Cytokine-induced killer (ClK) cells:from basic research to clinical translation

The accumulation of basic researches and clinical studies related to cytokine-induced killer(CIK) cells has confirmed their safety and feasibility in treating malignant diseases.This review summarizes the available published literature related to the biological characteristics and clinical applications of CIK cells in recent years.A number of clinical trials with CIK cells have been implemented during the progressive phases of cancer,presenting potential widespread applications of CIK cells for the future.Furthermore,this review briefly compares clinical applications of CIK cells with those of other adoptive immunotherapeutic cells.However,at present,there are no uniform criteria or large-scale preparations of CIK cells.The overall clinical response is difficult to evaluate because of the use of autologous CIK cells.Based on these observations,several suggestions regarding uniform criteria and universal sources for CIK cell preparations and the use of CIK cells either combined with chemotherapy or alone as a primary strategy are briefly proposed in this review.Large-scale,controlled,grouped,and multi-center clinical trials on CIK cell-based immunotherapy should be conducted under strict supervision.These interventions might help to improve future clinical applications and increase the clinical curative effects of CIK cells for a broad range of malignancies in the future.

Intraperitoneal perfusion of cytokine-induced killer cells with local hyperthermia for advanced hepatocellular carcinoma

AIM:To study the effect and tolerance of intraperitoneal perfusion of cytokine-induced killer(CIK) cells in combination with local radio frequency(RF) hyperthermia in patients with advanced primary hepatocellular carcinoma(HCC).METHODS:Patients with advanced primary HCC were included in this study.CIK cells were perfused intraperitoneal twice a week,using 3.2 × 10 9 to 3.6 × 10 9 cells each session.Local RF hyperthermia was performed 2 h after intraperitoneal perfusion.Following an interval of one month,the next course of treatment was administered.Patients received treatment until disease progression.Tumor size,immune indices(CD3 +,CD4 +,CD3 + CD8 +,CD3 + CD56 +),alpha-fetoprotein(AFP) level,abdominal circumference and adverse events were recorded.Time to progression and overall survival(OS) were calculated.RESULTS:From June 2010 to July 2011,31 patients diagnosed with advanced primary HCC received intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia in our study.Patients received an average of 4.2 ± 0.6 treatment courses(range,1-8 courses).Patients were followed up for 8.3 ± 0.7 mo(range,2-12 mo).Following combination treatment,CD4 +,CD3 + CD8 + and CD3 + CD56 + cells increased from 35.78% ± 3.51%,24.61% ± 4.19% and 5.94% ± 0.87% to 45.83% ± 2.48%(P = 0.016),39.67% ± 3.38%(P = 0.008) and 10.72% ± 0.67%(P = 0.001),respectively.AFP decreased from 167.67 ± 22.44 to 99.89 ± 22.05 ng/mL(P = 0.001) and abdominal circumference decreased from 97.50 ± 3.45 cm to 87.17 ± 4.40 cm(P = 0.002).The disease control rate was 67.7%.The most common adverse events were low fever and slight abdominal erubescence,which resolved without treatment.The median time to progression was 6.1 mo.The 3-,6-and 9-mo and 1-year survival rates were 93.5%,77.4%,41.9% and 17.4%,respectively.The median OS was 8.5 mo.CONCLUSION:Intraperitoneal perfusion of CIK cells in combination with local RF hyperthermia is safe,can efficiently improve immunological status,and may prolong survival in HCC patients.

Immunotherapy with dendritic cells and cytokine-induced killer cells for hepatocellular carcinoma: A meta-analysis

BACKGROUND Hepatocellular carcinoma(HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells(DCs) and cytokine-induced killer cells(CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored.AIM To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs,combined with different conventional treatments of HCC.METHODS We performed a literature search on PubMed and Web of Science up to February15, 2019. Long-term efficacy(overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis.RESULTS A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio(RR) = 1.07;95%confidence interval(CI): 1.01-1.13, P = 0.02], 1 year(RR = 1.12;95%CI: 1.07-1.17, P< 0.00001), 3 years(RR = 1.23;95%CI: 1.15-1.31, P < 0.00001) and 5 years(RR =1.26;95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo(RR = 0.50;95%CI: 0.36-0.69, P < 0.0001) and 1 year(RR = 0.82;95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe,feasible treatment.CONCLUSION Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients’ prognosis by increasing overall survival and reducing cancer recurrence.

