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Chimeric Antigen Receptor (CAR) is a research hotspot in the field of cellular immunotherapy in recent years, and CAR-T cells therapy are developing rapidly in hematological malignant tumors, but their clinical application is still limited by related risks. It is particularly important to find more optimized immunoreactive cells. Natural killer (NK) cells, as key effector cells of innate immunity, can kill tumor or infected cells quickly without prior sensitization. Autologous or allogeneic NK cell infusion has become an effective cell therapy for acute myeloid leukemia (AML). CAR-NK cells combine the advantages of CAR targeting tumor specific antigens and enhancing immune cells activity with the innate antitumor function of NK cells to enhance the targeting and lytic activity of NK cells to AML primordial cells. At present, most of the CAR-NK treatments for AML are still in the stage of specific target screening and verification. This article reviews the latest research progress of CAR-NK cell therapy in the field of AML therapy.
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Humans , Receptors, Chimeric Antigen , Killer Cells, Natural , Leukemia, Myeloid, Acute/drug therapy , Immunotherapy, Adoptive , ImmunotherapyABSTRACT
@#In recent years,considerable progress has been made in the treatment of multiple myeloma(MM).However,despite the current improved prognosis of this malignancy,it always ends in relapse and therefore new therapeutic approaches are urgently needed to overcome it.The chimeric antigen receptor(CAR)-T cells targeting B cell maturation antigen(BCMA),cluster of differentiation 19(CD19),cluster of differentiation 38(CD38) and kappa light chains have been evaluated,and have achieved remarkable results in clinical trials.However,even when MM is treated with CAR-T cell therapy,most patients eventually relapse,which is the greatest limitation of this therapy.This paperreviewedthe research progress,limitations and optimization of CAR-T cell immunotherapy in the treatment of MM.
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@#[Abstract] T cell receptors (TCR) are specifically expressed on T cell surface, which can recognize different tumor antigens to kill and scavenge cancerous cells. TCR-engineered T cells (TCR-T) therapy is to harbor TCR specific to tumor cells and modify the T cells with genetic engineering techniques to achieve the purpose of treating tumors after transfusion. Despite some achievements in TCR-T therapy, there are still some problems, such as treatment toxicity, limited T cell infiltration and antigen-specific deficiency and so on. So, the safety and effectiveness of TCR-T therapy need to be constantly optimized. Therefore，this paper summarizes the research status of TCR-T therapy for solid tumors in domestic and overseas, as well as the existing problems and countermeasures.
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With the rapid development of immunology, molecular biology, and associated technologies such as next-generation sequencing, cellular immunotherapy has recently become the fourth major cancer treatment. Immunotherapies based on T cells, natural killer cells, and dendritic cells play key roles in cancer immunotherapy. However, their application in clinical practice raises several ethical issues. Thus, studies should focus on proper adherence to basic ethical principles that can effectively guide and solve related clinical problems in the course of treatment, improve treatment effects, and protect the rights and interests of patients. In this review, we discuss cellular immunotherapy-related ethical issues and highlight the ethical practices and current status of cellular immunotherapy in China. These considerations may supplement existing ethical standards in cancer immunotherapy.
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Primary liver cancer is the third fatal tumor in China, and 85% of them are Hepatocellular Carcinoma (HCC). Liver cancer progresses quickly and is easy to metastasize, which brings great difficulties for treatment. In recent years, great breakthroughs have been made in the treatment of advanced HCC by chimeric antigen receptor T cell (CAR-T) immunotherapy and flora treatment. This article reviewed the current status of cellular immunotherapy and intestinal probiotics therapy for HCC, aiming at providing new ideas for clinical treatment of liver carcinoma.
