyme release in CIK cells, and the positive ratios of perforin release (46.7%±3.5%% vs. 35.1%±2.2%) and granzyme release (34.6%±3.8% vs. 25.7%±3.3%) in PD-1 monoclonal antibody combination with CIK cells group and CIK cells group were statistically different (P<0.05). Similarly, the secretion levels of IL-2, TNF-α, and IFN-γ cytokines were also increased in the PD-1 monoclonal antibody combined with CIK cells group compared with the CIK group (5 409.0±168.8 pg/mL vs. 4 300.0±132.3 pg/mL, 252.7±16.7 pg/mL vs. 172.5±8.6 pg/mL, 327.2±23.5 pg/mL vs. 209.7±16.0 pg/mL, P<0.05). Conclusion PD-1 monoclonal antibody can promote the release of tumoricidal substances in CIK cells and improve the killing effect of CIK cells on lung cancer A549 cells. It is speculated that the infusion of PD-1 monoclonal antibody before CIK cell adoption in lung cancer patients may be more beneficial to the treatment of disease. PD-1 monoclonal antibody combined with CIK cell therapy is promising as a new type of lung cancer immunotherapy.
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At present, coronavirus disease 2019 (COVID-19) caused by 2019 novel coronavirus (2019-nCoV) infection has spread rapidly in China and more than 70 countries around the world and thus become a public health event of international concern. In addition to fever and respiratory symptoms, varying degrees of liver injury is also observed after 2019-nCoV infection. This article reviews the clinical features, pathology, pathogenic mechanism, and therapeutic strategies of liver injury associated with COVID-19, hoping to provide a reference for clinical decision-making on the prevention and treatment of COVID-19.
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PURPOSE: The treatment of triple-negative breast cancer (TNBC) remains challenging, due to the absence of estrogen, progesterone, and human epidermal growth factor receptors. This study was designed to evaluate the efficiency and safety of cytokine-induced killer (CIK) cell immunotherapy, following regular chemotherapy, for patients with TNBC. METHODS: A total of 340 patients with postmastectomy TNBC, from January 1, 2010 to June 30, 2014, were included in this retrospective study. Seventy-seven patients received CIK cell immunotherapy, following regular chemotherapy (arm 1), and 263 patients received regular chemotherapy alone (arm 2). The primary aim was overall survival (OS) and disease-free survival (DFS), and the treatment responses and adverse events were also evaluated. RESULTS: The 5-year DFS and OS rates in arm 1 were 77.9% and 94.3%, compared with 69.8% and 85.6% in arm 2, respectively (p=0.159 and p=0.035, respectively). This clearly shows that there was no statistical difference in the 5-year DFS between the two groups. Multivariate analyses of arm 1 indicated that a Karnofsky performance score (KPS) ≥90 and stage I/IIA disease were significantly associated with a prolonged DFS period (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.09–0.74; p=0.012; and HR 0.21; 95% CI, 0.06–0.82; p=0.024, respectively), but a KPS ≥90 and stage I/IIA disease were not independent prognostic factors for OS. Toxicity was mild in patients who received the CIK therapy. CONCLUSION: The data suggested that CIK cell immunotherapy improved the efficiency of regular chemotherapy in patients with TNBC, and the side effects of CIK cell immunotherapy were mild.
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Humans , Arm , Cytokine-Induced Killer Cells , Disease-Free Survival , Drug Therapy , Estrogens , Immunotherapy , Multivariate Analysis , Progesterone , Prognosis , ErbB Receptors , Retrospective Studies , Triple Negative Breast NeoplasmsABSTRACT
The treatment outcomes of relapsed or refractory neuroblastoma have been unsatisfactory till date. We reported two cases of adoptive immunotherapy using cytokine-induced killer (CIK) cells against relapsed or refractory neuroblastoma. CIK cell production was attempted in three patients, out of which two patients exhibited adequate levels of CIK cell production. Two patients completed full term of CIK cell infusions (weekly for 6 weeks and then biweekly for 8 wk) without serious adverse events. The progression-free survivals for the two patients were 1.9 and 4.1 months. Their overall survivals were 16.7 and 28.7 months. Although the efficacy was unclear, CIK cell infusion combined with other treatment strategies may have prolonged overall survival in refractory neuroblastoma patients. Further studies are needed to determine the exact role of CIK cell-based immunotherapy in relapsed or refractory neuroblastoma patients.