Effect of anti-asthma Chinese medicine Chuankezhi on the anti-tumor activity of cytokine-induced killer cells

Chuankezhi(CKZ),a new Chinese medicine,plays an important role in immunoregulation.Cytokineinduced killer(CIK)cells have been commonly used for immunotherapy in recent years.In this study,we aimed to investigate the immunoregulatory effect of CKZ on CIK cells.Peripheral blood monocytes were isolated from healthy donors,and CIK cells were generated by culturing monocytes with interferon-gamma(IFN-γ)and interleukin 2.Different concentrations of CKZ were added on day 2.After incubation for 14days in culture,the antitumor effects of CIK cells were measured by cytotoxicity assay.Flow cytometry was used to explore the effect of CKZ on CIK cell immunophenotype,intracellular cytokine production,and apoptosis.The effect of CKZ on the antitumor activity of CIK cells in nude mice was also investigated.CKZ increased the percentage of CD3+CD56+CIK cells but did not significantly change the percentage of CD4+,CD8+,or CD4+CD25+CIK cells.CKZ-conditioned CIK cells showed a greater ability to kill tumor cells,as well as a higher frequency of IFN-γand TNF-αproduction,compared with the CIK cells in the control group.CKZ also suppressed the apoptosis of CIK cells in vitro.Furthermore,CKZ combined with CIK cells had a stronger suppressive effect on tumor growth in vivo than the CIK,CKZ,or normal saline control groups.Our results indicate that CKZ enhances the antitumor activity of CIK cells and is a potential medicine for tumor immunotherapy.

Adjuvant treatment for triple-negative breast cancer: a retrospective study of immunotherapy with autologous cytokine-induced killer cells in 294 patients

Objective: To examine the efficacy and safety of a sequential combination of chemotherapy and autologous cytokine-induced killer(CIK) cell treatment in triple-negative breast cancer(TNBC) patients.Methods: A total of 294 post-surgery TNBC patients participated in the research from January 1, 2009 to January 1, 2015. After adjuvant chemotherapy, autologous CIK cells were introduced in 147 cases(CIK group), while adjuvant chemotherapy alone was used to treat the remaining 147 cases(control group). The major endpoints of the investigation were the disease-free survival(DFS) and overall survival(OS). Additionally, the side effects of the treatment were evaluated.Results: In the CIK group, the DFS and OS intervals of the patients were significantly longer than those of the control group(DFS:P = 0.047;OS: P = 0.007). The multivariate analysis demonstrated that the TNM(tumor-node-metastasis) stage and adjuvant CIK treatment were independent prognostic factors for both DFS [hazard ratio(HR)= 0.520, 95% confidence interval(CI):0.271-0.998, P = 0.049;HR = 1.449, 95% CI:1.118-1.877, P = 0.005, respectively] and OS(HR=0.414, 95% CI:0.190-0.903, P = 0.027;HR= 1.581, 95% CI:1.204-2.077, P = 0.001, respectively) in patients with TNBC. Additionally, longer DFS and OS intervals were associated with increased number of CIK treatment cycles(DFS: P = 0.020;OS: P = 0.040). The majority of the patients who benefitted from CIK cell therapy were relatively early-stage TNBC patients.Conclusion: Chemotherapy in combination with adjuvant CIK could be used to lower the relapse and metastasis rate, thus effectively extending the survival time of TNBC patients, especially those at early stages.

