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1
Lee, Jae Hee, Ji Sung Kim, Hong Kyung Lee, Ki Hun Kim, Jeong Eun Choi, A. Young Ji, Jin Tae Hong, Youngsoo Kim, and Sang-Bae Han. "Comparison of cytotoxic dynamics between cytokine-induced killer cells and natural killer cells at the single cell level." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 198.12. http://dx.doi.org/10.4049/jimmunol.198.supp.198.12.
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Abstract Although much has been learned about the cytotoxic mechanisms of cytokine-induced killer (CIK) and natural killer (NK) cells, little is known about how they kill cancer cells at the single-cell level. In the present study, we examined the contact dynamics of CIK and NK cells at the single-cell level by using time-lapse imaging. CIK cells killed MHC-I-negative and -positive cancer cells, but NK cells destroyed MHC-I-negative cells only. Moreover, CIK cells moved in all directions and showed longer tracks than did NK cells. CIK cells showed higher displacement and straightness scores than did NK cells, which indicates long-distance random migration of CIK cells. CIK and NK cells moved at 6.7 mm/min and 4.5 mm/min on average, respectively. These data suggest that CIK cells are likely moving more actively than NK cells. The average threshold number of CIK cells required to kill an individual cancer cell was 6.7 for MHC-I-negative cells and 6.9 for MHC-I-positive cells. That of NK cells was 2.4 for MHC-I-negative cells. Likely due to the higher threshold numbers, killing by CIK cells was delayed in comparison with NK cells: 40% of MHC-negative target cells were killed after 5 h when co-cultured with CIK cells and after 2 h with NK cells. Our data have implications for the rational design of CIK or NK cell–based immunotherapy of cancer patients
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Han, Lu, Yi-Man Shang, Yong-Ping Song, and Quan-Li Gao. "Biological Character of RetroNectin Activated Cytokine-Induced Killer Cells." Journal of Immunology Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/5706814.
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Adoptive cell therapy (ACT) using autologous cytokine-induced killer (CIK) cells is a promising treatment for metastatic carcinomas. In this study, we investigated the impact of RetroNectin on the proliferation, phenotype alternation, cytokine secretion, and cytotoxic activity of CIK cells from pancreatic cancer patients. Furthermore, we treated 13 patients with metastatic or locally advanced pancreatic cancer using autologous RetroNectin-activated CIK cells (R-CIK cells) alone or in combination with chemotherapy. Compared with only CD3 activated CIK cells (OKT-CIK cells), R-CIK cells showed stronger and faster proliferative ability, with a lower ratio of spontaneous apoptosis. Moreover, this ability continued after IL-2 was withdrawn from the culture system. R-CIK cells could also secrete higher levels of IL-2 and lower levels of IL-4 and IL-5 versus OKT-CIK cells. There was no difference between OKT-CIK and R-CIK cells in cytotoxic ability against lymphoma cell line K562. In patients who received auto-R-CIK cell infusion therapy, the overall objective response rate was 23.1%. Median survival time (mOS) after first R-CIK cell infusion was 10.57 months; the 1-year survival rate was 38.5%. No serious toxicity was associated with R-CIK cell infusion. In conclusion, RetroNectin may enhance antitumor activity of CIK cells: it is safe for use in treating pancreatic cancer.
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Timalsena, S., and P. P. Lamichhane. "Cytokine Induced Killer (CIK) Cells Based Adoptive Immunotherapy." Journal of Gandaki Medical College-Nepal 10, no. 2 (August 17, 2018): 58–63. http://dx.doi.org/10.3126/jgmcn.v10i2.20810.
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Cytokine induced killer (CIK) cells has been increasingly used in adoptive immunotherapy against various cancers and viral infections. This review summarizes the basic overview of CIK cells as a therapeutic immunocyte. Herein, the basic concepts on CIK cells, their general characteristics, approaches in enhancing their functions, cytotoxic mechanism of CIK cells and their therapeutic benefits in tumors and viral infections are explored. J-GMC-N | Volume 11 | Issue 01 | January-June 2018, Page: 58-63
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Chu, Hongjin, Fengcai Du, Lixin Jiang, Zhixin Wang, Zhaohua Gong, Peiwen Lian, Peng Li, and Jian Chen. "The Efficacy of CIK-Based Immunotherapies for Advanced Solid Tumors." Technology in Cancer Research & Treatment 16, no. 5 (July 19, 2016): 577–85. http://dx.doi.org/10.1177/1533034616659163.
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Objective: To investigate the efficacy of cytokine-induced killer cell-based immunotherapies in patients with advanced malignant solid tumors and the difference in clinical efficiency among 3 kinds of cytokine-induced killer cell-based immunotherapies. Methods: One hundred forty-six cases with advanced solid tumor, 230 cycles of cytokine-induced killer cell-based immunotherapies, were involved in this study. T-lymphocyte subsets, carcinoembryonic antigen, and adverse reactions were recorded. Results: CD3+ T lymphocyte, Th, NKT, and Th/Tc were increased after cytokine-induced killer cell-based treatment, from 55.67 ± 3.64 to 84.12 ± 5.15, 26.56 ± 4.47 to 42.76 ± 3.68, 1.82 ± 0.58 to 7.08 ± 0.92, 0.79 ± 3.64 to 1.35 ± 0.20, respectively ( P < .001). Carcinoembryonic antigen was decreased from 398.39 ± 219.16 to 127.26 ± 153.41 ( P < .001). Difference values were greater than 0 ( P < .001). Difference value of carcinoembryonic antigen was obviously less than 0 ( P < .001). There was no obvious difference in all variations between cytokine-induced killer cell and DC+CIK groups ( P > .05). The highest amount of CD3+ T lymphocyte and Th was recorded after at least 4 cycles of immunotherapy. And CD8+ T/CD4+ T also began to decrease after 4 cycles of immunotherapy. Difference value of T lymphocyte and Tc of patients with surgery is higher than that of patients without surgery. Conclusion: Cytokine-induced killer cell-based immunotherapy is capable of increasing T-lymphocyte subsets, recovering cellular immunity without severe side effects, and is suitable for different kinds of solid cancer. Clinical efficiency of cytokine-induced killer cell-based immunotherapy is influenced by many factors such as surgery, stage.
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Jäkel, Clara E., Stefan Hauser, Sebastian Rogenhofer, Stefan C. Müller, P. Brossart, and Ingo G. H. Schmidt-Wolf. "Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma." Clinical and Developmental Immunology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/473245.
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Metastatic renal cell carcinoma (RCC) seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK) cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable.In vitrostudies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.
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Zhang, Ying, Jörg Ellinger, Manuel Ritter, and Ingo G. H. Schmidt-Wolf. "Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma." Cancers 12, no. 9 (September 1, 2020): 2471. http://dx.doi.org/10.3390/cancers12092471.
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There is growing interest in cytokine-induced killer (CIK) cells on the integrated therapy of patients with RCC, especially those in the late stage or refractory to conventional chemotherapy and radiotherapy. In this review, a total of 15 clinical studies including 681 patients enrolled in CIK cell immunotherapy were outlined. Three-hundred-and-eighty-two patients with RCC were treated with CIK cells alone or in combination with DC vaccination, targeted agents sunitinib or sorafenib, and the PD-1 inhibitor pembrolizumab. Significantly improved 3-year overall survival rate was reported in four trials, whereas remarkably longer median progression-free survival was observed in three studies. Adverse reactions were mild and usually controllable fever and fatigue. Besides, preclinical research progresses were reviewed to increase our understanding about the underlying mechanisms of CIK cell cytotoxicity and identify potential targets to enhance their anti-tumor activity. These studies suggest that CIK cell-based immunotherapy has potential clinical benefits with a good safety profile and could become a promising approach in the combined therapies of RCC patients. However, further large-scale studies are required to evaluate the clinical efficacy of CIK cells and more efforts should be performed to identify the optimal CIK cell-based therapeutic regimen for RCC patients.
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Lu, Xu-zhang, Bao-An Chen, Lin-di Ma, Xiao-hui Cai, and Min Zhou. "Role of NKG2D in Cytokine-Induced Killer (CIK) Cells Against Multiple Myeloma Cells." Blood 118, no. 21 (November 18, 2011): 5119. http://dx.doi.org/10.1182/blood.v118.21.5119.5119.
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Abstract Abstract 5119 Cytokine-induced killer (CIK) cells are T lymphocytes enriched in CD3+CD56+ cells, which can be easily and rapidly expanded in vitro from human peripheral blood, bone marrow or cord blood mononuclear cells with the sequential addition of interferon (IFN)-{gamma}, OKT-3 and high doses of interleukin (IL)-2. The cytokine-induced killer (CIK) cells have been reported to have potent cytotoxicity against a variety of tumor cells including multiple myleoma (MM) cells. The mechanism of CIK cell recognizing MM cells remains unknow. Recent studies indicated that ligation of NKG2D on immunological cells directiy induce cytotoxicity. We suspect whether NKG2D receptor induction on CIK cells by cytokines is responsible for the killing of MM cells by CIK. We expended CIK cells from healthy controlswith interferon (IFN)-γ, CD3 monoclonal antibodies (mAb) and IL-2, and checked expression of NK cell receptors on CIK cells by flow cytometry. We found higher expression of NKG2D receptor and lower other NK receptors, such as CD158a,CD158b and NCRs on expanded CIK. These CIK cells showed higer cytotoxicity to multiple myleoma cell line U266 expressing NKG2D ligands. Interestingly, when cocultured with U266 cells, only NKG2D expressing CIK cells released IFN-γ detected by flow cytometry. We next analyzed NKG2D ligands expression on primary plasma cells in 22 MM patients by flow cytometry, the primary plasma cells in 16/22 (72.7%) MM patients expressed different levels of ULBPs or MICA/B on the cell surface. CIK cells showed higher cytotoxicity (12.5%) to NKG2D ligands expressing primary plasma cells compared to those did not express NKG2D ligands. The killing of CIK against MM cells were partially blocked by treatment of CIK with anti-NKG2D antibody. We conclude that NKG2D-NKG2D ligangd interaction may be one of the mechanisms by which CIK cells kill MM cells. Disclosures: No relevant conflicts of interest to declare.
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Mase, Shintaro, Ryosei Nishimura, Rie Kuroda, Hideaki Maeba, Kazuhito Naka, Raita Araki, Yasuhiro Ikawa, Shoichi Koizumi, and Akihiro Yachie. "Cytokine-Induced Killer Cells Facilitate Immune Reconstitution After Allogeneic BMT In Mice." Blood 116, no. 21 (November 19, 2010): 3719. http://dx.doi.org/10.1182/blood.v116.21.3719.3719.
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Abstract Abstract 3719 Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft versus host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. With the purpose of potential application of CIK cells in a clinical hematopoietic stem cell transplantation, the problem we have to consider next is whether CIK cells could promote an engraftment and facilitate an immune reconstitution. To this end, lethally irradiated BALB/c mice were injected with minimal number of MHC incompatible C57BL/6 bone marrow (BM) cells alone, in which almost half of mice died because of graft failure, or with CIK concurrently. The mice receiving BM plus CIK cells survived with 93% without GVHD, demonstrating that CIK cells significantly promote an engraftment (P<0.05). In particular, recovery of CD3+ T-cells was significantly faster (p<0.05) in the mice receiving BM plus CIK cells than those receiving BM cells alone. Next we further evaluated whether CIK cells also promote an engraftment in the mice receiving non-myeloablative conditioning using low dose total body irradiation. As expected, CIK cells promoted an engraftment and favored immunoreconstitution, especially from the early time point after BMT. In conclusion, our study clearly demonstrated that CIK cells promote an engraftment and facilitate an immure reconstitution without GVHD. As recent studies demonstrated that sufficient number of CIK cells could be expanded even from washouts of cord blood units bags, infusion of CIK cells would be a potent strategy for preventing a graft-failure in clinical settings, especially after cord blood transplantation. Disclosures: No relevant conflicts of interest to declare.