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With the rapid development of immunology, molecular biology, and associated technologies such as next-generation sequencing, cellular immunotherapy has recently become the fourth major cancer treatment. Immunotherapies based on T cells, natural killer cells, and dendritic cells play key roles in cancer immunotherapy. However, their application in clinical practice raises several ethical issues. Thus, studies should focus on proper adherence to basic ethical principles that can effectively guide and solve related clinical problems in the course of treatment, improve treatment effects, and protect the rights and interests of patients. In this review, we discuss cellular immunotherapy-related ethical issues and highlight the ethical practices and current status of cellular immunotherapy in China. These considerations may supplement existing ethical standards in cancer immunotherapy.
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Humans , China , Dendritic Cells/immunology , Immunity, Cellular , Immunotherapy/methods , Killer Cells, Natural/immunology , Neoplasms/therapy , Patient Selection/ethics , T-Lymphocytes/immunologyABSTRACT
Allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion for multiple myeloma (MM) can induce graft-versus-myeloma immunity and long-term survival,but limited efficacy and associated toxicities have prevented its widespread application.Cellular immunotherapies and vaccines are explored to induce more specific,reliable,and potent antimyeloma immune responses with less treatmentrelated risk.Advances in molecular biology,basic and applied immunology,have led to several promising approaches such as genetically engineered T cells with chimeric antigen receptors and T-cell receptors targeting myeloma-specific epitopes,vaccine primed ex vivo expanded autologous T cells,expanded marrowinfiltrating lymphocytes,and plasma cell/dendritic cell fusion vaccines.The combination of these emerging therapies to immunomodulatory drugs and inhibitors of programmed death-1 T-cell regulatory pathways could improve the outcome for MM patients.This article reviews the latest progress of cellular and vaccine immunotherapy for MM at the 58th American Society of Hematology (ASH) Annual Meeting,and discusses how these therapies might integrate and synergize with existing treatment paradigms.
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Chimeric antigen receptor T-cell (CAR-T) immunotherapy is a new type of immunotherapy,which has been developed rapidly in recent years.By using gene recombination and transfection techniques,CAR-modified effector T cells that specially recognize tumor-associated antigen was produced,which show better properties of targeting,killing activity and durability than conventional T cells.With the development of translational medicine research,CAR-T technology has experienced four generations of optimization and innovation,and presented a promising clinical efficacy in the treatment of various cancers,especially hematological malignancies.However,there are also potential risks with clinical use of this new technology,such as the off-target effect and cytokine storm.In this review,the progress,side effects,coping strategy,and development prospects of CAR-T in hematological malignancies immunotherapy were discussed.
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Objective To investigate whether decreasing affinity of CAR-T cells can increase their therapeutic outcome or not .Methods Moderate affinity La-G3HER2-CAR and high affinity Ha-G3HER2-CAR were constructed ,and electroporated to modify T cells .Western blot assay ,FCM assay and the RTCA DP cytotoxic equipment were applied to test the CAR expres-sion and cytotoxic function of CAR-T cells .Results 43000 and 58000 exogenous CD3ζfragments were expressed by both La-G3HER2-CAR-T cells and Ha-G3HER2-CAR-T cells with 58 .1% and 69 .0% transfection rate respectively .High affinity Ha-G3HER2-CAR-T cells effectively killed all target tumor cells by which HER2 was expressed at variable expression levels , while moderate affinity La-G3HER2-CAR-T cells specifically killed HER2 high-level expressing SK-OV-3 and BT474 cells ,and showed weaker cytotoxicity on HER2 moderate-level expressing MDA-MB-231 and HCC-202 cells ,and showed no cytotoxicity on HER2 low-level expressing MCF-7 and 293 cells .The underlying mechanic investigation found that La-G3HER2-CAR-T cells and Ha-G3HER2-CAR-T cells were differentially activated by co-culture with MDA-MB-231 (CD107a:8 .2% vs 71 .6% , IFN-γ:66 .3% vs 83 .4% ,TNF-α:73 .4% vs 94 .1% ) .Conclusion Moderate affinity La-G3HER2-CAR-T cells have en-hanced specific cytotoxicity toward target tumor cells compared to high affinity Ha-G3HER2-CAR-T cells ,decreasing affinity of CAR-T cell is a promising strategy to increase the therapeutic outcome of CAR-T cell based immunotherapies .