Hepatocellular carcinoma-specific immunotherapy with synthesized α1,3-galactosyl epitope-ulsed dendritic cells and cytokine-induced killer cells

AIM： To evaluate the safety and clinical efficacy of a new immunotherapy using both α-Gal epitope-pulsed dendritic cells （DCs） and cytokine-induced killer cells. METHODS： Freshly collected hepatocellular carcinoma （HCC） tumor tissues were incubated with a mixture of neuraminidase and recombinant αl,3-galactosyltrans- ferase （αI,3GT） to synthesize α-Gal epitopes on car- bohydrate chains of the glycoproteins of tumor mem- branes. The subsequent incubation of the processed membranes in the presence of human natural anti-Gal IgG resulted in the effective phagocytosis to the tumor membrane by DCs. Eighteen patients aged 38-78 years with stage 111 primary HCC were randomly chosen for the study; 9 patients served as controls, and 9 patients were enrolled in the study group.RESULTS： The evaluation demonstrated that the pro- cedure was safe; no serious side effects or autoimmune diseases were observed. The therapy significantly pro- longed the survival of treated patients as compared with the controls （17.1 ± 2.01 mo vs 10.1 ±4.5 mo, P = 0.00121）. After treatment, all patients in the study group had positive delayed hypersensitivity and robust systemic cytotoxicity in response to tumor lysate as measured by interferon-y-expression in peripheral blood mononuclear cells using enzyme-linked immunosorbent spot assay. They also displayed increased numbers of CD8-, CD45RO- and CD56-positive cells in the peripheral blood and decreased α-fetoprotein level in the se- rum. CONCLUSION： This new tumor-specific immunotherapy is safe, effective and has a great potential for the treat- ment of tumors.

A clinical trial of cytokine induced killer cells treating patients with malignant tumor after radiochemotherapy

Objective: Our study investigated the immunity changes and life quality changes after the treatment of cytokine induced killer (CIK) cells for patients with malignant tumor after radiochemotherapy, and explored the therapeutic effects of CIK cells on these patients. Methods: Thirty-one patients with malignant tumor after radiochemotherapy were treated with CIK cells. Before and after CIK cells being transfused back, the immunity indexes of the peripheral blood of these cases were detected and the changes of life quality of these cases were compared. Results: After radiochemotherapy, the percentage of CD3+, CD4+ cells declined, the percentage of CD8+ cells rose; the ratio of CD4+/CD8+ declined, and the percentage of CD16+, CD56+ cells declined. As all the above indexes compared with that of normal people, the difference was significant (P < 0.05). After CIK cells therapy, the above indexes improved (P < 0.05). Life quality improved significantly after CIK cells therapy (P < 0.05). Conclusion: Radiochemotherapy can inhibit the immunity in patients with malignant tumor. CIK cells therapy is safe and effective. It may improve the recent immunity and life quality of the patients, which suggesting that it may be an alternative maintenance treatment for patients with malignant tumor after radiochemotherapy.

Effects of Various Factors on Proliferation Capacity and Cytotoxicity of Induced CIK of Patients with Tumor In Vitro

Objective： To evaluate effects of different factors on proliferation capacity and cytotoxicity of induced cytokine induced killer （CIK） cells in vitro, so as to provide experimental basis for cell therapy of CIK in tumor. Methods： Cytometry and MTT assay were used in detecting proliferation capacity and cytotoxicity of CIK. Results： The proliferation capacity and cytotoxicity of CIK in vitro were stronger in the group of low age and serum free medium than in the group of advanced age or serum medium. And the proliferation of CIK in vitro increased with time during a certain period of incubation. Furthermore, CIK had equal cytotoxicity to various tumor cells. Conclusion： Various factors might influence the proliferation capacity and cytotoxicity of CIK of tumor patients in vitro.

Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients

AIM: To analyze the correlation between cytokineinduced killer (CIK) cells adoptive immunotherapy and cancer-related death in gastric cancer patients. METHODS: One hundred and fifty-six gastric cancer patients after operation at the Third Affiliated Hospital of Soochow University were enrolled in this study. Their clinical data including demographic characteristics, operation time, tumor size, pathological type and staging, tumor metastasis, outcome of chemotherapy or CIK cells adoptive immunotherapy, survival time or time of death were collected with a standard structured questionnaire. Kaplan-Meier method was used to estimate the median survival time, and the 2- and 5- year survival rates. Hazard risk (HR) and 95% confidence interval (95% CI) of CIK cells adoptive immunotherapy for gastric cancer were calculated using the two-stage time-dependent covariates Cox model. RESULTS: The survival time of gastric cancer patients was longer after CIK cells adoptive immunotherapy than after chemotherapy (χ 2 = 10.907, P = 0.001). The median survival time of gastric cancer patients was also longer after CIK cells adoptive immunotherapy than after chemotherapy (49 mo vs 27 mo, P < 0.05). The 2- and 5-year survival rates of gastric cancer patients were significantly higher after CIK cells adoptive immunotherapy than after chemotherapy (73.5% vs 52.6%, 40.4% vs 23.9%, P < 0.05). A significant difference was observed in the survival curve for patients who received CIK cells adoptive immunotherapy (0, 1-10, 11-25, and over 25 frequencies) (χ 2 = 14.534, P = 0.002). The frequencies of CIK cells adoptive immunotherapy were significantly related with the decreasing risk of death in gastric cancer patients after adjustment for sex and age of the patients, tumor stage and relapse (HR = 0.54, 95% CI: 0.36-0.80) when the first stage Cox model was used to define the subjects who remained alive beyond 36 mo as survivors. However, no correlation was observed between the frequencies of death in CIK cells adoptive immunotherapy and the risk of gastric cancer patients (HR = 1.09, 95% CI: 0.63-0.89) when the second stage Cox model was used to define the subjects who survived for more than 36 mo as survivors. CONCLUSION: The survival time of the gastric cancer patients treated with chemotherapy combined with CIK cells adoptive immunotherapy is significantly longer than that of the patients treated with chemotherapy alone and increasing the frequency of CIK cells adoptive immunotherapy seems to benefit patients more.

A randomized controlled trial of postoperative tumor lysate-pulsed dendritic cells and cytokine-induced killer cells immunotherapy in patients with localized and locally advanced renal cell carcinoma

Background It remains a challenge to inhibit the local recurrence or distant metastasis of localized or locally advanced renal cell carcinoma （RCC） after surgical resection. We investigated the feasibility, safety and efficacy of immunotherapy using autologous tumor lysate （TL）-pulsed dendritic cells （DCs） and cytokine-induced killer （CIK） cells in patients with localized or locally advanced RCC.

Antitumour activities of cytokine-induced killer cells and dendritic cells in vitro and in vivo

Solid tumour cells show a resistance to immunological effector cells in vitro. The resistance may be one reason why these tumours withstand immunotherapeutic approaches in humans. Dendritic cells （DC） play an important role in the immune response to tumour associated antigens in humans. DC in the periphery capture and process antigens, express lymphocyte costimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune response.

Clinical study of co-treatment with DC-CIK cells for advanced solid carcinomas

Objective： The aim of this study was to observe the therapeutic effect of cytokine induced killer （CIK） cells in combination with dendritic cells （DCs） on advanced solid carcinoma patients. Methods： Isolated peripheral blood mononuclear cells （PBMCs） from 110 advanced solid tumor patients. Added granulocyte-macrophage colony-stimulating factor （GM-CSF）, tumor necrosis factor-a （TNF-a） and interleukin-4 （IL-4） to adherent cells to induce DCs, and sensitized DCs with antigens of autologous tumor cells or extrinsic tumor cell lines. Cultured suspending cells with interferon-y （IFN-y）, interleukin-2 （IL-2） and CD3 monoclonal antibody （CD3 McAb） to prepare CIK cells, then co-cultured with DCs. After analyzing the phenotype and checking tumor markers and immune function, the autologous CIK cells and DCs were transfused into the cancer patients. Results： Forty-two patients with measurable nidus, 2 achieved complete remission （CR）, 9 partial remission （PR） and 15 stable disease （SD）, while 37 patients with immeasurable nidus, 25 had efficient response. The tumor markers and immune function both improved significantly compared with those before treatment. Conclusion： DCs and CIK cells combinational treatment is safe and effective on advanced solid carcinoma and provide a new and efficacious immunity therapeutic methods for the cancer patients.