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Arai, Sally, Kevin Sheehan, Sherry Moore, Ginna Laport, Laura Johnston, Robert Lowsky, David Miklos, et al. "Autologous Cytokine-Induced Killer Cells as Post-Transplant Cellular Immunotherapy." Blood 110, no. 11 (November 16, 2007): 580. http://dx.doi.org/10.1182/blood.v110.11.580.580.
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Abstract Disease relapse remains a major cause of treatment failure following autologous hematopoietic cell transplantation (HCT) for patients with high-risk malignancies. Cellular immunotherapy using activated autologous effector cells to recognize and kill tumor targets in a minimal disease state after transplant is a novel strategy to reduce relapse and improve survival. In this phase I/II study, we investigated the safety and efficacy of administering ex-vivo expanded autologous cytokine-induced killer (CIK) cells as post-transplant cellular immunotherapy. Patients with high risk recurrent or refractory Hodgkin’s disease (HD)- defined as B symptoms at relapse, pulmonary or bone marrow disease at relapse and more than minimal disease at the time of transplantation- and patients with multiple myeloma (MM) and acute myelogenous leukemia undergoing single autologous HCT were eligible. The autologous CIK cells were ex-vivo expanded from an aliquot of the patient’s autologous apheresis product for 21–28 days in the presence of IFN-γ, IL-2, and OKT-3 to a maximal cell dose of 2×108 CIK cells/kg. The CIK cell population is uniquely characterized by having the functional and phenotypic properties of both T cells and NK cells, (i.e. expressing CD3 and CD56 molecules) and kills tumor targets through an NKG2D-mediated mechanism. A single infusion of CIK cells was given on day 42–63 following autologous transplantation. Monitoring for infusion-related toxicities was performed for the first 28 days. Disease response assessments were done at day 90, 180, one year and annually. Correlative studies on cytokine profile, primary tumor cytotoxicity and NKG2D ligand expression are being performed. Thirteen patients (ages 19–64) have received autologous CIK cell infusions to date. Nine patients have high risk HD; four patients have MM with a single autologous HCT. The median CIK cell dose for infusion was 0.9×108 cells/kg (range 0.2–2×108/kg). The only infusional toxicities observed have been one grade 1 headache and one grade 1 nausea- both were transient and resolved. Hematologic parameters have not been affected by the infusion. In vitro cytotoxicity of cultured CIK cells was assessed against a panel of leukemia and lymphoma cell lines including Jurkat, DB, OCI-Ly8 and SUDHL4. Median 51-Cr release at 40:1 (E:T) ranged from 71% killing against Jurkat cells to 21% against DB. The first patient on the trial with high risk HD involving the lung and bone marrow is one year from HCT without evidence of disease relapse. Four other patients (all high risk HD) have completed day 180 disease response assessments and have no evidence of disease relapse. One HD patient had progressive disease at day 100. The three evaluable MM patients have no disease progression at day 90–180. In this first phase of study, we have confirmed the safety of administering autologous CIK cells at a single maximal dose at day 42–63 post-transplant. Maintenance of disease response in these high risk patients is encouraging in the first year following transplantation.
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Jäkel, Clara E., Annabelle Vogt, Maria A. Gonzalez-Carmona, and Ingo G. H. Schmidt-Wolf. "Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Gastrointestinal Tumors." Journal of Immunology Research 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/897214.
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Tumors of the gastrointestinal system represent a significant share of solid tumors worldwide. Despite the advances in diagnosis and treatment, the prognosis of gastrointestinal tumors is still very poor and improved therapies are indispensable. Cytokine-induced killer (CIK) cells are feasible for an immunotherapeutic approach as they are easily available and have an advantageous biologic profile; they are rapidly proliferating and their high cytotoxicity is non-MHC-restricted. We summarize and discuss twenty recent clinical studies applying CIK cells for the treatment of gastric, pancreatic, hepatocellular, and colorectal cancer. Autologous CIK cells were transfused intravenously, intraperitoneally, or via the common hepatic artery. In all studies side effects and toxicity of CIK cell therapy were mild and easily controllable. The combination of CIK cell therapy with conventional adjuvant or palliative therapies was superior to the standard therapy alone, indicating the benefit of CIK cell therapy for cancer patients. Thus, CIK cells represent a promising immunotherapy for the treatment of gastrointestinal tumors. The optimal treatment schedule and ideal combination with conventional therapies should be evaluated in further clinical studies.
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Ryu, Hwa Sun, Yeon Jin Kim, Hong Kyung Lee, Jee Youn Kim, Jin Tae Hong, Youngsoo Kim, and Sang-Bae Han. "Characterization of antitumor cytokine-induced killer cells generated from immature precursors (87.31)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 87.31. http://dx.doi.org/10.4049/jimmunol.184.supp.87.31.
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Abstract Cytokine-induced killer (CIK) cells have been explored for active immunotherapy of cancer. CIK cells gave strong anti-tumor effects and their cytotoxicity is MHC-unrestricted. In most clinical trials, CIK cells were generated from human PBMCs, mostly containing mature T cell precursors. However, whether immature T cells could be used as precursors of CIK cells was not clarified yet. The possible usage of immature T cells as sources of CIK cells was evaluated in this study. CIK cells were generated from immature T cells of bone marrow and thymus, and their functions were compared with CIK cells generated from mature T cells of spleen. Interferon gamma, anti-CD3 monoclonal antibody, and interleukin 2 (IL-2) were timely added to cultures to generate CIK cells. The absolute number of splenocytes, bone marrow cells, and thymocytes increased by 249, 54, and 14-fold, and CD3+NK1.1+ cells were 30%, 30%, and 33%, respectively. These three different cell populations showed similar profiles in cytokine gene expression, in that they highly expressed IFN-gamma and TNF-alpha. And they showed similar gene expression profiles of granzynme A/B, perforin, and FasL. In addition, they showed similar antitumor activity against B16F10 melanoma. In summary, although CIK cells generated from immature or mature T cells showed similar profiles in phenotypes, cytokine expression, and antitumor activity in vivo, clinical application of immature T cells might be impeded by low ex vivo expansion.
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Tang, Peijun, Xingnian Chen, Junchi Xu, Yunlong Hu, Zhijian Ye, Xiafang Wang, Yumei Xiao, et al. "Autologous Cytokine-Induced Killer Cell Immunotherapy Enhances Chemotherapy Efficacy against Multidrug-Resistant Tuberculosis." Journal of Immunology Research 2022 (March 17, 2022): 1–10. http://dx.doi.org/10.1155/2022/2943113.
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Objective. Multidrug-resistant tuberculosis (MDR-TB) causes persistent infection and challenges tuberculosis control worldwide. T cell-mediated immunity plays a critical role in controlling Mycobacterium tuberculosis (Mtb) infection, and therefore, enhancing Mtb-specific T cell immune responses represents a promising therapeutic strategy against TB. Cytokine-induced killer (CIK) immunotherapy is based on autologous infusion of in vitro expanded bulk T cells, which include both pathogen-specific and nonspecific T cells from patient peripheral blood mononuclear cells (PBMC) into TB patients. Preclinical mouse studies have shown that the adoptive T cell therapy inhibited Mtb infection. However, the efficacy of CIK immunotherapy in the treatment of MDR-TB infection has not been evaluated in clinical trials. Methods. We performed a retrospective study of MDR-TB patients who received CIK immunotherapy in combination with anti-TB chemotherapy and those who had standard chemotherapy. Results. Our results showed that CIK immunotherapy in combination with anti-TB chemotherapy treatment increased the conversion rate of sputum smear and Mtb culture, alleviated symptoms, improved lesion absorption, and increased recovery. The kinetics of serology and immunology index monitoring data showed good safety profiles for the CIK treatment. Conclusion. Our study has provided strong evidence that CIK immunotherapy in combination with anti-TB chemotherapy is beneficial for MDR-TB patients. A multicenter clinical trial is warranted to evaluate CIK as a new immune therapy for MDR-TB.
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Dehno, Mojgan Naghizadeh, Yutao Li, Hans Weiher, and Ingo G. H. Schmidt-Wolf. "Increase in Efficacy of Checkpoint Inhibition by Cytokine-Induced-Killer Cells as a Combination Immunotherapy for Renal Cancer." International Journal of Molecular Sciences 21, no. 9 (April 27, 2020): 3078. http://dx.doi.org/10.3390/ijms21093078.
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Cytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes that have acquired the expression of several natural killer (NK) cell surface markers following the addition of interferon gamma (IFN-γ), OKT3 and interleukin-2 (IL-2). Treatment with CIK cells demonstrates a practical approach in cancer immunotherapy with limited, if any, graft versus host disease (GvHD) toxicity. CIK cells have been proposed and tested in many clinical trials in cancer patients by autologous, allogeneic or haploidentical administration. The possibility of combining them with specific monoclonal antibodies nivolumab and ipilimumab will further expand the possibility of their clinical utilization. Initially, phenotypic analysis was performed to explore CD3, CD4, CD56, PD-1 and CTLA-4 expression on CIK cells and PD-L1/PD-L2 expression on tumor cells. We further treated CIK cells with nivolumab and ipilimumab and measured the cytotoxicity of CIK cells cocultured to renal carcinoma cell lines, A-498 and Caki-2. We observed a significant decrease in viability of renal cell lines after treating with CIK cells (p < 0.0001) in comparison to untreated renal cell lines and anti-PD-1 or anti-CTLA-4 treatment had no remarkable effect on the viability of tumor cells. Using CCK-8, Precision Count Beads™ and Cell Trace™ violet proliferation assays, we proved significant increased proliferation of CIK cells in the presence of a combination of anti-PD-1 and anti-CTLA-4 antibodies compared to untreated CIK cells. The IFN-γ secretion increased significantly in the presence of A-498 and combinatorial blockade of PD-1 and CTLA-4 compared to nivolumab or ipilimumab monotreatment (p < 0.001). In conclusion, a combination of immune checkpoint inhibition with CIK cells augments cytotoxicity of CIK cells against renal cancer cells.
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Laport, Ginna G., Kevin Sheehan, Robert Lowsky, Judith A. Shizuru, Keith Stockerl-Goldstein, Laura J. Johnston, David Miklos, Sally Arai, Jeanette Baker, and Robert S. Negrin. "Cytokine Induced Killer (CIK) Cells as Post-Transplant Immunotherapy Following Allogeneic Hematopoietic Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 412. http://dx.doi.org/10.1182/blood.v108.11.412.412.
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Abstract Donor leukocyte infusions induce remissions in some patients(pts) with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation(AHCT). Response rates are disease-specific and acute graft vs host disease(GVHD) remains the major complication of this strategy. CIK cells are a unique population of cytotoxic T lymphocytes that express the CD3+CD56+ phenotype and show marked upregulation of the NK cell receptor, NKG2D. CIK cells are non-MHC restricted, NKG2D dependent in target recognition and killing and demonstrate cytotoxicity against a broad array of tumor cell lines including leukemia targets. In preclinical studies, CIK cells have exhibited superior antitumor activity compared to IL-2 activated NK cells with a markedly reduced capacity for acute GVHD. The primary objective of this trial was to determine the feasibility of ex vivo expansion of allogeneic CIK cells suitable for clinical application for pts with relapsed hematologic malignancies after AHCT(myeloablative or non-myeloablative) and to determine the maximum tolerated dose of CIK cells based on CD3+ cell dose. CIK cells were generated from CD3+ precursors by culturing unmobilized peripheral blood mononuclear cells (PBMC) from the patient’s matched sibling donor. The PBMCs were cultured for 21–28 days in the Aastrom Replicell® biochamber in the presence of anti-CD3+ monoclonal antibody, IL-2 and IFN-γ. Ten patients with a median age of 50 yo(range 29–63 yo) received CIK cell infusions based on CD3+cells/kg at a dose of 1x107 (n=3), 5x107 (n=6) and 1x108 (n=1). The diagnoses of these pts included acute myeloid leukemia(n=4), non-Hodgkins lymphoma(n=2), multiple myeloma(n=3) and Hodgkins disease(n=1). Prior to CIK infusion, all pts underwent cytoreduction for tumor debulking. One pt experienced infusional toxicities consisting of ventricular arrhythmias and transient hypotension. After infusion, grade 3–4 toxicities were seen at the 2nd dose level and included symptomatic ventricular arrhythmias in two patients with 1 of these pts also experiencing transient elevation of transaminases. These dose limiting toxicities(DLTs) resulted in expansion of the cohort at this dose level. No further DLTs were seen in subsequent pts allowing escalation to the 3rd and current dose level. Grade 1 skin acute GVHD was seen in 1 pt and 2 pts had limited chronic GVHD. After a median follow-up time of 432 days (range 2–649) from CIK infusion, the 1 year event free survival and overall survival was 20% and 76%, respectively. The median time to progression was 90 days(range 9–577). Analysis of cell cultures showed that most recovered cells were CD3+ (median 98%, range 90–99%) with a median viability of 87%( range 73–95%) with the median expansion of CD3+ cells being 16 fold(range 9–91 fold). CD3+CD56+ cells represented a median of 12% (range 8–32%) of the harvested cultures with a median 96 fold (range 26–515 fold) expansion. CD8+NKG2D+ expression ranged from 17–61%(median 38%) of harvested cells. Upregulation of the activation markers, CD25+ and CD69+ was also seen. Significant tumor cell killing was demonstrated in vitro by cytotoxicity assays against a panel of tumor cell lines. This data demonstrates successful ex vivo expansion of allogeneic CIK cells in the clinical setting. This form of adoptive immunotherapy is well tolerated by pts, induces a low incidence of GVHD and shows evidence for clinical efficacy.
