射頻消融與細胞因子誘導的殺傷細胞協(xié)同抗腫瘤效應的研究
發(fā)布時間：2018-07-29 18:42
【摘要】：射頻消融(Radiofrequency ablation,RFA)是目前廣泛應用于臨床的微創(chuàng)治療手段。其不僅通過物理熱效應直接損毀腫瘤,而且消融使腫瘤抗原暴露,刺激機體產(chǎn)生免疫反應。然而,射頻消融引起的抗腫瘤免疫反應并不足以阻止腫瘤的復發(fā)及轉(zhuǎn)移。細胞因子誘導的殺傷(Cytokine-induced killer,CIK)細胞是外周血單個核細胞在體外經(jīng)有序添加多種細胞因子(IL-2、抗CD3單克隆抗體、IFN-γ等)培養(yǎng)后獲得的一組異質(zhì)性細胞群。其兼有T淋巴細胞的殺瘤活性和自然殺傷細胞樣非組織相容性復合物(MHC)限制性的抗瘤特點。然而,在實體瘤治療方面,CIK細胞治療仍然處于輔助地位,單獨應用往往療效不佳。影響CIK細胞在體內(nèi)發(fā)揮作用的一個重要因素是:效應性免疫細胞能否到達靶器官,實現(xiàn)與腫瘤細胞的直接接觸,從而有效殺傷腫瘤細胞。據(jù)此,理論上,在消融治療后的恰當時間內(nèi)輸注CIK細胞,消融產(chǎn)生的免疫刺激可能促進CIK細胞向腫瘤部位遷移、定植,增強CIK細胞的體內(nèi)抗腫瘤效應。同時,CIK細胞在腫瘤部位聚集又可放大消融誘發(fā)的抗腫瘤免疫反應,兩者相互增效產(chǎn)生最大的協(xié)同治療效能。本課題從動物實驗到臨床試驗兩部分探討射頻消融聯(lián)合CIK細胞的協(xié)同抗腫瘤效應。第一部分射頻消融與CIK細胞協(xié)同抗腫瘤效應的動物實驗研究目的觀察RFA聯(lián)合CIK細胞的協(xié)同抗腫瘤作用,探討RFA對CIK細胞體內(nèi)遷移及殺瘤活性的影響及可能作用機制。方法1、建立小鼠雙側(cè)背部B16黑色素瘤與CT26結(jié)腸癌皮下移植瘤模型,利用荷瘤鼠脾臟細胞培養(yǎng)CIK細胞,檢測CIK細胞表面趨化因子受體的表達。2、成瘤小鼠分四組:單獨右側(cè)腫瘤RFA治療組、單獨CIK治療組、兩者聯(lián)合治療組及未治療對照組,記錄未消融側(cè)腫瘤大小與小鼠生存時間,繪制生存曲線。3、采用流式細胞術(shù)分析各治療組未消融側(cè)腫瘤內(nèi)淋巴細胞亞群比例與數(shù)量、免疫抑制性細胞群:調(diào)節(jié)性T細胞(T regulatory cell,Treg),髓源性抑制細胞(Myeloid-derived suppressor cells,MDSC)的比例。4、利用不同免疫表型小鼠檢測消融后浸潤至未消融側(cè)腫瘤內(nèi)外源性CIK細胞的數(shù)量與活性。5、采用ELISA法及Real Time-PCR技術(shù)檢測單純消融后1、3、6、9、12天未消融側(cè)腫瘤內(nèi)趨化因子CXCL10的表達,利用Cxcl10KO小鼠檢測CXCL10在RFA激發(fā)抗腫瘤免疫反應,促進CIK細胞遷移中的作用。6、評估RFA與CIK細胞輸注時間間隔對治療效果的影響。結(jié)果1、成功培養(yǎng)CIK細胞,高表達趨化因子受體CXCR3、CXCR4、CCR5。2、RFA與CIK單獨治療均可產(chǎn)生短暫的抑制腫瘤生長作用,而聯(lián)合治療能顯著抑制未消融側(cè)腫瘤生長;聯(lián)合治療組生存期為42±3.3d,顯著長于未治療對照組(20.5±2.2d)、單獨右側(cè)腫瘤RFA治療組(26±2.2d)及單獨CIK治療組(31.5±2.2d)(P0.001)。3、聯(lián)合治療組小鼠未消融側(cè)腫瘤內(nèi)淋巴細胞浸潤增加,其中CD8+、CD4+T、NK(CD3-NK1.1+)和NKT(CD3+NK1.1+)細胞數(shù)量均顯著增加;CD8+/Treg(CD4+Fox P3+)比值增大;MDSC比例降低。4、RFA聯(lián)合CIK組較單獨CIK組小鼠未消融側(cè)腫瘤內(nèi)外源性CIK細胞聚集增加,并且外源性CIK細胞Ki-67、可誘導共刺激分子(Inducible costimulator,ICOS)與顆粒酶B(Granzyme B)的表達水平較未RFA組明顯上調(diào)。5、RFA動態(tài)上調(diào)遠處腫瘤組織CXCL10,CXCL10基因敲除減弱RFA激發(fā)的抗腫瘤免疫應答,影響CIK細胞的遷移。6、RFA后3天輸注CIK細胞能產(chǎn)生協(xié)同抗腫瘤效應,12天后則無明顯協(xié)同效應。結(jié)論1、RFA聯(lián)合CIK細胞治療可增強消融區(qū)外腫瘤微環(huán)境中抗腫瘤免疫反應。2、RFA治療可促進外源性CIK細胞向消融區(qū)外腫瘤內(nèi)遷移,提高CIK細胞在腫瘤內(nèi)的增殖能力與殺瘤活性,二者聯(lián)用具有協(xié)同抗腫瘤作用。3、RFA激發(fā)的抗腫瘤免疫反應和CIK細胞的遷移依賴于趨化因子CXCL10。4、RFA與CIK細胞的輸注時間間隔影響療效,應盡早輸注,這對指導兩者聯(lián)合的臨床應用具有重要意義。第二部分射頻消融聯(lián)合CIK細胞治療結(jié)直腸癌肝轉(zhuǎn)移瘤的臨床研究目的觀察RFA聯(lián)合靜脈輸注CIK細胞治療結(jié)直腸癌術(shù)后單純肝轉(zhuǎn)移患者的有效性和安全性,評估二者聯(lián)合應用對機體腫瘤抗原特異性免疫能力的影響。方法入組結(jié)直腸癌術(shù)后單純肝轉(zhuǎn)移患者60例,經(jīng)多學科團隊討論,簽署知情同意書后分為單純消融組(RFA):對肝臟轉(zhuǎn)移瘤消融,不行CIK細胞治療。消融聯(lián)合CIK細胞治療組(RFA+CIK):消融前7天,分離患者外周血單個核細胞(PBMC),體外培養(yǎng)CIK細胞,肝轉(zhuǎn)移瘤消融后7天輸注體外培養(yǎng)好的CIK細胞。比較兩組患者的無疾病進展時間(PFS)、總生存時間(OS)、不良反應。ELISPOT法檢測RFA+CIK組中外周血CEA50ng/ml的患者消融前、消融后7天(CIK細胞治療前)、消融后14天(CIK細胞治療后)三個時間點,PBMC在CEA抗原肽刺激下分泌IFN-γ的能力。結(jié)果RFA+CIK組和RFA組中位PFS分別是23個月、18個月,2年P(guān)FS率分別為41.9%和26.7%,3年P(guān)FS率分別為20.3%和13.3%,差異具有統(tǒng)計學意義(P=0.0336)。RFA組的中位OS為43個月,RFA+CIK組目前還在隨訪中。RFA組3年OS率為64.6%,而RFA+CIK組3年OS率為81%,但差異無統(tǒng)計學意義(P=0.1187)。ELISPOT試驗發(fā)現(xiàn)RFA+CIK組,8名外周血CEA50ng/ml的患者中,消融后7天(CIK細胞治療前)有6名患者PBMC中具有分泌IFN-g能力的細胞數(shù)量較消融前增加(P=0.010);而在消融后14天(CIK細胞治療后),有7名患者PBMC中具有分泌IFN-γ能力的細胞數(shù)量較消融后7天(CIK細胞治療前)增加(P=0.028)。這8名患者在消融聯(lián)合CIK細胞治療后PBMC中具有分泌IFN-γ能力的細胞數(shù)量均較治療前增加(P=0.001),差異有統(tǒng)計學意義。結(jié)論RFA聯(lián)合CIK細胞治療可增強結(jié)直腸癌肝轉(zhuǎn)移患者腫瘤抗原特異性免疫應答,延長疾病進展時間(PFS),具有協(xié)同抗腫瘤效應。綜上所述,本研究通過動物實驗和臨床試驗兩部分探討RFA聯(lián)合CIK細胞的協(xié)同抗腫瘤效應。動物實驗建立雙側(cè)背部荷瘤小鼠模型,利用荷瘤鼠脾臟細胞制備CIK細胞,臨床研究入組結(jié)直腸癌術(shù)后單純肝轉(zhuǎn)移患者。本研究明確了:1)RFA聯(lián)合CIK細胞治療可增強消融區(qū)外腫瘤微環(huán)境中抗腫瘤免疫反應;2)RFA治療可促進外源性CIK細胞向消融區(qū)外腫瘤內(nèi)遷移,增強CIK細胞在腫瘤內(nèi)的增殖能力與殺瘤活性;3)趨化因子CXCL10在RFA激活的抗腫瘤免疫應答及CIK細胞的遷移中發(fā)揮重要作用;4)RFA與CIK細胞的輸注時間間隔影響療效,應盡早輸注CIK細胞。5)RFA聯(lián)合CIK細胞治療可增強結(jié)直腸癌肝轉(zhuǎn)移患者腫瘤抗原特異性免疫應答,延長疾病進展時間(PFS)。二者聯(lián)用具有協(xié)同抗腫瘤效應。