Infusions of recipient-derived cytokine-induced killer cells of donor origin eradicated residual disease in a relapsed leukemia patient after allo-hematopoietic stem cell transplantation

A female patient diagnosed with acute myelocytic leukemia M5a （AML-M5a） relapsed 986 days after her allogeneic peripheral blood stem cell transplantation （alIo-PBSCT） from an unrelated male donor with matched human leukocyte antigen （HLA）. Three re-induction chemotherapies were administered, and partial remission was achieved. The patient was given repetitive infusion of cytokine-induced killer （CIK） cells expanded from recipient peripheral mononuclear cells of full donor chimerism due to loss of contact of quondam donor for donor lymphocyte infusion （DLI） and rejection of second transplantation. The patient achieved complete cytogenetical remission. This strategy might overcome the obstacle of donor unavailability and present an appealing new therapeutic alternative to donor-recruited adoptive immunotherapy for relapsed disease at post-transplantation.

Research on the biological activity and anti-tumor effect against lymphoma cells of DC-CIK cells

Objective： To investigate the proliferation capabilities, immunophenotype changes, level of secreted cytokines and activities against lymphoma cells under the condition that cytokine-induced killer （CIK） cells co-cultured with dendritic cells （DC） in vitro. Methods： DC and CIK cells were induced from peripheral blood mononuclear cells of healthy volunteers. They were co-cultured meanwhile CIK cells were cultured alone as controls. Increased number of cells were counted by tapan-blue staining, killing activities were detected by MTT assay, immunophenotype changes were analyzed by flow cytometry, the IL-12 and INF-y levels of the cultured supernatants were detected by ELISA kits. Results： The proliferation capabilities of DC-CIK cells were significantly higher than that of CIK cells （P 〈 0.05）. Under the same condition, the ratio of double positive cells such as CD3^＋ CD8^＋, CD3^＋ CD56^＋ in CIK cells was significantly enhanced by co-cultured with DC cells （P 〈 0.05）. The level of IL-12 and INF-y secreted in supernatants was increased noticeably by co-cultured DC-CIK cells on day 3 compared to CIK cells which were cultured alone （P 〈 0.01 and P 〈 0.05）. Within the effector-target ratio range between 5：1 to 40：1, the activities against lymphoma cells of DC-CIK cells were much higher than that of CIK cells （P 〈 0.05）, and this effect was showed a positive correlation with the effector-target ratio. Conclusion： The proliferation capabilities, the level of secreted cytokines and the activities against lymphoma cells of DC-CIK cells were significantly higher than those of CIK cells. The research might provides theoretical and experimental basis for clinical immunotherapy of DC-CIK cells.

Immune Cell SR对冻存PBMNC诱导培养CIK的效果研究

目的:探讨Immune Cell SR(血清替代物)在冻存复苏后PBMNC诱导CIK细胞培养过程中的效果,为免疫细胞的工业化生产提供一个新的策略。方法:提取健康志愿者外周血单个核细胞,经短期冻存后复苏并诱导培养CIK细胞,采用台盼蓝拒染法检测细胞活率,流式细胞术分析免疫细胞亚群,并用Calcein-AM/PI双染法检测其杀伤活性;结果:冻存后PBMNC中在对照组未能正常扩增,与新鲜组相比,2%SR组细胞扩增倍数较低,且差异显著(P<0.05),5%SR组、10%AP组与新鲜组比较,差异均无统计学意义(P>0.05);冻存前后CD3^+、CD3^+CD8^+、CD3^+ CD56^+细胞亚群比较均无明显差异(P>0.05);细胞培养后,各组间CD3^+、CD3^+CD4^+、CD3^+CD8+、CD3^+CD56^+、CD3^-CD56^+亚群及体外杀伤活性比较均无明显差异(P>0.05);结论:采用5%SR替代自体血浆可以很好地诱导冻存的PBMNC培养CIK细胞,且无外源性蛋白,安全可靠,为免疫细胞冻存技术在细胞治疗中的应用提供条件。