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Koh, M. B. C., and Y. Ching Linn. "Clinical expansion of cytokine induced killer (CIK) cells." ISBT Science Series 7, no. 1 (June 13, 2012): 154–56. http://dx.doi.org/10.1111/j.1751-2824.2012.01599.x.
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Zhang, Ying, Amit Sharma, Hans Weiher, Matthias Schmid, Glen Kristiansen, and Ingo G. H. Schmidt-Wolf. "Clinical Studies on Cytokine-Induced Killer Cells: Lessons from Lymphoma Trials." Cancers 13, no. 23 (November 29, 2021): 6007. http://dx.doi.org/10.3390/cancers13236007.
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Cancer is a complex disease where resistance to therapies and relapses often pose a serious clinical challenge. The scenario is even more complicated when the cancer type itself is heterogeneous in nature, e.g., lymphoma, a cancer of the lymphocytes which constitutes more than 70 different subtypes. Indeed, the treatment options continue to expand in lymphomas. Herein, we provide insights into lymphoma-specific clinical trials based on cytokine-induced killer (CIK) cell therapy and other pre-clinical lymphoma models where CIK cells have been used along with other synergetic tumor-targeting immune modules to improve their therapeutic potential. From a broader perspective, we will highlight that CIK cell therapy has potential, and in this rapidly evolving landscape of cancer therapies its optimization (as a personalized therapeutic approach) will be beneficial in lymphomas.
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Garofano, Francesca, and Ingo G. H. Schmidt-Wolf. "High Expression of Cannabinoid Receptor 2 on Cytokine-Induced Killer Cells and Multiple Myeloma Cells." International Journal of Molecular Sciences 21, no. 11 (May 27, 2020): 3800. http://dx.doi.org/10.3390/ijms21113800.
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Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized. Cannabidiol (CBD) may be used to treat various diseases. CBD is known to exert immunomodulatory effects through the activation of cannabinoid receptor 2 (CB2), which is expressed in high levels in the hematopoietic system. Cytokine-induced killer (CIK) cells are a heterogeneous population of polyclonal T lymphocytes obtained via ex vivo sequential incubation of peripheral blood mononuclear cells (PBMCs) with interferon-γ (IFN-γ), anti CD3 monoclonal antibody, and IL-2. They are characterized by the expression of CD3+ and CD56+, which are surface markers common to T lymphocytes and natural killer (NK) cells. CIK cells are mainly used in hematological patients who suffer relapse after allogeneic transplantation. Here, we investigated their antitumor effect in combination with pure cannabidiol in KMS-12 MM cells by lactate dehydrogenase LDH cytotoxicity assay, CCK-8 assay, and flow cytometry analysis. The surface and intracellular CB2 expressions on CIK cells and on KMS-12 and U-266 MM cell lines were also detected by flow cytometry. Our findings confirm that the CB2 receptor is highly expressed on CIK cells as well as on MM cells. CBD was able to decrease the viability of tumor cells and can have a protective role for CIK cells. It also inhibits the cytotoxic activity of CIKs against MM at high concentrations, so in view of a clinical perspective, it has to be considered that the lower concentration of 1 µM can be used in combination with CIK cells. Further studies will be required to address the mechanism of CBD modulation of CIK cells in more detail.
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Han, Sang-Bae, Yeon Jin Kim, Jee Youn Kim, Hwa Sun Ryu, Hyung Suk Kim, Jun Ho Yun, Hwan Mook Kim, et al. "Analysis of in vivo homing of cytokine-induced killer cells into lymph nodes (41.17)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 41.17. http://dx.doi.org/10.4049/jimmunol.182.supp.41.17.
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Abstract The goal of immune cell-based cancer therapy is to eliminate cancer cells through the transfer of ex vivo expanded and activated immune cells. Cytokine-induced killer (CIK) cells are ex vivo expanded T cell mixture with proven anticancer activity in vitro and in vivo. In the presence of immobilized anti-CD3 antibody and IL-2 for 14 days, mouse splenocytes changed to heterogeneous CIK cell population, which comprised 97% CD3+, 86% CD8+, 7% CD4+, 25% CD3+NK1.1+, and 30% CD8+NK1.1+. Although CD3+NK1.1+ cells were rare in fresh human peripheral blood mononuclear cells, they could expand more than 1,000-fold on day 14. Ex vivo proliferation of splenocytes was critically dependent on IL-2 concentration and cell density; in that IL-2 was required at least 750 U/ml and cell number was maintained at one or two million cells per milliliter during the cultivation. CIK cells strongly expressed IFN-gamma and IL-2, moderately IL-4 and TNF-alpha, but not IL-1beta, IL-5, and IL-10. Compared with purified T cells, CIK cells also expressed lower levels of adhesion molecules, such as L-selectin and CD49d, and chemokine receptors, such as CCR7 and CXCR4. It was resulted in less trafficking of CIK cells to lymph nodes than purified T cells did, which was determined by confocal microscopic and flow cytometric analysis. The data shown here demonstrated that inappropriate trafficking of CIK cells to lymph nodes might be one of the hurdles for in vivo application of CIK cell therapy, and suggest that L-selectin, CD49d, CCR7 and CXCR4 might be good targets to increase CIK cell trafficking to lymph nodes.
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Wang, Yao, Hanren Dai, Hong Li, Haiyan Lv, Tao Wang, Xiaobing Fu, and Weidong Han. "Growth of Human Colorectal Cancer SW1116 Cells Is Inhibited by Cytokine-Induced Killer Cells." Clinical and Developmental Immunology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/621414.
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Previous reports have suggested that treatment with cytokine-induced killer (CIK) cells may benefit patients with various types of tumor. The aim of this study was to evaluate the antitumor effects of CIK cells against the colorectal cancer line SW1116in vitroandin vivo. CIK cells were generated routinely from peripheral blood mononuclear cells of healthy human donors, and the number of CD3+CD56+cells was expanded more than 1300-fold after 14-day culture. At an effector : target cell ratio of 50 : 1, the percentage lysis of SW1116 cells reached 68% in the presence of CIK cells, Experimental mice injected with SW1116 cells subcutaneously were divided randomly into four groups: untreated, 5-fluorouracil (5-FU)-treated, CIK-consecutive treated (injected once/day) and CIK-interval treated (injected once every 5 days). CIK cells were injected abdominally five times in total. Compared with the untreated group, xenograft growth was inhibited greatly by CIK treatment, to nearly the same extent as with 5-FU treatment. We demonstrated that the necrotic area in the tumor xenograft was markedly larger in the CIK-treated groups than in the other groups. These findings suggest that CIK-based immunotherapy may represent an effective choice for patients with colorectal cancer.
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Yang, Chan-Keng, Chien-Hao Huang, Ching-Hsun Hu, Jian-He Fang, Tse-Ching Chen, Yung-Chang Lin, and Chun-Yen Lin. "Immunophenotype and antitumor activity of cytokine-induced killer cells from patients with hepatocellular carcinoma." PLOS ONE 18, no. 1 (January 4, 2023): e0280023. http://dx.doi.org/10.1371/journal.pone.0280023.
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Background Cytokine-induced killer (CIK) cells are heterogeneous lymphocytes from human peripheral blood mononucleated cells (PBMCs) co-cultured with several cytokines. The main purpose of this study is to evaluate the functional characteristics and anticancer ability of CIK cells from hepatocarcinoma (HCC) patients. Methods CIK cells were activated ex-vivo and expanded from PBMCs from HCC patients. The immunophenotype and the ex-vivo killing ability of CIK cells were evaluated. Human CIK cells were intravenously injected into NOD/SCID mice to evaluate the in vivo anticancer ability. Results More than 70% of CIK cells were CD3+CD8+, and 15%–30% were CD3+CD56+. These cells expressed an increased number of activated natural killer (NK) receptors, such as DNAM1 and NKG2D, and expressed low-immune checkpoint molecules, including PD-1, CTLA-4, and LAG-3. Among the chemokine receptors expressed by CIKs, CXCR3 and CD62L were elevated in CD8+ T cells, representing the trafficking ability to inflamed tumor sites. CIK cells possess the ex-vivo anticancer activity to different cell lines. To demonstrate in vivo antitumor ability, human CIK cells could significantly suppress the tumor of J7 bearing NOD/SCID mice. Furthermore, human immune cells could be detected in the peripheral blood and on the tumors after CIK injection. Conclusions This study revealed that CIK cells from HCC patients possess cytotoxic properties, and express increased levels of effector NK receptors and chemokine molecules and lower levels of suppressive checkpoint receptors. CIK cells can suppress human HCC ex-vivo and in vivo. Future clinical trials of human CIK cell therapy for HCC are warranted.
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Mase, Shintaro, Hideaki Maeba, Toshihiro Fujiki, Rie Kuroda, Raita Araki, Shoichi Koizumi, Akihiro Yachie, and Ryosei Nishimura. "Allogeneic Cytokine-Induced Killer Cell-Dependent Eimination of Host Dendritic Cells Leads to Less Graft-Versus-Host Disease." Blood 120, no. 21 (November 16, 2012): 3011. http://dx.doi.org/10.1182/blood.v120.21.3011.3011.
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Abstract Abstract 3011 Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer (NK)- and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. The mechanism of suppression of GVHD with CIK cells is not fully understood. Host residual dendritic cells (DCs) are most important cells in initiating GVHD reaction. Therefore, we hypothesized that alloreactive NK cells, even when infused in large numbers, do not cause GVHD by killing recipient DCs with a same mechanism as CIK cells kill tumor cells. To test this, DCs generated from rodent bone marrow cells were used for 51-Cr release cytotoxicity assays as target cells. We demonstrated that though autologous CIK cells (Balb/c) had relatively strong killing activity against mature DCs (Balb/c), allogeneic CIK cells (B6) had much more killing activity even from at a 10:1 effector -target ratio as shown in Fig 1 below. In addition, killing activity against DCs did not changed with/without adding NKG2D blocking antibody, suggesting that there were possible mechanisms for cell killing other than NKG2D/NKG2D ligand system in CIK cells. To further evaluate whether allogeneic CIK cells eliminate host DCs to reduce GVHD in vivo, lethally irradiated Balb/c recipients were given BM (B6) with CIK cells or splenocytes to compare the number and activation status of residual host-typed DCs in the spleen after bone marrow transplantation. As shown in Fig 2, on day 1 after BMT absolute number of host DCs in spleen receiving splenocytes and CIK cells were almost same, however, the numbers of DCs in the mice receiving BM alone were much less. On day 3, absolute number of host DCs in all groups decreased. In particular, the number of host DCs in the mice receiving CIK cells dramatically decreased and finally reached to the same number of host DCs in the mice receiving BM alone. On the contrary, the number of host DCs in the mice receiving splenocytes didn't decrease so much and was significantly greater than number of host DCs in the mice receiving BM alone. Considering the above, when allo-CIK cells first met to DCs, both DCs and CIK cells were expanded on day 1 after BMT, and then allo-CIK cells turned to kill host DCs. In conclusion, allogeneic CIK cells caused less GVHD due in part to elimination of host DCs. Disclosures: No relevant conflicts of interest to declare.