[Abstract]:Radiofrequency ablation (RFA), which is widely used in clinical minimally invasive treatment, not only directly damage the tumor by physical heat effect, but also exposes the tumor antigen to stimulate the body to produce immune response. However, the immune response to the anti swelling tumor caused by radiofrequency ablation is not enough to prevent the recurrence and metastasis of the tumor. Cytokine induced cytotoxic (Cytokine-induced killer, CIK) cells are a group of heterogeneous cells obtained from peripheral blood mononuclear cells cultured in vitro after a variety of cytokines (IL-2, anti CD3 monoclonal antibodies, IFN- gamma, etc.). The cytotoxic activity of T lymphocytes and the natural killer cell like non tissue compatibility complex are also obtained. However, CIK cell therapy is still in an auxiliary position in the treatment of solid tumors, and the effect of individual application is often poor. One of the important factors that affect the role of CIK cells in the body is whether the effector cells can reach the target organs and achieve direct contact with the tumor cells, thus effectively killing the CIK. Therefore, in theory, CIK cells are transfused within the appropriate time after the ablation treatment. The immune stimulation produced by the ablation may promote the migration of CIK cells to the tumor site, colonize and enhance the anti tumor effect of CIK cells in vivo. At the same time, the aggregation of CIK cells at the tumor site can also increase the anti-tumor immune response induced by large ablation. Both of them increase each other. The maximum synergistic efficacy was produced. In this subject, the synergistic antitumor effect of radiofrequency ablation combined with CIK cells was investigated from two parts of animal experiment to clinical trial. Part 1 animal experimental study on the synergistic anti tumor effect of radiofrequency ablation and CIK cells was studied in order to observe the synergistic antitumor effect of RFA combined with CIK cells, and to explore the RFA to CIK cells. Effect and possible mechanism of tumor activity in vivo and in vivo. Methods 1, a mouse model of subcutaneous transplantation of B16 melanoma on the bilateral back and CT26 colon cancer was established. The expression of CIK cells in the spleen cells of the tumor mice was used to detect the expression of.2 in the CIK cell surface chemokine receptor, and the tumor mice were divided into four groups: the alone right tumor RFA treatment group, and CIK alone CIK. The treatment group, both combined treatment group and untreated control group, recorded the size of unablative side tumor and the survival time of mice, and plotted survival curve.3. Flow cytometry was used to analyze the proportion and quantity of lymphocyte subsets in the unablative side tumor of each treatment group, and the immunosuppressive cell group: regulatory T cells (T regulatory cell, Treg), myelinated inhibition. The proportion of Myeloid-derived suppressor cells (MDSC) was.4, and the number and active.5 of the endogenous and external CIK cells infiltrated to the non ablation side tumor were detected by different immunophenotype mice. The expression of chemokine CXCL10 was detected by ELISA method and Real Time-PCR technique in the non ablation side tumor after pure ablation. Cxcl10KO