肿瘤特异性个体化多靶点DC-CIK治疗原发性肝癌的临床疗效与安全性

目的:评价肿瘤特异性个体化多靶点自体树突状细胞-细胞因子诱导的杀伤细胞(DC-CIK)治疗中晚期原发性肝癌(PLC)的临床疗效与安全性。方法:回顾性分析2019年10月至2021年9月东部战区总医院肿瘤科行DC-CIK治疗的119例中晚期PLC患者的临床资料。根据患者治疗时负载DC的抗原不同将患者分为两组,一组使用患者自体特异性多肽负载为pDC-CIK组(n=21),另一组使用肿瘤细胞裂解物负载为DC-CIK组(n=98)。分析两组患者治疗前后的临床资料,包括治疗效果和治疗前后甲胎蛋白、淋巴细胞亚群、细胞因子(IL-2、IFN-γ、TNF-α和IL-6)水平的变化、不良反应发生情况等。结果:119例PLC患者治疗后,pDC-CIK和DC-CIK组两组客观缓解率均为0%,疾病控制率分别为76.1%和72.4%(P>0.05)。治疗后两组患者CD3^(+)、CD4^(+)、CD8^(+)、CD56^(+)、CD25^(+)和CD4^(+)/CD8^(+)T淋巴细胞水平无统计学差异(均P>0.05),治疗后两组患者外周血IL-2、IFN-γ、TNF-α和IL-6的平均水平均显著高于治疗前(均P<0.001),两组患者治疗后外周血IL-2、TNF-α和IL-6的平均水平无显著差异(均P>0.05),而pDC-CIK组IFN-γ水平显著高于DC-CIK组(P<0.05)。pDC-CIK组患者平均生存时间为59.84个月,高于DC-CIK组的46.54个月,但无统计学差异(P=0.16)。治疗过程中无严重不良反应的发生。结论:PLC患者行肿瘤特异性个体化多靶点DC-CIK治疗是安全有效的,并能改善免疫功能,相较肿瘤细胞裂解物负载DC-CIK有进一步获益趋势。

DC联合CIK治疗156例局部晚期或晚期胰腺癌的临床疗效

目的:评价DC联合CIK治疗156例局部晚期或晚期胰腺癌的临床疗效。方法:回顾性分析2011年11月至2023年12月在东部战区总医院肿瘤科进行自体DC联合CIK治疗的156例局部晚期或晚期胰腺癌患者的临床资料。统计患者治疗前后血清肿瘤标志物、淋巴细胞亚群、细胞因子水平的变化、不良反应发生情况以及近期疗效、远期疗效。结果:156例胰腺癌患者中有92例治疗前后均进行了影像学检查,结果显示CR 0例,PR 0例,SD 42例,PD 50例,ORR为0%,DCR为45.65%。外周血CA199水平在治疗前后无显著差异,但有19例患者治疗后下降超过20%。治疗前后患者外周血CD3^(+)、CD4^(+)、CD8^(+)、CD56^(+)、CD25^(+)淋巴细胞亚群水平和CD4+/CD8+T细胞比值无统计学差异(P>0.05),治疗后患者外周血IL-2、IFN-γ的平均水平均显著高于治疗前(P<0.05),TNF-α和IL-6无显著差异(P>0.05)。156例患者mOS为8.53个月,1年累积生存率为39%,2年累积生存率为15%,3年累积生存率为15%,没有随访到5年的生存数据。治疗过程中未发生严重不良反应。结论:DC-CIK能使局部晚期和晚期胰腺癌患者产生抗肿瘤免疫反应,取得一定的客观疗效并可能使患者生存期延长。