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Dalla Pietà, A., E. Cappuzzello, P. Palmerini, R. Sommaggio, G. Astori, K. Chieregato, O. Perbellini, et al. "P09.01 Adoptive cell therapy of hematological malignancies using cytokine-induced killer cells retargeted with monoclonal antibodies." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A51.2—A52. http://dx.doi.org/10.1136/jitc-2020-itoc7.101.
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BackgroundCytokine-Induced Killer (CIK) cells are a population of effector cells that represents a promising tool for adoptive cell therapy. They are easily expandable ex-vivo, safe, and exert cytotoxicity against a broad range of tumor histotypes.1 We recently reported that they have a relevant expression of FcγRIIIa (CD16a), which can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their cytotoxicity in an antigen-specific manner, to improve their antitumor activity.2 Indeed, the engagement of CD16a on CIK cells leads to a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian cancer both in vitro and in vivo. Based on this observation, we investigated whether CIK cells can be specifically retargeted against B-cell malignancies by combination with anti-CD20 mAbs, namely Rituximab® (RTX) and Obinutuzumab® (OBI).Materials and MethodsCIK cells were obtained from peripheral blood mononuclear cells of healthy donors, and stimulated in vitro with IFN-γ, CD3 mAb and IL-2 for 14 days; fresh IL-2 was provided every 3–4 days. CIK cell phenotype was analyzed by multicolor flow cytometry; cytotoxic activity was assessed by calcein AM-release assay against B-cell lines, primary samples and patient-derived xenografts (PDX) obtained from B-cell lymphoma patients after written informed consent.ResultsThe combination with both RTX and OBI significantly increased specific CIK cells lysis against several CD20-expressing lymphoma B cell lines, primary tumors from B-cell lymphoma patients and an established PDX, compared to the combination with a control mAb (cetuximab, CTX). NK-depletion demonstrated that the mAb-mediated cytotoxicity is accountable to the CIK cells fraction within the bulk population since no difference in the lytic activity was detectd in the absence of NK cells. In addition, these results are further supported by in vivo preliminary experiments where the treatment with CIK cells in combination with OBI extensively reduced the growth of PDX and increased mice survival, compared to CIK cells or OBI administered alone.ConclusionsHere we proved that CIK cells can be retargeted with clinical-grade mAbs against CD20-expressing lymphomas. These data indicate that the combination of CIK cells with mAbs can represent a novel approach for the treatment of haematological malignancies.ReferencesFranceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J, et al. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol 2009;37:616–28.Cappuzzello E, Tosi A, Zanovello P, Sommaggio R, Rosato A. Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies. Oncoimmunology 2016 Aug;5(8):e1199311.The research leading to these results has received funding from Fondazione AIRC under IG 2018 - ID. 21354 project - P.I. Rosato AntonioDisclosure InformationA. Dalla Pietà: None. E. Cappuzzello: None. P. Palmerini: None. R. Sommaggio: None. G. Astori: None. K. Chieregato: None. O. Perbellini: None. M. Tisi: None. C. Visco: None. M. Ruggeri: None. A. Rosato: None.
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Nishimura, Ryosei, Jeanette Baker, Andreas Beilhack, Robert Zeiser, Janelle A. Olson, Emanuela I. Sega, Mobin Karimi, and Robert S. Negrin. "In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity." Blood 112, no. 6 (September 15, 2008): 2563–74. http://dx.doi.org/10.1182/blood-2007-06-092817.
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Abstract Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. CIK cells are cytotoxic against autologous and allogeneic tumors. We previously showed that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD). However, the precise mechanism of reduced GVHD is not fully understood. Therefore, we evaluated the trafficking and survival of luciferase-expressing CIK cells in an allogeneic bone marrow transplant model. The initial trafficking patterns of CIK cells were similar to conventional T cells that induced GVHD; however, CIK cells infiltrated GVHD target tissues much less and transiently. CIK cells accumulated and persisted in tumor sites, resulting in tumor eradication. We evaluated different properties of CIK cells compared with conventional T cells, demonstrating a slower division rate of CIK cells, higher susceptibility to apoptosis, persistent increased expression of interferon gamma (IFN-γ), and reduced acquisition of homing molecules required for entry of cells into inflamed GVHD target organs that lack expression of NKG2D ligands recognized by CIK cells. Due to these properties, allogeneic CIK cells had reduced expansion and caused less tissue damage. We conclude that CIK cells have the potential to separate graft-versus-tumor effects from GVHD.
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Kuroda, Rie, Shintaro Mase, Toshihiro Fujiki, Hideaki Maeba, Raita Araki, Yasuhiro Ikawa, Masaki Fukuda, Shoichi Koizumi, Akihiro Yachie, and Ryosei Nishimura. "Third Party Cytokine-Induced Killer Cells Protect from Murine Lethal Graft-Versus-Host Disease." Blood 126, no. 23 (December 3, 2015): 3092. http://dx.doi.org/10.1182/blood.v126.23.3092.3092.
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Abstract Cell adoptive immunotherapy protect from lethal graft-versus-host disease (GVHD) while preserving graft-versus-tumor effects is ideal in allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. Moreover, the use of third party cells would open a huge source of availability and feasibility across major histocompatibility barriers. In fact, some studies demonstrated that infusion of third party derived cells such as whole bone marrow cells or iNKT cells could ameliorate lethal GVHD in a murine model. Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer and T-cell markers. We have previously reported that donor-type CIK cells have potential to separate graft-versus-tumor effects from GVHD by eliminating host dendritic cells due to the enhanced killing activity by interferon-gamma. Actually, donor-typed CIKs infusion for refractory hematological malignancies after HSCT has been started in some clinical trails. In the present study, we examine the effect of third party cells against GVHD protection, in particular third party CIK cells for prevention from lethal GVHD in a murine model of allogeneic HSCT. To test this, lethally irradiated host Balb/c (H-2d) mice were given C3H (H-2k) or B6 (H-2b) bone marrow cells and splenocytes to induce lethal GVHD with/without third-party cells (C57/BL6 or C3H) such as CIK cells, whole splenocytes, or bone marrow derived dendritic cells (BMDCs) on day 0, which were cultured from bone marrow cells with GM-CSF. Mice receiving third party CIK cells showed much less GVHD and significant survival benefit compared those with third party splenocytes, or BMDCs as shown in the figure below. Interestingly, when infusion of third party splenocytes was delayed until day 4 after bone marrow transplantation, host mice receiving splenocytes survived much better compared with mice receiving splenocytes on day 0, even though reduced number of third party splenocytes was used. This result indicated that timing of third party cell infusion was quite important, especially when third party splenocytes were used. As expected, the mice given reduced number of third CIK cells also showed excellent survival with much less GVHD. Taken together, our results clearly demonstrated that third party CIK cells have strong potential to prevent lethal GVHD without attention to timing of cell infusion. Next, to further investigate the advantage of third party CIK cells rather than whole splenocytes, we compared the hematological reconstitution between the mice given third party CIK cells on day 4 after BMT and whole splenocytes. Both mice showed much less GVHD with the same level, however the recovery of white blood cell count on day 21 after BMT was significantly better in the mice receiving third party CIK cells. In conclusion, infusion of third party CIK cells has strong potential to prevent lethal GVHD with faster hematological recovery after HSCT. Disclosures No relevant conflicts of interest to declare.
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Pievani, Alice, Gianmaria Borleri, Daniela Pende, Lorenzo Moretta, Alessandro Rambaldi, Josée Golay, and Martino Introna. "Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity." Blood 118, no. 12 (September 22, 2011): 3301–10. http://dx.doi.org/10.1182/blood-2011-02-336321.
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Abstract CD3+CD56+ cytokine-induced killer (CIK) cells display a potent cytolytic activity. The adhesion molecule lymphocyte function-associated antigen-1 plays a crucial role in binding as well as in cytolytic activity of CIK cells against tumor target cells expressing the corresponding ligands. CIK cells express activating natural killer (NK) receptors, including NKG2D, DNAX accessory molecule-1 (DNAM-1), and low levels of NKp30. Cell signaling not only through TCR/CD3 but also through NKG2D, DNAM-1, and NKp30 leads to CIK cell activation resulting in granule exocytosis, cytokine secretion, and cytotoxicity. Antibody blocking experiments showed that DNAM-1, NKG2D, and NKp30 are involved in the TCR-independent tumor cell recognition and killing. Anti–CMV-specific CIK cells could be expanded in standard CIK cultures and mediate both specific, MHC-restricted recognition and TCR-independent NK-like cytolytic activity against leukemic cell lines or fresh leukemic blasts. Antibody blocking of lymphocyte function-associated antigen-1 and DNAM-1 led to significant reduction of both CTL and NK-cell functions, whereas blocking of NKG2D and NKp30 only inhibited NK-like cytotoxicity. Their dual-effector function suggests that CIK cells, when used in a clinical setting, may control both neoplastic relapses and viral infections, 2 frequently associated complications in patients who received a transplant.
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Vu, Binh Thanh, Nguyet Thi-Anh Tran, Tuyet Thi Nguyen, Quyen Thanh-Ngoc Duong, Phong Minh Le, Hanh Thi Le, and Phuc Van Pham. "The priming role of dendritic cells on the cancer cytotoxic effects of cytokine-induced killer cells." Science and Technology Development Journal 22, no. 2 (May 27, 2019): 196–212. http://dx.doi.org/10.32508/stdj.v22i2.1683.
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Introduction: In vitro cultivation of DCs and cytokine-induced killer cells (CIK cells) - a special phenotype of T lymphocyte populations — for cancer treatment has gained significant research interest. The goal of this study is to understand whether the priming from DCs helps CIK cells to exert their toxic function and kill the cancer cells.
Methods: In this research, DCs were differentiated from mononuclear cells in culture medium supplemented with Granulocyte-macrophage colony-stimulating factor (GM-CSF), and Interleukin-4 (IL-4), and were induced to mature with cancer cell antigens. Umbilical cord blood mononuclear cells were induced into CIK cells by Interferon-γ (IFN-γ), anti-CD3 antibody and IL-2. After 4-day exposure (with DC:CIK = 1:10), DCs and CIK cells interacted with each other.
Results: Indeed, DCs interacted with and secreted cytokines that stimulated CIK cells to proliferate up to 133.7%. In addition, DC-CIK co-culture also stimulated strong expression of IFN-γ. The analysis of flow cytometry data indicated that DC-CIK co-culture highly expressed Granzyme B (70.47% ± 1.53, 4 times higher than MNCs, twice higher than CIK cells) and CD3+CD56+ markers (13.27% ± 2.73, 13 times higher than MNCs, twice higher than CIK cells). Particularly, DC-CIK co-culture had the most specific lethal effects on cancer cells after 72 hours.
Conclusion: In conclusion, co-culture of DCs and CIK cells is capable of increasing the expression of CIK-specific characteristics and CIK toxicity on cancer cells.
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Mehta, BA, IG Schmidt-Wolf, IL Weissman, and RS Negrin. "Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells." Blood 86, no. 9 (November 1, 1995): 3493–99. http://dx.doi.org/10.1182/blood.v86.9.3493.bloodjournal8693493.