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Humans , Cytokine-Induced Killer Cells , Disease-Free Survival , Immunotherapy , Immunotherapy, Adoptive , NeuroblastomaABSTRACT
Objective To evaluate the clinical efficacy and safety of dendritic cell (DC) combined with cytokine induced killer cell (CIK) in treatment of advanced non-small-cell lung carcinoma (NSCLC).Methods Peripheral blood mononuclear cells (PBMCs) were collected from 39 patients with advanced NSCLC,who were admitted to Affiliated Hospital of Academy of Military Medical Sciences,and cultured in vitro to produce DCs and CIK cells which,after phenotypic characterization by flow cytometry,were then returned to the patients.DCs were given subcutaneously on day 7,9,11 and 13 and CIK cells were given intravenously on day 11 and 13.The clinical efficacy and safety were analyzed before and after DCs-CIK cells treatment.Results Following up displayed that,in 39 patients with advanced NSCLC and eligible for evaluation,the objective response rate (ORR) was 30.8％ including 2 cases of completed response (CR) and 10 cases of partial response (PR),the disease control rate (DCR) was 69.2％.No significant difference existed pre-and post-treatment on the proportion of T cell subsets including CD3+CD4+CD8ˉ,CD3+CD4ˉ CD8+,CD3+CD19ˉ,CD3ˉCD 19+,CD3 CD16+CD56+,CD3+CD16+D56+,CD3+HLA-DRˉ,CD3+HLA-DR+ and CD3+CD28+CD8+ (P＞0.05),while obvious changes were found in Th1,Th2 and CD3+CD4+CD25+ T cells (Treg cells) (P＜0.05).No serious adverse events were observed.Conclusion Combined DCs-CIK cells immunotherapy provides a safe and effective treatment for patients with advanced NSCLC,improves the quality of life and relieves the probability of metastasis and recurrence.
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Objective:To obtain a high specificity and high affinity anti-human PD-L1 monoclonal antibody which can be used for clinical diagnosis and block PD-L1 and PD-1 binding.Methods:BALB/c mice were immunized with recombinant PD-L1 protein.The positive cell clones stably secreting anti-human PD-L1 monoclonal antibody were obtained by classical hybridoma cell fusion technique.The specificity,affinity,subtype and other characteristics of the antibody were identified by ELISA.Immunofluorescence and indirect immunofluorescence were used to detect the tumor cells.Antibody blocking activity was confirmed by tumor killing test.Results:Two cell strains stably secreting monoclonal antibodies against human PD-LI were screened out.Abl and Ab2 had high titer and affinity.The antibody titers were 1:2.56×106 and 1:3×105,and the affinity was 1.5×109 L/mol and 2.5×10s L/mol respectively.There was no cross reaction between these two antibodies and PD-L2.Immunoblotting,indirect immunofluorescence confirmed that the antibody can be used to the diagnosis.Experiment showed that PD-L1 antibodies can increases tumor-killing activity of CIK cells.Conclusion:Two hybridoma cell lines capable of stably secreting highly specific and high affinity anti-human PD-L1 monoclonal antibody are obtained.They can specifically bind to PD-L1 molecules on tumor cells and can be used to the diagnosis of tumor phenotype and prognosis.Antibody blocking function can be applied to combined CIK cell immunotherapy.