mice detected CXCL10 in RFA to stimulate the anti-tumor immune response and promote the role of CIK cell migration,.6, to evaluate the effect of the time interval between RFA and CIK cells. Results 1, the successful culture of CIK cells, high expression of chemokine receptor CXCR3, CXCR4, CCR5.2, RFA and solitary therapy can produce a brief inhibition of tumor growth. Combined therapy could significantly inhibit the growth of unablative side tumors; the survival period of the combined treatment group was 42 + 3.3D, significantly longer than that in the untreated control group (20.5 + 2.2d), the individual right tumor RFA treatment group (26 + 2.2d) and the single CIK treatment group (31.5 + 2.2d) (P0.001).3, and the increase of lymphocyte infiltration in the unablative side tumor of the combined treatment group, of which CD8+ was in the combined treatment group. The number of CD4+T, NK (CD3-NK1.1+) and NKT (CD3+NK1.1+) cells increased significantly, the ratio of CD8+/Treg (CD4+Fox P3+) increased, the proportion of MDSC decreased.4, RFA joint CIK group increased the aggregation of endogenous and external tumor cells in the non ablation side tumor of mice. The expression level of granulase B (Granzyme B) was significantly up-regulated than that in the non RFA group, and RFA dynamically up-regulated the CXCL10 in the distant tumor tissue. CXCL10 gene knockout weakened the anti tumor immune response of RFA stimulated and influenced the.6 migration of CIK cells. 3 days after RFA, the transfused cells could produce synergistic antitumor effects and no obvious synergistic effect in 12 days. Conclusion 1 Cell therapy can enhance the anti tumor immune response.2 in the tumor microenvironment outside the ablation area. RFA therapy can promote the migration of exogenous CIK cells into the tumor outside the ablation area, improve the proliferation and tumor activity of CIK cells in the tumor. The two combined anti-tumor immune response and CIK cell migration dependence with.3, RFA excitation and CIK cells are combined. The time interval between chemokines CXCL10.4, RFA and CIK cells affects the curative effect and should be delivered as early as possible. This is of great significance for guiding the combination of the two clinical applications. Second parts of the clinical study on the combination of radiofrequency ablation combined with CIK cells in the treatment of colorectal cancer liver metastases; RFA combined intravenous infusion of CIK cells for the treatment of colorectal cancer The effectiveness and safety of the patients with simple liver metastasis were evaluated by the combined application of two patients with tumor antigen specific immunity. Methods 60 patients with simple liver metastasis after colorectal cancer surgery were discussed by a multidisciplinary team. After signing informed consent books, the patients were divided into simple ablation group (RFA): liver metastases ablation, and no CIK cell treatment Treatment. Ablation combined with CIK cell therapy group (RFA+CIK): 7 days before the ablation, the peripheral blood mononuclear cells (PBMC) were isolated, CIK cells were cultured in vitro, and the CIK cells were transfused for 7 days after the liver metastases were ablated. The time of disease progression (PFS), total survival time (OS) and adverse reaction.ELISPOT method were compared between the two groups and the RFA+CIK group. Before ablation of blood CEA50ng/ml, 7 days after ablation (CIK cell therapy), 14 days after ablation (after CIK cell