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As the research work went further and more detailed, a variety of new treatments compete to come out.However, it remains unclear that how the antigen works to distinguish cancer cells and normal cells.Neoantigen, which is located in the tumor cell surface of a specific antigen, its presence makes human immunotherapy into new areas which may make personalized treatment possible in the near future.Emerging data suggest that the identification of such newantigens is a major factor in clinical immunotherapy.They can form a biomarker in cancer immunotherapy to provide targets for a variety of therapeutic approaches to attack, which allows T cells to selectively enhance the immune response against this class of antigens.
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In recent years,considerable progress has been made in the treatment of hematologic malig-nancies.However,most patients will eventually relapse and suffer from severe side effects caused by chemotherapy or radiation.Thus,as a well tolerated,safe,effective and innovative therapy,adoptive cellular immunotherapy e-merges at this very moment.This therapy can kill tumors or control recurrence by reinfusing the in vitro amplifi-cated or treated immune effective cells into the patients.It has been actively used in the treatment of various he-matological malignancies and achieved significant effects,which brings hope for more and more patients with re-lapsed or refractory hematological diseases.
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Objective To observe the clinical efficacy of autologous dendritic cells (DCs) vaccine combined with cytokine-induced killer (CIK) cells for treatment of patients with biliary tract cancer. Methods Peripheral blood mononuclear cells (PBMCs) were collected from the patients with biliary tract cancer and were stimulated with multiple tumor-associated antigens (TAA) for amplification and culture. Mature DCs were harvested and made into vaccine for intradermal administration, and at the same time the patients were given autologous CIK cells via vein transfusion. The clinical efficacy, immune function, side effect, and overall survival of 85 patients with biliary tract cancer were observed before and after treatment. Results The clinical symptoms were improved significantly in the 85 patients after autologous DC-CIK therapy (P +, CD3+CD4+, CD3+CD8+, CD3+CD56+ and CD4+/CD8+ ratio were elevated in the lymhocyte subpopulation, but the regulatory T cells were reduced (P <0.05). At the end of the follow-up, 58 patients died, 2 patients were lost in follow-up, and 25 patients survived, with the median overall survival time being 16.5 months (95%CI: 12.1-20.9 months). Conclusion Autologous DC-CIK therapy is a safe and effective treatment for patients with biliary tract cancer, with less side effect, but the relevant conclusion still needs to be confirmed by larger sample randomized controlled studies.
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Through the two-step method FST group and FST6 group both can successfully induce DC into mature functions;the induction in FST6 group is more efficient.
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The annually American Society of Hematology (ASH) annual meeting is the biggest feast in this area.The 56th ASH annual meeting showed many important data related with lymphoma.Applied brentuximab vedotin as maintenance therapy after autologous stem cell transplantion,Hodgkin lymphoma (HL) patients acquired significant prolonged progression free survival (PFS).A phase Ⅰ study demonstrated that PD-1 inhibitor,nivolumab,has a high response in heavily treated HL,with ORR 87 ％,which has acquired the approval from FDA.BTK inhibitor,PI3K inhibitor,new CD20 antibodies,bcl-2 inhibitor and lenalidomide all are effective in relapsed or refractory chronic lympholytic leukemia (CLL) and non-Hodgkin' s lymphoma (NHL),but how to apply these new targeted drugs appropriately and combined with current chemotherapy regimens are quite difficult.CAR-T cells targeting CD19,CD20,CD30 or CD138 positive lymphomas are a kind of new cellular therapy,which has showed excellent efficacy.