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Objective:To investigate the anti-tumor effects of cytokine-induced kill cells(CIK)methods combined with chemotherapeuticdrug Gemcitabine against Cholangiocarcinoma cancer cell lines QBC-939.Methods:Peripheral blood mononuclear cells(PBMC) of healthy people were stimulated by different cytokines,and were induced into CIK cells.CIK cells were cultured for 14 days as effector cells.The phenotype of CIK cells were analyzed by flow cytometer.QBC939 cells were cultured with the CIK cells at different effector-target ratio or various concentrations of Gemcitabine for 24 and 48 hours.The antitumor effects were measured by CCK8 methods.The expression of Bax was detected by using Western blot.Results:The CD3+CD4+,CD3+CD8+,CD3+HLA-DR+,CD3+CD56+,CD4+CD25+ double positive cel1 was up to 10.89％,60.27％,71.82％,9.03％ and 4.01％ after 14 days' cultivation.The killing effect of CIK and Gemcitabine increased with the increase of effector-target ratio and drug concentration or the extension of time.The killing effect of combination of CIK and Gemcitabine was obviously higher than that of each single factor.The protein levels detected hints of CIK cells and gemcitabine can up-regulated the expression of Bax,and the joint action of both is more significant.Conclusions:CIK cells have strong anti-tumor effect against QBC939 cells by inducing apoptosis of QBC939 cells,and it can enhance the anti-tumor effects of Gemcitabine against QBC939 cells when CIK and Gemcitabine are combined together.
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Objective To evaluate the clinical efficacy of dendritic cells-cytokine induced killer cells combined with surgical treatment for primary liver cancer.Methods Totally 78 patients with primary liver cancer were randomly divided into experiment group (n =30) and control group (n =48).The patients in experiment group received hcpatectomy combined with dendritic cells-cytokine induced killer cell treatment while those in control group were given hepatectomy treatment.The median time to recurrence,progression-free survival,survival and quality of life were evaluated.Observed side effects of cell therapy in experiment group.Results Experiment group received a total of dendritic cells-cytokine induced killer cell treatment 78,an average of 2.6 times per person.Fever occured in 8 patients who received dendritic cells-cytokine induced killer cell treatment.After one cycle of immune therapy,the KPS score of 20 cases was improved,8 cases were stable and and 2 case was worsen in the experiment group.The KPS score of 10 cases were improved,32 cases were stable and and 6 cases were worsen in the control group,and the difference is statistically significant (P ＜ 0.05).The progression-free survival rates for 1,2 and 3 years in the experiment group were 73.3％,40.0％,23.3％ and 68.7％,27.0％,14.5％ in the control groups,respectively.The progression-free survival rates in the experiment group were improved compared to the control group and the difference is statistically significant (P ＜ 0.05).The median time of recurrence in the experiment group were (16.9 ± 2.6) months and (13.5 ± 2.9) months in the control group,respectively (P ＜ 0.05).The 1-2-3-years survival rates in the experiment group were 85.0％,50.0％,35.0％ and 85.0％,40.0％,23.3％ in the control group respectively.There was no statistically significant difference between these two groups (P ＞ 0.05).Conclusions Dendritic cellscytokine induced killer cells combined with surgical treatment on primary liver cancer is safe and effective,it can improve quality of life,and delay the recurrence time after surgery.But not improve long-term survival.