therapy), the ability of PBMC to secrete IFN- gamma under the stimulation of CEA antigen peptide. Results the PFS in group RFA+CIK and RFA group was 23 months, 18 months, 2 years, 41.9% and 26.7% respectively, and 20.3% and 13.3% respectively in 3 years, respectively, and the difference was 20.3% and 13.3% respectively. The difference was 20.3% and 13.3% respectively. The median OS in group.RFA was 43 months, and the RFA+CIK group was still followed up with the OS rate of 64.6% in the.RFA group and 81% in the RFA+CIK group for 3 years, but the difference was not statistically significant (P=0.1187) in the RFA+CIK group and 8 of the 8 peripheral blood CEA50ng/ml. The 7 days after the ablation (before the treatment) there were 6 patients. The number of cells with the ability to secrete IFN-g increased in C (P=0.010), and in 7 patients, the number of cells with the ability to secrete IFN- gamma in PBMC increased (P=0.028) at 14 days after ablation (after CIK cell therapy). These 8 patients secreted IFN- gamma ability in PBMC after ablation combined with CIK cell therapy. The number of cells increased in comparison with that before treatment (P=0.001), and the difference was statistically significant. Conclusion RFA combined with CIK cell therapy can enhance the specific immune response of patients with colorectal cancer liver metastasis, prolong the time of disease progression (PFS) and have synergistic antitumor effect. In summary, two parts of animal and clinical trials are discussed in this study. The synergistic anti-tumor effect of RFA combined with CIK cells. In animal experiments, a mouse model of bilateral back bearing tumor was established, and CIK cells were prepared by using the spleen cells of the tumor bearing mice. The clinical study was conducted in a group of patients with simple liver metastasis after the operation of rectal cancer. 1) RFA combined with CIK cell therapy could enhance the anti tumor immune response in the microenvironment of the ablation area. 2) RFA therapy can promote the migration of exogenous CIK cells into the tumor outside the ablation area, enhance the proliferation and tumor activity of CIK cells in the tumor; 3) chemokine CXCL10 plays an important role in the anti-tumor immune response activated by RFA and the migration of CIK cells; 4) the interval between the infusion time of RFA and CIK cells affects the curative effect, and the CIK fine should be injected as soon as possible. Cell.5) RFA combined with CIK cell therapy can enhance the specific immune response of cancer antigen in patients with colorectal cancer and prolong the time of disease progression (PFS). The combination of the two has a synergistic antitumor effect.
【學位授予單位】：蘇州大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R730.5
本文編號：2153644
[Abstract]:Radiofrequency ablation (RFA), which is widely used in clinical minimally invasive treatment, not only directly damage the tumor by physical heat effect, but also exposes the tumor antigen to stimulate the body to produce immune response. However, the immune response to the anti swelling tumor caused by radiofrequency ablation is not enough to prevent the recurrence and metastasis of the tumor. Cytokine induced cytotoxic (Cytokine-induced killer, CIK) cells are a group of heterogeneous cells obtained from peripheral blood mononuclear cells cultured in vitro after a variety of cytokines (IL-2, anti CD3 monoclonal antibodies, IFN- gamma, etc.). The cytotoxic activity of T lymphocytes and the natural