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Cytokine-induced killer (CIK) cells are non-major histocompatibility complex-restricted cytotoxic cells generated by incubation of peripheral blood lymphocytes with anti-CD3 monoclonal antibody (MoAb), interleukin-2 (IL-2), IL-1, and interferon-gamma. Cells with the greatest effector function in CIK cultures coexpress CD3 and CD56 surface molecules. CIK cell cytotoxicity can be blocked by MoAbs directed against the cell surface protein leukocyte function associated antigen-1 but not by anti-CD3 MoAbs. CIK cells undergo release of cytoplasmic cytotoxic granule contents to the extracellular space upon stimulation with anti-CD3 MoAbs or susceptible target cells. Maximal granule release was observed from the CD3+ CD56+ subset of effector cells. The cytoplasmic granule contents are lytic to target cells. Treatment of the effector cells with a cell-permeable analog of cyclic adenosine monophosphate (cAMP) inhibited anti-CD3 MoAb and target cell- induced degranulation and cytotoxicity of CIK cells. The immunosuppressive drugs cyclosporin (CsA) and FK506 inhibited anti-CD3- mediated degranulation, but did not affect cytotoxicity of CIK cells against tumor target cells. In addition, degranulation induced by target cells was unaffected by CsA and FK506. Our results indicate that two mechanisms of cytoplasmic granule release are operative in the CD3+ CD56+ killer cells; however, cytotoxicity proceeds through a cAMP- sensitive, CsA- and FK506-insensitive pathway triggered by yet-to-be- identified target cell surface molecules.
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Wu, Xiaolong, Ying Zhang, Yutao Li, and Ingo G. H. Schmidt-Wolf. "Increase of Antitumoral Effects of Cytokine-Induced Killer Cells by Antibody-Mediated Inhibition of MICA Shedding." Cancers 12, no. 7 (July 7, 2020): 1818. http://dx.doi.org/10.3390/cancers12071818.
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Natural killer group 2D (NKG2D) receptor plays a pivotal role in cytokine-induced killer (CIK) cell-mediated cytotoxicity against malignancies, and the expression of NKG2D ligands might allow targets to be more susceptible to the CIK cell-mediated destruction. In this study, we investigated the synergistic effects of CIK cells antitumor activity and antibody-mediated inhibition of MICA/B shedding. This monoclonal antibody (7C6) has been previously shown to be able to specifically target MICA/B a3 domain on tumor cells, resulting in the increase in cell surface MICA/B expression by inhibition of their shedding. In the current study, we show that 7C6 antibody could substantially inhibit MICA shedding and stabilize the expression of MICA/B on Hela cells and MDA-MB-231 cells. In combination with 7C6, CIK cells showed higher degranulation rate, more IFN-γ production and elevated cytotoxic capacity against tumor cells. Furthermore, we demonstrate that NKG2D-MICA/B ligation could lead to activation of both CD3+ CD56− T cells and CD3+CD56+ NKT subset cells of CIK culture and NKT subset was more sensitive to NKG2D signaling than the counterpart T cells. 7C6-mediated inhibition of MICA shedding could strengthen this signal and eventually enhance the antitumor activity of CIK cells. With multiple advantages of easy ex vivo expansion, minor GVHD, natural tumor trafficking and non-MHC restricted, CIK cell-based therapy may serve as a potent combination partner with MICA antibody-mediated immunotherapy.
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Sommaggio, R., E. Cappuzzello, A. Dalla Pietà, P. Palmerini, A. Tosi, D. Carpanese, L. Nicolè, and A. Rosato. "P06.06 Adoptive cell therapy of triple negative breast cancer with redirected cytokine-induced killer cells." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A44.1—A44. http://dx.doi.org/10.1136/jitc-2020-itoc7.85.
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BackgroundCytokine-Induced Killer (CIK) cells share several functional and phenotypical properties of both T and natural killer (NK) cells, and represent an attractive approach for cell-based immunotherapy as they do not require antigen-specific priming for tumor cell recognition, and can be efficiently and rapidly expanded in vitro. We recently reported that CIK cells have a relevant expression of FcγRIIIa (CD16a), which can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their lytic activity in an antigen-specific manner. Here, we report the assessment and the efficacy of this combined approach against triple negative breast cancer (TNBC), an aggressive tumor that still requires reliable therapeutic options.Materials and methodsDifferent primitive and metastatic TNBC cancer mouse models were established in NSG mice, either by implanting patient-derived TNBC samples or MDA-MB-231 cells subcutaneously or orthotopically into the mammary fat pad, or by injecting MDA-MB-231 cells intravenously. The combined treatment consisted in the repeated intratumoral or intravenous injection of CIK cells and cetuximab, while the mAb alone or CIK cells plus Rituximab served as control treatments. Tumor growth and metastasis were monitored by bioluminescence or immunohistochemistry, and survival was recorded.ResultsCIK cells plus cetuximab significantly restrained primitive tumor growth in mice, either implanted with TNBC patient-derived tumor xenografts or injected with MDA-MB-231 TNBC cell line. Moreover, in both experimental and spontaneous metastatic models the combined approach almost completely abolished metastasis spreading and dramatically improved survival. The antigen-specific mAb favored tumor and metastasis tissue infiltration by CIK cells, and in particular led to an enrichment of the CD16a+ subset.ConclusionsData highlight the potentiality of a novel immunotherapy approach where a non-specific cytotoxic cell population can be converted into tumor-specific effectors with clinical-grade antibodies, thus providing not only a therapeutic option for TNBC but also a valid alternative to more complex approaches based on chimeric antigen receptor-engineered cells.Disclosure InformationR. Sommaggio: None. E. Cappuzzello: None. A. Dalla Pietà: None. P. Palmerini: None. A. Tosi: None. D. Carpanese: None. L. Nicolè: None. A. Rosato: None.
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Linn, Yeh Ching, and Kam M. Hui. "Cytokine-Induced NK-Like T Cells: From Bench to Bedside." Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/435745.
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Cytokine-induced killer (CIK) cells are polyclonal T effector cells generated when cultured under cytokine stimulation. CIK cells exhibit potent, non-MHC-restricted cytolytic activities against susceptible tumor cells of both autologous and allogeneic origins. Over the past 20 years, CIK cells have evolved from experimental observations into early clinical studies with encouraging preliminary efficacy towards susceptible autologous and allogeneic tumor cells in both therapeutic and adjuvant settings. This paper is our attempt to summarize the available published literature related to CIK cells. Looking into the future, we anticipate that the continuous therapeutic application of CIK cells will likely be developed along two major directions: overcoming the challenge to organize large prospective randomized clinical trials to define the roles of CIK cells in cancer immunotherapy and expanding its spectrum of cytotoxicity towards resistant tumor cells through experimental manipulations.
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Mase, Shintaro, Hideaki Maeba, Rie Kuroda, Raita Araki, Toshihiro Fujiki, Hideo Yagita, Akihiro Yachie, Shoichi Koizumi, and Ryosei Nishimura. "Allogeneic Cytokine-Induced Killer Cells Kill Dendritic Cells Efficiently Resulting in Less Graft-Versus-Host Disease." Blood 118, no. 21 (November 18, 2011): 4308. http://dx.doi.org/10.1182/blood.v118.21.4308.4308.
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Abstract Abstract 4308 Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. The mechanism of suppression of GVHD after allogeneic bone marrow transplantation is, in part, due to the abundant production of IFN-gamma from the CIK cells, which has protective effect against GVHD. We have also demonstrated that allogeneic CIK cells displayed a significant lower acquisition of homing molecules, required for the entry of inflamed and GVHD target organs (a4b7, CCR9, E-selectin, CXCR3, and CCR5) and a higher susceptibility to apoptosis compared to allogeneic splenocytes. There also might be some causes other than we mentioned above. Host residual dendritic cells (DCs) have a crucial role for initiating GVHD reaction, because they present recipient alloantigens to donor T cells, which finally attack on recipient tissues. Murine alloreactive NK cells, even when infused in large numbers, do not cause GVHD in the mouse by killing recipient DCs. Similarly, it remains a possibility that the reduced GVHD in CIK cells receiving mice was due to the elimination of residual host DCs by CIK cells. To test this, DCs generated from bone marrow cells with the addition of GM-CSF were used for 51Cr release cytotoxicity assays as target cells. Although autologous CIK cells (Balb/c) had relatively strong killing activity against DCs (Balb/c), allogeneic CIK cells (B6) had much more killing activity even from at a 5:1 effector-target ratio as shown below. Allogeneic CD8+ cells did not show any killing activity against DCs. In addition, killing activity against DCs did not changed with/without adding NKG2D blocking antibody, suggesting that other mechanisms to undergo cell lysis should exist in CIK cells in addition to NKG2D/NKG2D ligand system, which are mainly involved in tumor eradication. To further evaluate whether allogeneic CIK cells kill host DCs in vivo, lethally irradiated Balb/c recipients were given BM (B6) with CIK cells or splenocytes to compare the percent of residual host-typed DCs in the spleen five days after bone marrow transplantation. Percent of host-typed DCs tended to be lower in the mice receiving alllogeneic CIK cells compared with those receiving fresh splenocytes or BM alone. In conclusion, allogeneic CIK cells caused less GVHD due in part to elimination of host DCs. Disclosures: No relevant conflicts of interest to declare.
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Schlimper, Claudia, Andreas A. Hombach, Hinrich Abken, and Ingo G. H. Schmidt-Wolf. "Improved Activation toward Primary Colorectal Cancer Cells by Antigen-Specific Targeting Autologous Cytokine-Induced Killer Cells." Clinical and Developmental Immunology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/238924.
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Adoptive therapy of malignant diseases with cytokine-induced killer (CIK) cells showed promise in a number of trials; the activation of CIK cells from cancer patients towards their autologous cancer cells still needs to be improved. Here, we generated CIK cellsex vivofrom blood lymphocytes of colorectal cancer patients and engineered those cells with a chimeric antigen receptor (CAR) with an antibody-defined specificity for carcinoembryonic antigen (CEA). CIK cells thereby gained a new specificity as defined by the CAR and showed increase in activation towards CEA+colon carcinoma cells, but less in presence of CEA−cells, indicated by increased secretion of proinflammatory cytokines. Redirected CIK activation was superior by CAR-mediated CD28-CD3ζ than CD3ζ signaling only. CAR-engineered CIK cells from colon carcinoma patients showed improved activation against their autologous, primary carcinoma cells from biopsies resulting in more efficient tumour cell lysis. We assume that adoptive therapy with CAR-modified CIK cells shows improved selectivity in targeting autologous tumour lesions.
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Yang, Yang, Run-Qing Wang, Yi-Ming Zhong, Ming-Yao Meng, Yi-Yi Zhao, Li-Rong Yang, Lin Li, and Zong-Liu Hou. "Efficacy of Enhanced Cytokine-Induced Killer Cells as an Adjuvant Immunotherapy for Renal Cell Carcinoma: Preclinical and Clinical Studies." Journal of Healthcare Engineering 2021 (September 8, 2021): 1–13. http://dx.doi.org/10.1155/2021/5709104.
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Cytokine-induced killer (CIK) cells have been proved to be an effective method of tumor immunotherapy in numerous preclinical and clinical studies. In our previous study, a new method was developed to prime and propagate CIK cells by the combination of IL-2 and IL-15, and this kind of CIK cells had enhanced antitumor effect on lung cancer. For renal cell carcinoma (RCC), immunotherapy plays an important role because of the poor efficacy of radiotherapy and chemotherapy. In this study, we further evaluated the antitumor effects of these enhanced CIK cells against RCC. Enhanced CIK cells were generated by IL-2 combined with IL-15 and identified by flow cytometry. HEK-293 and ACHN cell lines were used to verify the efficiency of CIK cells in vitro, and then the ACHN tumor xenograft model was also employed for in vivo study. In addition, the secreted cytokines including IFN-γ, granzyme B, TNF-α, and perforin, as well as the local microstructure were also studied. Subsequently, 20 patients with RCC were enrolled into our study, and 11 patients were randomly divided into the autologous CIK treatment group for clinical research. The results showed that enhanced CIK cells exert better antitumor effects in RCC in vitro ( p < 0.01 in HEK-293 and p < 0.05 in ACHN）and in vivo ( p < 0.05 ). Patients benefit overall survival from enhanced CIK therapy in our clinical study. Our present preclinical and clinical studies for the first time elucidated that these enhanced CIK cells would be used as an effective adjuvant therapy in the treatment of RCC.