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Objective To evaluate cytotoxic effects of cytokine-induced killer cells (CIK cells) transfected with the interleukin-2 (IL-2) gene on malignant melanoma cells.Methods Mouse spleen cells were extracted,lymphocyte cells were separated,and CIK cells were prepared from these lymphocyte cells.PEGF-N1 plasmids containing IL-2 gene (PEGF-NI-IL-2) were transfected into CIK cells.Fluorescence microscopy was used to observe transfection products,and reverse transcriptase-polymerase chain reaction (RT-PCR) was conducted to determine the IL-2 mRNA expression.Then,effector cells such as CIK cells and IL-2-transfected CIK cells were separately co-cultured with target cells (B16 melanoma cells) at effector-target ratios of 10∶ 1,20∶1 and 40∶1,then 4-hour lactate dehydrogenase release assay was performed to evaluate cytotoxic effects of the two kinds of CIK cells on B 16 cells.After effector cells were cocultured with target cells at the effector-target ratio of 40∶1 for 48 hours,enzyme-linked immunosorbent assay (ELISA) was conducted to detect levels of IL-2,interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the supernatant of the two kinds of CIK cells.Finally,mouse models of melanoma were established,and a total of 28 melanoma-bearing mice were divided into 4 groups to be peritumorally injected with 0.2 ml sodium chloride physiological solution (control group),100 IU IL-2 solution (IL-2 group),CIK cell suspension at a cell density of 1 × 106 cells per milliliter (CIK group) and IL-2-transfected CIK cell suspension at a cell density of 1 × 106 cells per milliliter (IL-2-transfected CIK group) respectively.Tumor morphology,tumor inhibition rate and cell apoptosis rate were used to evaluate tumor growth in the above groups.If data were normally distributed,t-test was used for comparing means between two groups,and analysis of variance and least significant difference (LSD)-t test were used for comparing means among multiple groups.Results Fluorescence microscopy and RT-PCR both showed that IL-2 was successfully transfected into CIK cells.The cytotoxic effect of IL-2-transfected CIK cells on B16 cells was strongest at the effector-target ratio of 40:1.Levels of IL-2,IFN-γ and TNF-α were also significantly higher in the supernatant of IL-2-transfected CIK cells [(1107.26 ± 6.49) pg/ml,(50.01 ± 3.35) pg/ml,(39.86 ± 3.25) pg/ml] than those in that of CIK cells [(51.09 ± 3.85) pg/ml,(32.71 ± 2.43) pg/ml,(30.11 ± 3.08) pg/ml,t =442.60,14.93,6.89,all P ＜ 0.01].Animal experiments showed that the tumor volume obviously increased in the control group (P ＜ 0.05),but significantly decreased in the IL-2 group,CIK group and IL-2-transfected CIK group (all P ＜ 0.001) after intervention compared with those before intervention.Furthermore,the tumor volume in the IL-2-transfected CIK group was significantly less than that in the other three groups (all P ＜ 0.01),but no significant difference was observed between the IL-2 group and CIK group (P ＞ 0.05).In addition,the apoptosis rate was significantly higher in the IL-2 group,CIK group,and IL-2-transfeeted CIK group than that in the control group (all P ＜ 0.01).The apoptosis rate and tumor inhibition rate were significantly higher in the IL-2-transfected CIK group than those in the IL-2 group and CIK group (all P ＜ 0.01),but insignificantly different between the IL-2 group and CIK group (P ＞ 0.05).Conclusion IL-2-transfected CIK cells had stronger killing effects on malignant melanoma.
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Objective To describe the phenotype of NK cells in Bama miniature pigs, and establish an efficient activation and culture method for porcine cytokine-induced killer ( CIK) cells in vitro. Methods The porcine peripheral blood mononuclear cells ( PBMCs) were isolated by Percoll gradient centrifugation, and the phenotype of NK cells was test-ed by detecting the CD2 + /CD8 + /CD3 - cell compartment. To establish an efficient activation and culture method for por-cine CIK cells, we optimized the culture conditions to improve the CIK activation efficiency. Results Using the optimized induction culture conditions, the ratio of CIK ( CD2 + /CD8 + /CD3 -) cells was up to 43. 63% at the fifth day, approxi-mately 5. 59 times increased compared with the initially separated PBMCs. Cell proliferation experiments showed that three obvious fluorescence peaks were observed on the fifth day. The results indicated that the induced CIK cells underwent three times cell division, in theory, about increased 8-fold compared with the initial separation of PBMCs. Furthermore, the qRT-PCR result of the surface markers of porcine NK cells also showed a similar variation tendency as the flow cytometry results. Conclusions Our findings demonstrate the successful establishment of an efficient activation and culture method for porcine CIK cells in vitro.