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Objective To study proliferation,secreted cytokines,immune phenotypes and cytotoxicity on Raji cells by cytokine induced killer (CIK) cells co-cultured with dendritic cells (DC).Methods The mononuclear cells from peripheral blood of healthy individuals were extracted,then cultured the cells under 5 ％ CO2 at 37 ℃ for 2 hours.DC were induced from suspended cells,and CIK cells were from adherent cells.After 9 days of nurturing,two types of cells were mixed.CIK cells were cultured alone as the control.The cytotoxic activity of CIK and DC-CIK cells were detected by MTT assay.The morphologies,proliferation,secreted cytokines,and immune phenotypes of the two cells in day 0,3,6,9,12,15 in culture were monitored.Results In day 12 in culture,comparing with CIK cells,DC-CIK cells significantly enhanced the proliferation rate [(42.44±2.68) fold vs (30.01±2.05) fold] (t =11.64,P ＜ 0.05) and had increased IL-2,IFN-γ,IL-12 and TNF-α secretion [(124.34±12.57) ng/L vs (56.32±6.58) ng/L,(496.60±95.32) ng/L vs (247.80± 69.45) ng/L,(84.92±6.07) ng/L vs (24.18±3.31) ng/L,(380.6±45.95) ng/L vs (196.61±24.19) ng/L] (t =15.16,P ＜ 0.05; t =6.67,P ＜ 0.05; t =27.78,P ＜ 0.05; t =11.20,P ＜ 0.05),and there were more CD3+ CD8+ cells and CD3+ CD56+ cells in the co-culture [(71.79±1.73) ％ vs (60.37±3.24) ％,(48.54±3.30) ％ vs (33.07±2.22) ％](t =9.83,P ＜ 0.05; t =12.30,P ＜ 0.05),and DC-CIK cells had a significandy increased cytotoxicity on Raji cells in vitro at the same ratio of effector cells to target cells.Conclusion CIK cells have higher proliferation rate and cytotoxicity against Raji cells when co-cultured with DC.
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Objective To evaluate the clinical effects of cytokine-induced killer (CIK) cells combined with chemotherapy on the treatment of patients with advanced colorectal cancer.Methods CIK cells were prepared from 50 ml peripheral blood mononuclear cells by stimulated with IL-2,IFN-γ,anti-CD3 monoclone antibody,IL-1 for 8 d.The clinical effects and survival rate were compared between CIK cells combined with chemotherapy group and the chemotherapy group (50 patients with advanced colorectal cancer for each).T cells and NK cells of patients were tested by FCM before and after CIK cells treatment.The improvement of quality of life and toxicity of this therapy were observed.Results The percentages of CD3+,CD4+,CD8+ T cells and NK cells were (54.779±14.228) ％,(30.821±11.554) ％,(16.676±6.256) ％,(18.705±9.347) ％ before CIK cells transfusion.After transfusion,the percentages were (65.236±14.901) ％,(37.292±8.880) ％,(25.229±6.711) ％,(22.950±8.933) ％,respectively.The percentages were expanded greatly (P ＜ 0.05).The patients quality of life were improved clearly with lower toxicity.The DCR of CIK cells combined with chemotherapy group (64 ％,32/50) was higher than the chemotherapy group (40 ％,20/50) (P ＜ 0.05).The survival rate between two groups had no statistical significance (P ＞ 0.05).Conclusion Administration of CIK cells combined with chemotherapy can enhance immune function in patients with advanced colorectal cancer and improve their quality of life,and get good clinical efficacy.
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Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic tool to treat multiple myeloma (MM). DC-based idiotype vaccination was recently suggested to induce idiotype-specific immune responses in MM patients. However, the clinical results so far have been largely disappointing, and the clinical effectiveness of such vaccinations in MM still needs to be demonstrated. DC-based therapies against MM may need to be boosted with other sources of tumor-associated antigens, and potent DCs should be recruited to increase the effectiveness of treatment. DCs with both high migratory capacity and high cytokine production are very important for effective DC-based cancer vaccination in order to induce high numbers of Th1-type CD4+ T cells and CD8+ cytotoxic T lymphocytes. The tumor microenvironment is also important in the regulation of tumor cell growth, proliferation, and the development of therapeutic resistance after treatment. In this review, we discuss how the efficacy of DC vaccination in MM can be improved. In addition, novel treatment strategies that target not only myeloma cells but also the tumor microenvironment are urgently needed to improve treatment outcomes.