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Baker, Jeanette, Kevin Sheehan, Gina Monterola, Nancy Staines, and Robert S. Negrin. "Analysis of Expanded Human Cytokine Induced Killer Cells for Cellular Therapy." Blood 106, no. 11 (November 16, 2005): 1063. http://dx.doi.org/10.1182/blood.v106.11.1063.1063.
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Abstract We have previously reported on the ex vivo expansion of cytotoxic effector T cells termed Cytokine Induced Killer (CIK) cells. CIK cells demonstrate both in vivo and in vitro anti-tumor activity in murine models with limited potential for GVHD induction. Human CIK cells are readily expanded from peripheral blood mononuclear cells (PBMC) when cultured with IFNg, CD3 and IL-2 and show cytotoxic activity against a variety of tumor cell lines and fresh autologous tumor cells through an NKG2D dependent mechanism. Clinical application of CIK cells requires expansion of effector cells in GMP-compliant manner. In this study, PBMC were collected by apheresis from 9 healthy non-mobilized donors and placed in closed, continuous perfusion cultures using Aastrom RepliCell@biochambers for 21–28 days. Cultures were inoculated with 3x108–7.5x108 nucleated cells containing a median of 46% CD3+ cells (range 29%–71%). At culture harvest, the median cell count was > 4x109 (range 2.6x109–8.7x109) with 97% CD3+ (86%–99%) and an average cell viability of 84.8% (range, 75%–99.6%). The average expansion of CD3+ cells in culture was > 30-fold (range13–91). CD3+CD56+ are the subpopulation of cells that demonstrated the highest cytotoxicity against tumor cell lines in culture. The mean percentage of these cells was 1.8% however at harvest, the mean CD3+CD56+ was 14% representing an average 34-fold expansion (range 19–515). The majority of CD3+ cells were CD8+ (range, 33–82%), NKG2D was predominately expressed by cells recovered from most cultures (range 47–76%). CD56+ was expressed by 1% – 36% of cells in different cultures and CD8+NKG2D+ expression ranged from 21%–50% of harvested cells. There was a moderate up-regulation of the activation markers CD25 and CD69 and the NK markers CD16, CD161 and CD94. In all cultures, the majority of CD8+ and CD56+ cells co-expressed the selectin marker a4b7. Furthermore the majority of the CD3+CD8+ cells were effector memory cells expressing CD62L−CD44+ (50%–71%) while the central memory cells CD62L+CD44+ ranged from 10%–40%, almost no naïve cells were detected in time of harvest. Cytotoxicity assays against a panel of tumor cell lines (B and T cell lymphomas, uterine cancer, erythroleukemia, ovarian cancer and plasmacytoma) showed significant yet variable killing. This system allows for the rapid expansion of cytotoxic cell in GMP-compliant manner suitable for clinical application.
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Wang, Jing-Bo, Tong Wu, Jun-Fang Yang, Jian-Ping Zhang, Xing-Yu Cao, Yu-Ming Yin, Yuan Sun, Rong-Mu Luo, Dao-Pei Lu, and Chun-Rong Tong. "Management of Early Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation by Donor’s Dendritic Cell-Primed Cytokine- Induced Killer Cells." Blood 112, no. 11 (November 16, 2008): 829. http://dx.doi.org/10.1182/blood.v112.11.829.829.
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Abstract Leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is one of the main obstacles for survival. Immunosuppressant withdraw, chemotherapy, and donor lymphocyte infusion(DLI) are usually employed for management of recurrence after HSCT, but some patients have poor response to above therapy or have contraindications for DLI due to relapse at early stage after transplant or with active graft-versus-host disease (GVHD). Dendritic cell-primed cytokine-induced killer cells (DC-CIK) have been successfully applied in treatment of minimal residual disease (MRD) in our center for 12 years. In present pilot clinical study, we explore to manage early leukemia relapse after HSCT with donor’s DC-CIK in appropriate patients. The patients who relapsed in hematological (5–20% blasts in BM) or molecular or immunological (MRD>0.1% by flow cytometry) with at least one of the following criteria were included in this clinical trial. 1. No response to DLI; 2. Relapsed within 60 days after HSCT; 3. Relapsed with active GVHD. Total 18 patients (male 9, female 9) with median age 26 (4 to 42) years were eligible to this clinical study. The diagnosis included acute myeloid leukemia (AML 13), acute lymphoblastic leukemia (ALL 4) and chronic myeloid leukemia (CML 1) who failed to reach molecular remission with imatinib before transplant. The types of donor were HLA identical sibling (11), haploidentical family member (5), and unrelated donor (2). Six of 18 patients had either molecular or immunological recurrence, while 12 of 18 cases relapsed hematologically. The median cell dosage of DC-CIK infused was 2.34×109 (0.2–44×109). With DC-CIK treatment, overall 11 of 18 (61.1%) patients achieved complete remission (CR, molecular or immunological or hematological based on the disease status before DC-CIK). Among 6 cases in molecular or immunological recurrence, five of them (83.3%) obtained CR, while 12 patients with early hematological relapse, 6 of them (50%) returned to CR. Seven of 13 patients with AML, and all 4 cases with ALL responded to DC-CIK treatment, while a patient with CML had no therapeutic benefit from it. Among 7 cases without response to DC-CIK, one patient with CML achieved molecular remission with high-dose Imatinib, 1 case obtained CR after DLI later on, 1 patient survived with primary disease so far, and the remaining 4 patients died from leukemia recurrence. In 11 cases who responded to DC-CIK, 10 of them survived with median 359(164 to 1233) days. One patient died from transplant-related complications. Four patients developed GVHD after DC-CIK infusion and controlled completely with Cyclosporin A and Methylprednisolone. Our encouraging results indicate that Donor’s DC-CIK is a safe and effective therapeutic option in management of early leukemia recurrence after allogeneic HSCT, especially for the patients who fail to or ineligible to current standard practice.
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Dalla Pietà, Anna, Elisa Cappuzzello, Pierangela Palmerini, Annavera Ventura, Andrea Visentin, Giuseppe Astori, Katia Chieregato, et al. "Innovative therapeutic strategy for B-cell malignancies that combines obinutuzumab and cytokine-induced killer cells." Journal for ImmunoTherapy of Cancer 9, no. 7 (July 2021): e002475. http://dx.doi.org/10.1136/jitc-2021-002475.
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BackgroundPatients affected by aggressive B-cell malignancies who are resistant to primary or salvage chemoimmunotherapy have an extremely poor prognosis and limited therapeutic options. Promising therapeutic success has been achieved with the infusion of CD19 chimeric antigen receptor-T cells, but several limits still restrain the administration to a limited proportion of patients. This unmet clinical need might be fulfilled by an adoptive immunotherapy approach that combines cytokine-induced killer (CIK) cells and monoclonal antibodies (mAb) to the CD20 antigen. Indeed, CIK cells are an effector population endowed with antitumor activity, which can be further improved and antigen-specifically redirected by clinical-grade mAb triggering antibody-dependent cell-mediated cytotoxicity.MethodsCIK cells were generated from peripheral blood of patients affected by different B-cell malignancies using a blinatumomab-based cell culture protocol. Effector cells were combined with the anti-CD20 mAb obinutuzumab and their therapeutic activity was assessed both in vitro and in vivo.ResultsCIK cells were successfully expanded in clinically relevant numbers, starting from small volumes of peripheral blood with extremely low CD3+ counts and high tumor burden. This relied on the addition of blinatumumab in culture, which leads to the simultaneous expansion of effector cells and the complete elimination of the neoplastic component. Moreover, CIK cells were highly cytotoxic in vitro against both B-cell tumor cell lines and autologous neoplastic targets, and had a significant therapeutic efficacy against a B-cell malignancy patient-derived xenograft on in vivo transfer.ConclusionsThe combination of an easily expandable CIK cell effector population with a mAb already in clinical use establishes a tumor antigen-specific redirection strategy that can be rapidly translated into clinical practice, providing an effective therapeutic alternative for B-cell malignancies without any need for genetic modifications. Additionally, the approach can be potentially applied to an extremely vast array of different tumors by simply substituting the targeting mAb.
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Chan, John K., Chad A. Hamilton, Michael K. Cheung, Mobin Karimi, Jeanette Baker, Jonathan M. Gall, Lawrence G. Lum, et al. "Immunotherapy of Primary Ovarian Cancer Using Autologous Cytokine Induced Killer Cells Retargeted with Bispecific Antibodies: A Preclinical Study." Blood 106, no. 11 (November 16, 2005): 2379. http://dx.doi.org/10.1182/blood.v106.11.2379.2379.
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Abstract Cytokine induced killer (CIK) cells are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have anti-tumor activity. This is the first study exploring cell killing of primary ovarian carcinoma with and without bispecific antibodies (BSAbs). Primary cancer cells and autologous CIK cells were collected from women with epithelial ovarian cancer. BSAbs against CA125 (BSAbxCA125) and Her2 (BSAbxHer2) were developed using chemical heteroconjugation. On FACS analysis, the expansion and stimulation of CIK cells resulted in a significant increase of CD3+CD8+ and CD3+CD56+ T cells. With enhancement by BSAbs, the mean percent lysis in a 51Cr release assay of fresh ovarian cancer cells exposed to autologous CIK cells increased from 22% (±0.3) to 89% (±2.1) at an effector to target ratio (E:T) of 100:1. Anti-NKG2D antibodies significantly attenuated the CIK activity by 57% on primary cells. In a xenograft SCID mouse model, real-time tumor regression and progression was visualized using a non-invasive in vivo bioluminescence imaging system. Four hours after CIK cell injection, we were able to visualize CD8+NKG2D+ CIK cells infiltrating Her2-expressing cancer cells on fluorescence microscopy. Mice that underwent adoptive transfer of CIK cells redirected with BSAbxCA125 (p=0.0002) and BSAbxHer2 (p=0.0002) had a significant reduction in tumor burden and improvement in survival versus those treated with CIK cells alone (p=0.03). BSAbs significantly enhanced the cytotoxicity of CIK cells in primary ovarian cancer cells and in our in vivo mouse model. The mechanism of cytolysis appears to be mediated in part by the NKG2D receptor.
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Han, Xiao, Xiaohui Wang, Li Wang, Xianyi Yao, Guangyu Zhao, and Zhongtao Cui. "Inhibition Human Nasopharyngeal Carcinoma Cells TNF-α Gene Transfected Cytokine-Induced Killer Cells Based on Nanomaterial Polyphthalamide Monoamine Dendrimer Nanomaterial." Journal of Nanoscience and Nanotechnology 20, no. 10 (October 1, 2020): 6133–39. http://dx.doi.org/10.1166/jnn.2020.18557.
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The present study aims to investigate the possibility of TNF-α gene transfection into CIK (cytokine-induced killer) cells using the nanomaterial PAMAM and the inhibitory effects of these cells on the growth of the human nasopharyngeal carcinoma cell line CNE-2. The pEGFP-N1-TNF-α recombinant plasmid was constructed and used to transfect the CIK cells using the nanomaterial PAMAM. Subsequently, the transfection efficiency was measured. The ELISA method was used to analyze the CIK cell culture supernatant. TNF-α concentration in fluid, and CIK cell phenotype was analyzed by the flow cytometry. The MTT assay was used to detect the inhibitory activity of CIK cells on the growth of nasopharyngeal carcinoma cell line CNE-2 after transfection. The CIK cells were transfected with the nanomaterial PAMAM using the successfully constructed recombinant plasmid pEGFP-N1-TNF-α. The growth characteristics and phenotypic characteristics of the transfected CIK cells were not changed, and an increase in the TNF-α secretion was observed, indicating that the CIK cells can significantly inhibit CNE-2 cell growth (P < 0005).
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Zhang, Lei, and Baoping Li. "Autologous cytokine-induced killer and dentritic cells in treatment of advanced and unresectable lung cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13069-e13069. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13069.