killer cell like non tissue compatibility complex are also obtained. However, CIK cell therapy is still in an auxiliary position in the treatment of solid tumors, and the effect of individual application is often poor. One of the important factors that affect the role of CIK cells in the body is whether the effector cells can reach the target organs and achieve direct contact with the tumor cells, thus effectively killing the CIK. Therefore, in theory, CIK cells are transfused within the appropriate time after the ablation treatment. The immune stimulation produced by the ablation may promote the migration of CIK cells to the tumor site, colonize and enhance the anti tumor effect of CIK cells in vivo. At the same time, the aggregation of CIK cells at the tumor site can also increase the anti-tumor immune response induced by large ablation. Both of them increase each other. The maximum synergistic efficacy was produced. In this subject, the synergistic antitumor effect of radiofrequency ablation combined with CIK cells was investigated from two parts of animal experiment to clinical trial. Part 1 animal experimental study on the synergistic anti tumor effect of radiofrequency ablation and CIK cells was studied in order to observe the synergistic antitumor effect of RFA combined with CIK cells, and to explore the RFA to CIK cells. Effect and possible mechanism of tumor activity in vivo and in vivo. Methods 1, a mouse model of subcutaneous transplantation of B16 melanoma on the bilateral back and CT26 colon cancer was established. The expression of CIK cells in the spleen cells of the tumor mice was used to detect the expression of.2 in the CIK cell surface chemokine receptor, and the tumor mice were divided into four groups: the alone right tumor RFA treatment group, and CIK alone CIK. The treatment group, both combined treatment group and untreated control group, recorded the size of unablative side tumor and the survival time of mice, and plotted survival curve.3. Flow cytometry was used to analyze the proportion and quantity of lymphocyte subsets in the unablative side tumor of each treatment group, and the immunosuppressive cell group: regulatory T cells (T regulatory cell, Treg), myelinated inhibition. The proportion of Myeloid-derived suppressor cells (MDSC) was.4, and the number and active.5 of the endogenous and external CIK cells infiltrated to the non ablation side tumor were detected by different immunophenotype mice. The expression of chemokine CXCL10 was detected by ELISA method and Real Time-PCR technique in the non ablation side tumor after pure ablation. Cxcl10KO mice detected CXCL10 in RFA to stimulate the anti-tumor immune response and promote the role of CIK cell migration,.6, to evaluate the effect of the time interval between RFA and CIK cells. Results 1, the successful culture of CIK cells, high expression of chemokine receptor CXCR3, CXCR4, CCR5.2, RFA and solitary therapy can produce a brief inhibition of tumor growth. Combined therapy could significantly inhibit the growth of unablative side tumors; the survival period of the combined treatment group was 42 + 3.3D, significantly longer than that in the untreated control group (20.5 + 2.2d), the individual right tumor RFA treatment group (26 + 2.2d) and the single CIK treatment group (31.5 + 2.2d) (P0.001).3, and the increase of lymphocyte infiltration in the unablative side tumor of the combined treatment group, of which CD8+ was in the combined treatment group. The number of CD4+T, NK (CD3-NK1.1+) and NKT (CD3+NK1.1+) cells increased significantly, the ratio of CD8+/Treg (CD4+Fox P3+) increased, the proportion of MDSC decreased.4, RFA joint CIK group increased the aggregation of endogenous and external tumor cells in the non ablation side tumor of mice. The expression level of granulase B (Granzyme B) was significantly up-regulated than that in the non RFA group, and RFA dynamically up-regulated the CXCL10 in the distant tumor tissue. CXCL10 gene knockout weakened the anti tumor immune response of RFA stimulated and influenced the.6 migration of CIK cells. 3 days after RFA, the transfused cells could produce synergistic antitumor effects and no obvious synergistic effect in 12 days. Conclusion 1 Cell therapy can enhance the anti tumor immune response.2 in the tumor microenvironment outside the ablation area. RFA therapy can promote the migration of exogenous CIK cells into the tumor outside the ablation area, improve the proliferation and tumor activity of CIK cells in the tumor. The two combined anti-tumor immune response and CIK cell migration dependence with.3, RFA excitation and CIK cells are combined. The time interval between chemokines CXCL10.4, RFA and CIK cells affects the curative effect and should be delivered as early as possible. This is of great significance for guiding the combination of the two clinical applications. Second parts of the clinical study on the combination of radiofrequency ablation combined with CIK cells in the treatment of colorectal cancer liver metastases; RFA combined intravenous infusion of CIK cells for the treatment of colorectal cancer The effectiveness and safety of the patients with simple liver metastasis were evaluated by the combined application of two patients with tumor antigen specific immunity. Methods 60 patients with simple liver metastasis after colorectal cancer surgery were discussed by a multidisciplinary team. After signing informed consent books, the patients were divided into simple ablation group (RFA): liver metastases ablation, and no CIK cell treatment Treatment. Ablation combined with CIK cell therapy group (RFA+CIK): 7 days before the ablation, the peripheral blood mononuclear cells (PBMC) were isolated, CIK cells were cultured in vitro, and the CIK cells were transfused for 7 days after the liver metastases were ablated. The time of disease progression (PFS), total survival time (OS) and adverse reaction.ELISPOT method were compared between the two groups and the RFA+CIK group. Before ablation of blood CEA50ng/ml, 7 days after ablation (CIK cell therapy), 14 days after ablation (after CIK cell therapy), the ability of PBMC to secrete IFN- gamma under the stimulation of CEA antigen peptide. Results the PFS in group RFA+CIK and RFA group was 23 months, 18 months, 2 years, 41.9% and 26.7% respectively, and 20.3% and 13.3% respectively in 3 years, respectively, and the difference was 20.3% and 13.3% respectively. The difference was 20.3% and 13.3% respectively. The median OS in group.RFA was 43 months, and the RFA+CIK group was still followed up with the OS rate of 64.6% in the.RFA group and 81% in the RFA+CIK group for 3 years, but the difference was not statistically significant (P=0.1187) in the RFA+CIK group and 8 of the 8 peripheral blood CEA50ng/ml. The 7 days after the ablation (before the treatment) there were 6 patients. The number of cells with the ability to secrete IFN-g increased in C (P=0.010), and in 7 patients, the number of cells with the ability to secrete