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Objective:To observe the efficacy of cytokine-induced killer (CIK) cells on patients with advanced lung cancer. Methods:A total of 90 patients with advanced lung cancer were identified from January 2011 to December 2013. CIK therapy was given to 41 pa-tients in the observation group, whereas the other 49 patients in the control group received the best support treatments without che-motherapy or radiotherapy within one month of inclusion. Following up was conducted for the patients in the two groups, and KPS scores, median survival, and adverse reactions compared. Results:The KPS score in the observation group was higher than that of the control group after treatment (P=0.034). The median survival period of the observation group was eight months, which was one month longer than that of the control group (P=0.044). Major adverse reactions included fever, joint pain, and insomnia, which were recorded 51.22%, 36.58%, and 29.27%of occurrence, respectively. Conclusion:CIK cell therapy improved the quality of life and pro-longed the survival of advanced lung cancer patients with tolerable adverse reactions.
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Objective To evaluate effects of autologous cytokine-induced killer cell (CIK) transfusion on the survival and hepatitics B virus (HBV) reactivation after radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE).Methods A retrospective analysis was conducted on 185 patients with hepatocellular carcinoma treated from Mar 2007 to Oct 2013.Patients were divided into study group (RFA,TACE,CIK) of 98 cases and control group (RFA,TACE) of 87 cases.According to tumor size,numbers and vascular invasion,patients were stratified into 4 subgroups:the high and the low risk group respectively with tumor ≤ 5 cm and ＞ 5 cm.Results The 1-,3-,5-year survival rate between study and control group were not significantly different:75.5％ (74/98),57.1％ (56/98),20.4％ (20/98) vs.71.2％ (62/87),54.0％ (47/87),21.8％ (19/87) (P ＞ 0.05).Only the study group's 1-,3-,5-year survival rate of high risk patients with tumor ≤ 5 cm were higher than the control group:75.0％ (21/28),53.6％ (15/28),35.7 ％ (10/28) vs.61.9％ (13/21),42.9％ (9/21),23.5％ (5/21) (P ＜ 0.05).The incidence of HBV reactivation was lower in dunantiviral patients who received CIK therapy than those who had 6.0％ (3/50) vs.23.5％ (12/61) (P ＜ 0.05).Conclusion Postoperative adjuvant CIK therapy with tumor≤5cm after RFA combined with TACE was beneficial to the survival of high risk patients and decreased the risk of HBV reactivation.
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Objective To study the killing effect of cytokine-induced killer cells (CIK cells) on human lung adenocarcinoma cell line (A549) and the lung adenocarcinoma' s radiation resistant cell line (A549RR).Methods Peripheral blood mononuclear cells (PBMC) of healthy volunteers were stimulated by different cytokines,and were induced into killer activity CIK cells.The phenotype of CIK cells were analyzed by flow cytometer.A549 and A549RR cell lines were cultured separately with the CIK cells.The absorbance value (A) of the cells was measured by CCK8,and the killing rates of all cells which were cultured for 24 and 48 hours with the CIK were calculated.Results The rate of CD3+ CD56+ cell was 45.8 ％ after culture for 14 d.The killing rates of CIK cells to lung adenocarcinoma A549 cells and its radiation resistant cells A549RR were increased with the rise of the ratio of effective cells to target (5∶1-40∶1) and the increasing of culturing time (all P ＜ 0.001).The killing effect of CIK to A549 and A549RR cells had no obvious difference in the same culturing time and the same ratio of effective cells to target(all P ＞ 0.05).Conclusion CIK cells have strong anti-tumor effect against lung adenocarcinoma and its radiation resistant cells with high clinical application value.