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Humans , Dendritic Cells , Immunotherapy , Multiple Myeloma , T-Lymphocytes , T-Lymphocytes, Cytotoxic , Tumor Microenvironment , VaccinationABSTRACT
Adoptive cellular immunotherapy is a novel treatment that uses immunological cells with antitumor activity,expanded in vitro and infused into the patient with tumor.The activated immunological cells mediate direct or indirect anti-tumor response via tumor ceUs killing or lysis.This article reviews some novel advances of immunological cells used in adoptive cellular immunotherapy for leukemia,such as NK cell,artificial antigen-presenting ceils,leukemia-derived dendritic cells,CD4+T ceHs,Th17 cells and mixed immunological cells.
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OBJECTIVE: The objective of this study was to establish a clinically applicable culture system by investigating the use of autologous cord blood plasma (ACBP) instead of fetal bovine serum (FBS) for the ex vivo expansion of umbilical cord blood (UCB) T-lymphocytes. METHODS: Fresh UCB mononuclear cell (MNC) fractions were isolated by Ficoll-Hypaque density centrifugation. The nonadherent MNC fractions were then cultured with the anti-CD3 antibody 5 microgram/mL plus IL-2 175 U/mL in the presence of 10% FBS, 10% ACBP or homologous cord blood plasma (HCBP). On day 8, proliferation rate, cell surface markers, cytotoxic assay of UCB T-lymphocytes according to the medium supplemented with FBS, ACBP or HCBP were evaluated. RESULTS: Proliferation studies demonstrated a significant increase in the proliferative ability of UCB T-lymphocytes incubated in anti- CD3 and IL-2 irrespective of the medium supplemented with FBS or ACBP. In the FBS supplemented medium, expressions of the activated T-lymphocytes were increased significantly after culture: CD3+CD8+, CD3+CD25+, CD3+CD38+, and CD45RO+ (p<0.05). Also in the ACBP supplemented medium, expressions of the activated T-lymphocytes were increased significantly after culture: CD3+ CD8+, CD3+CD25+, and CD45RO+ (p<0.05). In the HCBP supplemented medium, expressions of the activated T-lymphocytes were increased significantly after culture as in the ACBP: CD3+CD8+, CD3+CD25+, and CD45RO+ (p<0.05). Of the activated T-lymphocytes, increase of cytotoxic CD3+CD8+ cells increased significantly in the ACBP and HCBP groups compared to FBS group (p<0.05). CONCLUSION: These findings support the feasibility of ex vivo expansion of umbilical cord blood T-lymphocytes in the medium supplemented with autologous cord blood plasma, instead of fetal bovine serum, for future adoptive cellular immunotherapy.
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Centrifugation , Fetal Blood , Immunotherapy, Adoptive , Interleukin-2 , Plasma , T-Lymphocytes , Umbilical CordABSTRACT
Objective To investigate the feasibility of lymphokine activated killer(LAK) cells induced from cord blood used as adoptive cellular immunotherapy for human cancer.Methods Mononuclear cells were separated from umbilical blood(UBMC) by Ficoll,and stimulated by IL-2.The phenotypes(CD3/ CD4/ CD8) of the mononuclear cells were assayed by Flow cytometry,and their lethal activity on K562 or SKOV6 assayed by MTT colometric.The peripheral blood mononuclear cells were used as the control.Results The in vitro anti-tumor effect of LAK from cord blood was significant.Conclusion LAK from cord blood can be a source of adoptive cellular immunotherapy in the treatment of human cancer.