IFN- gamma in PBMC increased (P=0.028) at 14 days after ablation (after CIK cell therapy). These 8 patients secreted IFN- gamma ability in PBMC after ablation combined with CIK cell therapy. The number of cells increased in comparison with that before treatment (P=0.001), and the difference was statistically significant. Conclusion RFA combined with CIK cell therapy can enhance the specific immune response of patients with colorectal cancer liver metastasis, prolong the time of disease progression (PFS) and have synergistic antitumor effect. In summary, two parts of animal and clinical trials are discussed in this study. The synergistic anti-tumor effect of RFA combined with CIK cells. In animal experiments, a mouse model of bilateral back bearing tumor was established, and CIK cells were prepared by using the spleen cells of the tumor bearing mice. The clinical study was conducted in a group of patients with simple liver metastasis after the operation of rectal cancer. 1) RFA combined with CIK cell therapy could enhance the anti tumor immune response in the microenvironment of the ablation area. 2) RFA therapy can promote the migration of exogenous CIK cells into the tumor outside the ablation area, enhance the proliferation and tumor activity of CIK cells in the tumor; 3) chemokine CXCL10 plays an important role in the anti-tumor immune response activated by RFA and the migration of CIK cells; 4) the interval between the infusion time of RFA and CIK cells affects the curative effect, and the CIK fine should be injected as soon as possible. Cell.5) RFA combined with CIK cell therapy can enhance the specific immune response of cancer antigen in patients with colorectal cancer and prolong the time of disease progression (PFS). The combination of the two has a synergistic antitumor effect.
【學位授予單位】：蘇州大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R730.5
【參考文獻】
相關(guān)期刊論文 前7條
1 Hui-Ju Ch'ang;;Optimal combination of antiangiogenic therapy for hepatocellular carcinoma[J];World Journal of Hepatology;2015年16期
2 Alexander Schlachterman;Willie W Craft Jr;Eric Hilgenfeldt;Avir Mitra;Roniel Cabrera;;Current and future treatments for hepatocellular carcinoma[J];World Journal of Gastroenterology;2015年28期
3 Kai-Wen Chen;Tzu-Ming Ou;Chin-Wen Hsu;Chi-Ting Horng;Ching-Chang Lee;Yuh-Yuan Tsai;Chi-Chang Tsai;Yi-Sheng Liou;Chen-Chieh Yang;Chao-Wen Hsueh;Wu-Hsien Kuo;;Current systemic treatment of hepatocellular carcinoma:A review of the literature[J];World Journal of Hepatology;2015年10期
4 Jun Gao;Jian Kong;Xue-Mei Ding;Shan Ke;Hai-Gang Niu;Zong-Hai Xin;Chun-Min Ning;Shi-Gang Guo;Xiao-Long Li;Long Zhang;Yong-Hong Dong;Wen-Bing Sun;;Laparoscopic vs computerized tomography-guided radiofrequency ablation for large hepatic hemangiomas abutting the diaphragm[J];World Journal of Gastroenterology;2015年19期
5 Huisong Lee;Jin Seok Heo;Yong Beom Cho;Seong Hyeon Yun;Hee Cheol Kim;Woo Yong Lee;Seong Ho Choi;Dong Wook Choi;;Hepatectomy vs radiofrequency ablation for colorectal liver metastasis:A propensity score analysis[J];World Journal of Gastroenterology;2015年11期
6 Jia-Yan Ni;Shan-Shan Liu;Lin-Feng Xu;Hong-Liang Sun;Yao-Ting Chen;;Meta-analysis of radiofrequency ablation in combination with transarterial chemoembolization for hepatocellular carcinoma[J];World Journal of Gastroenterology;2013年24期
7 ;Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients[J];World Journal of Gastroenterology;2010年48期
，本文編號：2153644
本文鏈接：http://sikaile.net/yixuelunwen/zlx/2153644.html
最近更新
教材專著