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e13069 Background: Both experimental and clinical studies showed cytokine-induced killer (CIK) cells have been shown capable of efficiently lysing target tumor cells, which activity can be enhanced by dendritic cell (DC) stimulation. This study demonstrated that co-cultured autologous CIK and tumor antigen-pulsed DC are effective in in treatment of advanced and unresectable lung cancer Methods: Sixteen patients having stage III-IV lung cancer with a malignant pleural effusion, 9 females and 7 males with an average age of 54.3 years old, were included in this study. Autologous CIK and DC were prepared from isolated peripheral blood mononuclear cells and were induced by multiple cytokines. Generated DCs were pulsed by the antigen generated from tumor tissues and co-cultured with CIK. Those patients received 4-6 times of CIK-DC intravenous infusion, 2-3 ×109 cells each time. Results: Eleven (68.8%) patients achieved a partial remission. The pleural effusion decreased in all those patients, and in 9 of them the effusion decreased over 50%. The clinical symptoms were relieved in all the patients. There were no significant adverse effects were found. Those patients are still followed for long-term survival outcome. Conclusions: CIK-DCs immunotherapy provides a new and effective treatment for the late stage lung cancer.
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Pievani, Alice, Camilla Belussi, Christian Klein, Alessandro Rambaldi, Josée Golay, and Martino Introna. "Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell (CIK) cultures and anti-CD20 antibodies." Blood 117, no. 2 (January 13, 2011): 510–18. http://dx.doi.org/10.1182/blood-2010-06-290858.
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Abstract We have investigated combining adoptive immunotherapy with cytokine-induced killer (CIK) cells and anti-CD20 monoclonal antibodies (mAb) GA101 or rituximab to optimize B-cell non-Hodgkin lymphoma (B-NHL) therapy. CIK cultures alone demonstrated significant cytotoxic activity against B-NHL cell lines or freshly isolated samples in either an autologous or allogeneic combination. This natural cytotoxicity (NC) was mainly due to the predominating CD3+CD56+ CIK population (40%–75%) present in the cultures. The addition of anti-CD20 mAb GA101 or rituximab further increased cytotoxicity by 35% and 15%, respectively. This enhancement was mainly due to antibody-dependent cytotoxicity (ADCC) mediated by the 1%–10% NK cells contaminating CIK cultures. The addition of human serum (HS) inhibited NK-cell activation induced by rituximab, but not activation induced by GA101.Overall lysis in presence of serum, even of a resistant B-NHL cell line, was significantly increased by 100 μg/mL of rituximab, but even more so by GA101, with respect to CIK cultures alone. This was due to the combined action of complement-mediated cytotoxicity (CDC), ADCC, and CIK-mediated NC. These data suggest that rituximab, and even more so GA101, could be used in vivo to enhance CIK therapeutic activity in B-NHL.
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Vu, Binh Thanh, Dat Tan Le, and Phuc Van Pham. "Synergistic effect of chimeric antigen receptors and cytokine-induced killer cells: An innovative combination for cancer therapy." Biomedical Research and Therapy 3, no. 06 (June 26, 2016): 653–65. http://dx.doi.org/10.15419/bmrat.v3i06.99.
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In recent years, the combination of gene and immunotherapy for cancer treatment has been regarded as innovative and promising; together, both therapies can help overcome limitations associated with conventional treatments. In order to augment anti-cancer efficacy and to maintain the specificity of antibody therapy, chimeric antigen receptor (CAR)-modified T cells, directed toward tumor-specific antigens, have emerged as a novel and promising therapeutic platform. CARs consist of a B cell receptor (BCR)-derived extracellular domain and T cell receptor (TCR)-associated signaling elements. Cytokine-induced killer (CIK) cells are the effector immune cells that can be activated ex vivo and possess both the anti-tumor potency of T lymphocytes and the non-major histocompatibility complex-restricted elimination of natural killer cells. With their pre-eminent ability for robust proliferation, CIK cells may overcome the main limitations of adoptive immunotherapy strategies. CIK cells have strong tumor cell killing capacity; they are effective against a wide variety of malignant tumors and have been shown to be safe in cancer patients. This review summarizes the characteristics of CARs which make them attractive for in cancer treatment strategies. In addition, the role of CIK cells and the advantages of combining CIK cells with CAR-based therapy will be discussed. Scientific evidence to support their combined therapeutic application will be highlighted, with a focus on how their innovative combination may be translated into cancer clinical trials.
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Zhang, Yajing, Jin Wang, Yao Wang, Xue-Chun Lu, Hui Fan, Yang Liu, Yan Zhang, et al. "Autologous CIK Cell Immunotherapy in Patients with Renal Cell Carcinoma after Radical Nephrectomy." Clinical and Developmental Immunology 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/195691.
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Objective. To evaluate the efficacy of autologous cytokine-induced killer (CIK) cells in patients with renal cell carcinoma (RCC).Methods. 20 patients diagnosed with TNM stage I or II RCC were randomly divided into two groups, a CIK cell treatment group and a control group. The endpoint was progression-free survival (PFS) evaluated by Kaplan-Meier analyses.Results. CD3+, CD3+/CD8+, CD3+/CD4+, and CD3+/CD56+levels increased after CIK cell culture (P<0.01). The median PFS in CIK cell treatment group was significantly longer than that in control group (PFS, 32.2 months versus 21.6 months; log-rank,P=0.032), all patients were alive during the course of followup, and there are no statistically significant differences between two groups in OS (log-rank,P=0.214). Grade III or greater adverse events were not observed.Conclusions. CIK cells treatment could prolong survival in patients with RCC after radical nephrectomy and showed acceptable curative effect with potential enhancement of cellular immune function. This trial is registered with Clinicaltrials.govNCT01799083.
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Qian, Shenxian, Pengfei Shi, Yaping Xie, Ying Xu, Daquan Gao, Lirong Liu, Xilian Huang, Kuang Chen, and Junfeng Tan. "Clinical Study of Autologous Cytokine-Induced Killer Cells for the Consolidation Treatment of Elderly Patients with Diffuse Large B-Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 4463. http://dx.doi.org/10.1182/blood.v124.21.4463.4463.
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Abstract Cytokine-induced killer (CIK) cells are activated T cells with natural killer (NK) properties that can be expanded in vitro in presence of recombinant human interleukin-2 (rhIL-2) starting from peripheral blood mononuclear cells stimulated by interferon-γ and anti-CD3 antibody. They express CD3 and CD56 as well as the NKG2D antigen and show major histocompatibility complex (MHC)–unrestricted cytotoxicity toward neoplastic but not normal targets. CIK cells express several chemokine receptors, and in vivo models suggest that they can migrate to the site of tumors after intravenous administration, there carrying out their cytotoxic potential and helping to control tumor growth. CIK cells have shown cytotoxic activity in vitro and in vivo against hematopoietic neoplastic cells, including AML (acute myeloid leukemia), CML (chronic myelogenous leukemia), and CLL (chronic lymphocytic leukemia). Their cytotoxicity against patient with B-NHL (B-cell non-Hodgkin lymphoma) , however, has not been fully investigated. The elderly population is susceptible to haematological malignancies, and these elderly patients are intolerant to cytotoxic drugs. Therefore, the exploration of a safe and reliable strategy reduse dose of chemotherapy is critical in improving the prognosis of elderly patients with haematological malignancies. To evaluate the effectiveness and safety of autologous cytokine-induced killer (CIK) cells for consolidation treatmemt in elderly patients with diffuse large B-cell lymphoma. Peripheral blood mononuclear cells (PBMC) were isolated from 20 elderly patients with diffuse large B-cell lymphoma. PBMCs were augmented by priming with interferon gamma (IFN-γ) followed by IL-2 and monoclonal antibody (mAb) against CD3. Autologous CIK cells (range 5 × 10(9)-1 × 10(10)) were then infused back to individual patients. The regimen was repeated every 4 weeks. The host cellular immune function, tumour-related biological parameters, imaging characteristics, disease condition, quality of life and survival time were assessed. Fourteen patients received 6 cycles of transfusion and 6 received 4 cycles. After treatment of CIK cells plus IL-2, the general conditions of 20 patients were to different extent improved No adverse effects were observed. The percentages of CD3(+), CD3(+) CD8(+) and CD3(+) CD56(+) cells were significantly increased (p < 0.05), and the levels of serum β2 microglobulin and lactate dehydrogenase (LDH) were markedly decreased (p < 0.05) after autologous CIK cell transfusion. Cancer-related symptoms were profoundly alleviated, as demonstrated by the improved quality of life (p < 0.01)., Complete remission(CR) observed in 11 patients before the treatmemt of CIK was still CR; Partial remission(PR) in 9 patients ,After the treatmemt of CIK, the transformation of disease state from partial remission to complete remission was seen in 4 patients. At the end of follow-up, the mean survival time was 24 months. Transfusion with autologous CIK cells is safe and effective for treating haematological malignancies in elderly patients. Disclosures No relevant conflicts of interest to declare.
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Rotiroti, Maria Caterina, Chiara Buracchi, Silvia Arcangeli, Chiara F. Magnani, Claudia Cappuzzello, Zsuzsanna Izsvak, Stefania Galimberti, et al. "Preclinical Assessment of Non-Virally Engineered CD33.CAR Cytokine-Induced Killer (CIK) Cells in Chemoresistant AML Patient-Derived Xenografts." Blood 134, Supplement_1 (November 13, 2019): 2665. http://dx.doi.org/10.1182/blood-2019-130399.
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Background Chimeric Antigen Receptor (CAR)-T cell therapy has been successfully clinically deployed in the context of B-cell malignancies, paving the way for further development also in Acute Myeloid Leukemia (AML), a still unmet clinical need in the field of oncohematology. Among the potential AML targetable antigens, CD33 is so far one of the main validated molecule. Objectives The aim of the present study was to optimize a non-viral gene transfer method to engineer Cytokine-Induced Killer (CIK) cells with a CD33.CAR by using a novel version of the Sleeping Beauty (SB) transposon system, named "SB100X-pT4". Further, a preclinical assessment of SB-modified CD33.CAR-CIK cells was performed in chemoresistant AML Patient-Derived Xenografts (PDX), in order to address the unmet need of targeting drug-resistant AML cells. Methods Donor derived-CIK cells were stably transduced with a CD33.CAR by exploiting the novel hyperactive SB100X transposase and the pT4 transposon (SB100X-pT4). The novel SB system has been in vitro compared to the previous established SB11-pT. In vitro anti-AML activity of CD33.CAR-CIK cells was assessed by flow cytometry-based cytotoxicity (AnnV-7AAD), proliferation (CFSE) and cytokine production (intracellular IFNg and IL2 detection) assays. In vivo efficacy was evaluated in NSG mice transplanted with MA9-NRas AML cell line or PDX samples. A xenograft chemotherapy model mimicking induction therapy ("5+3" Ara-C and doxorubicin) was exploited to examine the potential benefit of CD33.CAR-CIK cells on chemoresistant/residual AML cells. Results By significantly reducing the amount of DNA transposase, the novel SB100X-pT4 combination resulted in higher CAR levels than the SB11-pT. SB100X-pT4-modified CD33.CAR CIK cells showed efficient expansion after 3 weeks (median fold increase of 38.89, n=4). Both transpositions conferred to CD33.CAR-CIK cells a specific killing (up to 70%) against CD33+ AML target cell lines and primary AML cells. The anti-AML proliferative response of SB-modified CD33.CAR-CIK cells was also considerable (up to 70% of CFSE diluted CAR-CIK cells), as well as the cytokine production (up to 35% for IFN-γ and up to 25% for IL-2). To evaluate the effect of SB100X-pT4-modified CD33.CAR-CIK cells particularly on Leukemia Initiating Cells (LICs), CD33.CAR-CIK cells were administered as an "early treatment" in mice transplanted with the MA9-NRas cell line, which retains a high frequency of LICs. At sacrifice, CD33.CAR-CIK cell-treated mice showed a significant bone marrow (BM) engraftment reduction (median 27.80 for the untreated group and 22.60 for the unmanipulated CIK cells vs 6.45 for CD33.CAR-CIK cell, n=4 NSG mice per group, p= 0.02). PDX of two different AML samples at the onset were established to be used as models mimicking different disease conditions. In an "early treatment" model using secondary transplanted PDX, a setting which presumably reflects the typical LIC properties, a clear engraftment reduction in the treated cohort was observed, nearly undetectable in 2/5 mice, as compared to the untreated mice (up to 70% in BM). A significant leukemia reduction was also measured in the peripheral blood and spleen of treated mice, showing CD33.CAR-CIK cell potential of reducing AML dissemination in the periphery. When ex vivo re-exposed to CD33.CAR-CIK cells residual AML cells were still sensitive to the treatment, indicating that no resistance mechanisms occurred. CD33.CAR-CIK cells were also effective in a second model by which the treatment started when AML engraftment was clearly manifested in the BM (> 1%). Finally, when starting CD33.CAR-CIK cell treatment after disease recurrence post induction therapy, a significant disease reduction was observed in the CD33.CAR-CIK-treated group, reaching undetectable levels in half of the mice, as compared to chemotherapy-only treated mice (up to 60% of engraftment in BM)(Figure 1). Conclusions The employment of a non-viral SB-based CD33.CAR-gene transfer approach, which is overall associated to less cumbersome protocols and reduces the cost of goods, offers a unique alternative to current viral-based strategies to be explored in the setting of resistant forms of AML. Disclosures No relevant conflicts of interest to declare.