DC-CIK不同输注方式治疗原发性肝癌的临床疗效和预后

目的:探讨不同途径输注DC-CIK对中晚期原发性肝癌(PLC)的治疗效果和预后价值。方法:回顾性分析2018年10月至2021年9月间东部战区总医院肿瘤科DC-CIK治疗的69例中晚期PLC患者的临床资料,根据DC-CIK治疗时采用的输注方式不同将患者分为肝动脉灌注(HAI)组(n=29)和静脉输注(Ⅳ)组(n=40),比较两组患者的临床疗效、外周血T淋巴细胞亚群(CD3^(+)、CD4^(+)、CD8^(+)T和CD4^(+)/CD8^(+)T细胞比值),以及细胞因子(IL-2、IL-6、IFN-γ和TNF-α)、甲胎蛋白(AFP)的变化、总生存期(OS)和不良反应发生情况。结果:69例PLC患者经DC-CIK治疗后,HAI组患者的客观缓解率(ORR)为0%,疾病控制率(DCR)为75.8%;Ⅳ组患者的ORR为0%,DCR为72.5%(P>0.05)。两组患者治疗前后T淋巴细胞亚群指标变化差异无统计学意义(均P>0.05),两组患者治疗后外周血IL-2、IL-6、IFN-γ和TNF-α的平均水平均显著高于治疗前(均P<0.01),两组间比较无显著差异(P>0.05);HAI组患者平均OS为48.17个月,Ⅳ组OS为39.65个月,两组间比较无显著差异(P>0.05)。治疗过程中无严重不良反应发生。结论:自体DC-CIK HAI治疗PLC安全有效,较Ⅳ治疗有提升临床获益的趋势,值得临床借鉴。

TACE联合PD-1抑制剂与DC-CIK治疗晚期肝细胞肝癌的临床研究

目的分析经肝动脉化疗栓塞术(TACE)联合程序性死亡受体1(PD-1)抑制剂与树突状细胞(DC)-细胞因子诱导的杀伤细胞(CIK)治疗晚期肝细胞肝癌的临床效果。方法前瞻性选择2019年5月至2022年3月扬州大学医学院海安临床学院收治的92例晚期肝细胞肝癌患者,依照随机数字表法将其分为研究组(n=46)及对照组(n=46)。对照组接受TACE联合DC-CIK治疗,研究组在对照组的基础上联合PD-1抑制剂治疗,2组均治疗3个月。对比2组疾病控制率(DCR),成纤维细胞生长因子(FGF)、癌胚抗原(CEA)、甲胎蛋白(AFP)、CD3^(+)、CD4^(+)、CD8^(+)水平,癌症患者生活质量核心量表(QLQ-C30)评分,以及不良反应情况。结果研究组DCR(71.74%)比对照组(50.00%)高(P<0.05)。治疗后,2组FGF、CEA、AFP水平均降低(P<0.05),且研究组更低(P<0.05)。治疗后,2组患者CD3^(+)、CD4^(+)均升高(P<0.05),且研究组更高(P<0.05);CD8^(+)均降低(P<0.05),且研究组更低(P<0.05)。治疗后,2组QLQ-C30评分均升高(P<0.05),且研究组更高(P<0.05)。2组Ⅰ~Ⅳ级甲状腺功能减退、高血压、手足综合征、皮疹发生率比较差异无统计学意义(P>0.05)。结论TACE联合PD-1抑制剂与DC-CIK治疗晚期肝细胞肝癌有效,可降低FGF、CEA、AFP水平,提高免疫功能,改善生存质量,且安全可靠。

DC-CIK细胞的生物学活性及体外抗白血病作用的研究(英文)

本研究探讨树突状细胞(DC)对细胞因子诱导的杀伤细胞(CIK)增殖能力、免疫表型、分泌细胞因子水平及抗白血病细胞的作用。健康人外周血单个核细胞诱导DC和CIK,将DC与CIK共培养,以CIK细胞单独培养为对照。用台盼蓝活细胞计数计算细胞扩增倍数,MTT法测定杀伤活性,流式细胞术分析免疫表型,ELISA双抗体夹心法测定干扰素-γ(IFN-γ)、白介素-12(IL-12)的水平。结果表明:DC-CIK细胞增殖能力明显高于CIK细胞(p<0.05);DC、CIK细胞共培养后,CD3+CD8+、CD3+CD56+细胞比率较相同条件下CIK细胞组显著增多(p<0.05);共培养3天,DC-CIK细胞上清液中IL-12、IFN-γ水平均比CIK细胞单独培养的水平高(p<0.01,p<0.05);在5∶1-40∶1的效靶比范围内,DC-CIK细胞对白血病细胞的杀伤率显著高于CIK细胞(p<0.05),且杀伤率与效靶比呈正相关。结论:DC增加CIK细胞的增殖能力和抗白血病活性,有可能作为一种临床有效的抗白血病免疫治疗手段。