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Objective To explore the clinical efficacy and immunological effects of photodynamic therapy combined with cell therapies for advanced esophageal cancer. Methods Ninety patients with advanced esophageal cancer were collected and divided into three groups by a non-randomized controlled trial according to treatment intention. Group A (30 patients) received photodynamic therapy (PDT) alone; group B (30 patients), PDT received PDT plus cytokine-induced killer (CIK) cell therapies; and group C (30 patients) received CIK cell therapy aloen. In all the patients, the efficacy was assessed, the quality of life was documented, the immune function was detected, and the 6-month and 1-year death tolls were counted. Results The total clinical effectiveness rate was much higher in groups B and A than in group C (90.0% and 86.7% vs. 63.3%, P 0.05). The rate of an increase in quality of life was significantly higher in group B than in groups A and C (86.7%vs. 60.0%and 33.3%, P 0.05), while the 1-year survival rate was much higher in group B than in groups A and C (73.9% vs. 55.6% and 29.4%, P < 0.05). Conclusion Photodynamic therapy combined with cell therapies has a synergistic effect, and it enhances the overall immune function, significantly improves the quality of life and prolongs the survival period, showing a better clinical prospect.
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Colorectal cancer is the third leading cancer worldwide. Although incidence and mortality of colorectal cancer are gradually decreasing in the US, patients with metastatic colorectal cancer have poor prognosis with an estimated 5-year survival rate of less than 10%. Over the past decade, advances in combination chemotherapy regimens for colorectal cancer have led to significant improvement in progression-free and overall survival. However, patients with metastatic disease gain little clinical benefit from conventional therapy, which is associated with grade 3~4 toxicity with negative effects on quality of life. In previous clinical studies, cell-based immunotherapy using dendritic cell vaccines and sentinel lymph node T cell therapy showed promising therapeutic results for metastatic colorectal cancer. In our preclinical and previous clinical studies, cytokine-induced killer (CIK) cells treatment for colorectal cancer showed favorable responses without toxicities. Here, we review current treatment options for colorectal cancer and summarize available clinical studies utilizing cell-based immunotherapy. Based on these studies, we recommend the use CIK cell therapy as a promising therapeutic strategy for patients with metastatic colorectal cancer.
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Humans , Cell- and Tissue-Based Therapy , Colorectal Neoplasms , Cytokine-Induced Killer Cells , Dendritic Cells , Drug Therapy, Combination , Immunotherapy , Incidence , Lymph Nodes , Mortality , Prognosis , Quality of Life , Survival Rate , VaccinesABSTRACT
Objective To evaluate the clinical efficacy, the immune function and follow-up observation of autologous dendritic cells (DCs) combined with cytokine-induced killer (CIK) cells in the treatment of metastatic renal cell carcinoma. Methods Peripheral blood mononuclear cells (PBMCs) were collected from 27 patients with metastatic renal cell carcinoma, and cultured in vitro to produce DCs and CIK cells. After sterility test, phenotypic character ization by flow cytometry and cell count, the produced DCs and CIK cells were then returned to the patient. DCs were given subcutaneously on day 7, 9, 11 and 13 respectively, after PBMCs collection, and CIK cells were given intravenously on day 11 and 13 respectively. This treatment regimen was repeated at a 3 months interval until the disease progresses. Clinical outcomes and immune function were recorded during the treatment period. Results After DCs-CIK cells treatment, clinical efficacy showed an objective response rate (ORR) of 37%, a disease control rate (DCR) of 85% and 2 years overall survival rate of 81.5%. There were no significant changes of T cell subsets including CD3+CD4+CD8–, CD3+CD4–CD8+, CD3+CD19–, CD3–CD19+, CD3–CD16+CD56+, CD3+CD16+CD56+, CD3+HLA-DR–, CD3+HLA-DR+, CD3+CD28+CD8+ and Th2 cells except CD3+CD4+CD25+ T cells (Treg cells) and Th1 in peripheral blood between pre- and post-treatment. No serious adverse events were observed. Conclusion DCs-CIK cells immunotherapy provides a safe and effective treatment approach for patients with metastatic renal cell carcinoma, and may improve the immunosuppression status and enhance the anti-tumor immunity without obvious adverse reaction.
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Objective: To investigate the regulatory role of microRNA-375 (miR-375) in the process of cytokine-induced killer (CIK) cells killing cervical cancer SiHa cells, and to determine the target genes of miR-375 and their molecular mechanisms. Methods: The peripheral blood mononuclear cells (PBMC) were isolated from the healthy people, and cultured in vitro with different cytokines for 14 d to induce into CIK cells. CIK cells were stimulated as the effector cells. The phenotype of CIK cells was analyzed by FCM, and the killing effect of CIK cells on cervical cancer SiHa cells was detected by CCK-8 method. Real-time fluorescent quantitative PCR was used to detect the change of miR-375 expression level in SiHa cells after co-culture with CIK cells. CCK-8 method was used to detect the proliferation of SiHa cells transfected with miR-375 mimic and the inhibitory effect of CIK cells on proliferation of SiHa cells transfected miR-375 inhibitor. The expression of Yes-associated protein (YAP) in SiHa cells transfected with miR-375 inhibitor and co-cultured with CIK cells was detected by immunofluorescence assay and Western blotting, respectively. Results: After co-culture with CIK cells for 24, 48 and 72 h, the growth inhibitory rates of SiHa cells were (22.97±3.54)%, (37.48±3.64)% and (54.32±4.25)%, respectively. The relative expression levels of miR-375 in SiHa cells after co-culture with CIK cells for 24, 48 and 72 h were about 1.39, 1.57 and 2.68 times higher than those before co-culture, respectively. The viability of SiHa cells transfected with miR-375 mimic was significantly decreased (P < 0.001). After co-culture with CIK cells, the suppression effect on the growth of SiHa cells transfected with miR-375 inhibitor was significantly decreased (P < 0.001). YAP protein was expressed abundantly in SiHa cells, and mainly concentrated in cell nucleus. After co-culture with CIK cells, the expression of YAP protein in SiHa cells transfected with miR-375 inhibitor was more significantly up-regulated (P < 0.01). Conclusion: CIK cells can effectively kill cervical cancer SiHa cells. As a tumor-suppressor factor, miR-375 may play an important role in the process of CIK cells killing SiHa cells through down-regulating the expression of YAP gene.
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Objective To investigate the changes of immunologic functions and life qualities after the auto-cytokine induced killer (CIK) cells combined with interleukin-2 (IL-2) being transfused back to the patients with non-small cell lung cancer (NSCLC).Methods Thirty-eight NSCLC patients were enrolled,and 19 patients received not only chemotherapy and radiotherapy but also adoptive immunotherapy with CIK cells combined with IL-2 compared with the other 19 patients who only accepted radiotherapy and chemotherapy.The changes of immunologic functions and life qualities after the CIK cells combined with IL-2 being transfused back to the patients with NSCLC were observed.Immune targets of the treatment group and control group,such as peripheral blood CD3 +,CD4 +,CD8 + T cell percentage,ratio of CD4 +/CD8 + and Th1/Th2,were observed at the end and after 3 month of the radiation and chemotherapy.Results Both of the two groups were neither having obvious adverse reactions.After CIK cells combined with IL-2 treatment,the life qualities of patients improved,such as 18 cases of mental improvement,15 cases of appetite improvement,12 cases of sleep improvement,and 3 cases of fatigue symptoms improvement.The percentage of CD3 +,CD4 + cells in the treatment group increased [(66.39 ± 9.22) ％ vs (42.98 ± 7.23) ％,t =5.45,P =0.00 ; (32.27 ± 3.75) ％ vs (26.38 ±2.51)％,t =5.73,P =0.00],the percentage of CD8 + cells declined [(17.51 ± 1.85)％ vs (20.90 ± 2.31) ％,t =5.21,P =0.00],the rate of CD4 +/CD8 + increased and the rate of Th1/Th2 obversed [(1.86±0.32) vs (1.27±0.19),t=7.13,P=0.00;(1.15±0.48) vs (0.91 ±0.30),t=2.42,P=0.02].There were significant differences between the two groups.Conclusion Adoptive immunotherapy with CIK cells combined with IL-2 is safe in clinical,which can improve the immunologic functions and life qualities of the patients with NSCLC.