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Yang, Yang, Yanxia Ma, Zhanzheng Wang, Li Wang, Yubo Zhao, Yang Hui, Chi Zhang, and Feixue Feng. "Compound Kushen Injection Promoted the Killing Effect of Cytokine-Induced Killer Cells Which Was Activated by Dendritic-Colon Cancer Stem Cell Fusion Cells on Colon Cancer Stem Cells." Journal of Biomaterials and Tissue Engineering 10, no. 7 (July 1, 2020): 957–65. http://dx.doi.org/10.1166/jbt.2020.2362.
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Colon cancer stem cells (cCSCs) are highly tumorigenic and resistant to traditional chemotherapeutic drugs. Therefore, they are an essential factor in colorectal cancer (CRC) metastasis and recurrence. Dendritic cells (DCs) could bind to the tumor cells and form the fusion cells (FCs). And these FCs could inhibit the development of malignant tumors. Furthermore, the cytokine induced killer (CIK) cells (CD3+ /CD56+ T lymphocytes) could also apply for the immunotherapy of cancer. And compound Kushen injection (CKI) is a traditional Chinese medicine (TCM) which has been used for the treatment of various tumors. However, whether the dendritic-colon cancer stem cell fusion cells (DC-cCSC FCs) could activate the CIK cells and kill the colon cancer stem cells is unknown. And whether the CKI could enhance the lethal effect is still unclear. In this study, we collected peripheral blood samples from healthy participants to acquire mononuclear cells and induced DC and CIK cells. Meanwhile, the CD44+ cells (cCSCs) were screened from SW480 cells. Next, the DC-cCSC FCs were established for the next experiments. At last, CCK-8 assays were performed to determine the effect of DC-cCSC FCs and CKI on the viability of cCSCs. We found that DC-cCSC FCs enhanced the proliferation of CIK cells and induce the CIK cells to secrete more IL-12. The DC-cCSC FCs enhanced the inhibitory effect of CIK cells on cCSCs. Furthermore, application of CKI enhanced the killing rates of DC-cCSC FCs and CIK cells on cCSCs. CIK cells activated by the DC-cCSC FCs had the lethal effect on the cCSCs. Furthermore, CKI enhanced this lethal effect of DC-cCSC FCs and CIK cells.
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Linn, Yeh Ching, Tsyr jong Lim, Madelaine Niam, Garnet Suck, Yeow Tee Goh, William Hwang, Yvonne Loh, Lee Hui Ng, Hao Xiang Yong, and Mickey Boon Chai Koh. "Cytokine Induced Killer Cells Are Feasible and Safe for Both Autologous and Allogeneic Applications in Patients with Haematological Malignancies." Blood 112, no. 11 (November 16, 2008): 2917. http://dx.doi.org/10.1182/blood.v112.11.2917.2917.
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Abstract Introduction: Cytokine-induced killer ( CIK) cells are polyclonal non-MHC restricted T cells with potent cytotoxicity against acute myeloid leukemia (AML) cells in vitro. We have established culture of CIK cells with GMP compliance and infused into patients with various haematological malignancies. These include group 1, as adjuvant therapy post autologous transplant for acute myeloid leukaemia (AML), group 2, in untreated disease and group 3, for relapse post allogeneic transplant (NCT 00460694, NCT 00394381). Patients, Methods and Results: A total of 39 CIK cultures was produced over a 2 year period which resulted in 65 infusions given to 21 patients. We have demonstrated that it is feasible to expand CIK in large scale culture from both patients and allogeneic stem cell donors. The CD3+CD56+ subset expanded a median of 42.7 fold from 1.3% (0.2–5.3%) to 31.1% (10.4–76.9%) post culture for CIK derived from patients’s leukapheresis product, which is comparable with that derived from healthy haemopoietic stem cell donors. The cytotoxicity of these CIK against a panel of allogeneic AML targets showed variable potency (0% to 69%), with a median of 38%. Self limiting fever was the only infusion related side effect. Patients In group 1 received an autologous transplant as consolidation for AML followed by adjuvant infusions of CIK cells., These were successfully cultured for 9 of 11 patients and infused into all 9 in aliquots of between 1–4 infusions. Follow up is short and a comparison against historical autologous transplant results are similar. Group 2 consisted of patients with overt leukemia who have failed or are unfit for chemotherapy. All 4 had CIK cells successfully cultured from a product containing variable % of leukemic cells, 3 of the patients who survived to receive CIK infusion did not have any response. However one of them had an incidental regression of basal cell carcinoma after 2 infusions. In group 3, 6 patients who relapsed after an allogeneic transplant received allogeneic CIK after failing donor lymphocyte infusions (DLI). Another 3 patients had CIK generated from their own leukapheresis product due to donor unavailability (1 post cord blood and 2 post MUD transplant). Amongst the 8 patients who have received CIK infusion, two with overt refractory relapse (1 AML and 1 Hodgkin’s disease) did not respond to 3 and 4 infusions respectively. Four patients (2 AML and 2 ALL) had CIK infusion post salvage chemotherapy and therefore remission could not be entirely attributed to CIK infusion. Two patients had measurable responses attributable solely to CIK infusion. One was a post-transplant relapsed T cell ALL refractory to 5 different salvage regimen and repeated DLI. A marrow remission was achieved after one further Gemcitabin/Mitoxantrone salvage chemotherapy followed by CIK infusion. Marrow remission was maintained for 10 months with 4–6 weekly infusion of CIK while extramedullary (EM) disease progressed, suggesting control of marrow leukemia by CIK while leukemia evolution manifested at EM sites, known to be less susceptible to immunotherapy. A second patient had refractory Hodgkin’s disease in the lungs and vertebrae. A partial reduction in the size of lung nodules was achieved after the second CIK infusion but this was not sustainable. The dose of allo- CIK ranged from 10 – 200 million CD34/kg given as a step-wise increment for each patient. Three patients developed acute GVHD, one grade II liver, one grade II skin andgut, and a third patient had grade I upper gut GVHD, at doses of 50, 100 and 10 million CD3/kg respectively. All responded promptly to prednisolone at 1mg/kg. Conclusion: We have shown that CIK infusion is feasible and safe in both the autologous and allogeneic setting, and GVHD that occurs is easily controlled. It is unlikely that CIK is effective against a large tumour burden. Its efficacy as an adjuvant therapy to eradicate minimal residual disease requires larger patient numbers and longer follow up. For allogeneic transplant, CIK culture has an additional advantage of expanding unrelated donor cells where availability is a problem by harvesting donor cells from patients for expansion. Further numbers are needed to compare against unmanipulated DLI in terms of efficacy and reduced GVHD severity.
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Chang, Boyang, and Peihong Wu. "High number of PD-1 positive tumoral lymphocytes as a potent biomarker for adopting cytokine-induced killer cells in hepatocellular carcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15680-e15680. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15680.
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e15680 Background: Adjuvant cytokine-induced killer cell (CIK) treatment has shown potential in reducing recurrence rate and prolong survival of patients with hepatocellular carcinoma (HCC). We aim to evaluate the PD-1/PD-L1 expression in tumor cells and tumor infiltrative lymphocytes in HCC patients and their correlation with survival benefit from cytokine-induced killer cell therapy. Methods: Between 2004 and 2011, 290 HCC patients received curative section were retrospectively enrolled by one-to-one propensity score matching, including 145 cases received adjuvant CIK cell transfusion after surgery (Surgery-CIK group), and 145 cases underwent surgery only (Surgery only group). Immunohistochemistry (IHC) was used to measure the PD-1 and PD-L1 expression in formalin fixed paraffin embedded tissue of all subjects; IHC of CD4, CD8 and Foxp3 were also conducted in the surgery-CIK group to explore their correlation with PD1/PD-L1 expression and survival of HCC patients. Results: The surgery-CIK group had significantly improved overall survival (OS; HR 0.55, 95% CI 0.33-0.92) and disease-free survival (DFS; HR 0.59, 95% CI 0.42-0.83) as compared to the surgery-only group. In the surgery-CIK group, univariate analysis showed both high PD-L1 expression and a high number of PD-1+ TILs were significantly associated with improved OS, while only the high number of PD-1+ TILs was associated with improved DFS. Multivariate analyses showed a high number of PD-1+ TILs was the only independent factor predicting favorable OS (HR 0.19, 95% CI 0.08-0.45) and DFS (HR 0.40, 95% CI 0.24-0.66) in the surgery-CIK group. By contrast, in the surgery-only group, no significant associations between PD-1/PD-L1 expression and survival of patients were identified. Conclusions: A high number of PD-1+ TILs can serve as a potent biomarker to adopt CIK cell therapy in HCC patients after curative resection.
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Pievani, Alice, Gianmaria Borleri, Camilla Belussi, Alessandro Rambaldi, Josee Golay, and Martino Introna. "Cytokine Induced Killer Cells Can Kill Target through Antigen/TCR Dependent and Independent Mechanisms: New Clinical Perspectives of Utilisation." Blood 114, no. 22 (November 20, 2009): 3024. http://dx.doi.org/10.1182/blood.v114.22.3024.3024.
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Abstract Abstract 3024 Poster Board II-1000 Cytokine induced killer (CIK) cells cultures can easily be obtained by stimulating PBMCs with monoclonal antibody anti-CD3 OKT3, IFNgamma and IL2. After 3-4 weeks at least 3 separate populations are present in the culture: CD3+/CD56-/CD8+ precursors (40.5 ± 19.9%), CD3-CD56+ NK cells (2.5 ± 1.5%) and CD3+/CD56+/CD8+ CIK cells (56.9 ± 21%) which show a T EMRA phenotype (Franceschetti et al., Exp Hematol. 37, 616-628, 2009). CIK cultures are currently used in allogeneic or autologous settings as potential anti-neoplastic effectors for adoptive transfer clinical approaches. We have further characterised the mechanism of target cell recognition and role of activating receptors and of lytic mediators in the cytotoxicity of purified CD3+/CD56+/CD8+ CIK cells. We have observed that CIK cells can kill targets through at least two distinct mechanisms: the first TCR-dependent and antigen-specific and the second non TCR-dependent. Indeed, upon TCR/CD3 crosslinking in CIK cells we observe ERK-1/2 phosphorylation, IFNgamma production (mean 32.6% of positive cells by intracellular staining) and TNFalpha production (mean 19.6%). CD3 ligation by OKT3 results in a significant increase over time in the percentage of CIK cells undergoing degranulation evaluated as CD107a positive cells (respectively 15.5 ± 2.2% at 60', 24.4 ± 1% at 120', 32,9 ± 8.7% at 180' and 34.2 ± 11.1% at 240'). CD3 ligation on CIK cells can induce cytotoxicity in a reverse Ab-dependent killing assay. Addition of OKT3 enhances also the cytotoxicity of CIK cells against K562 leukaemic target (from 16 ± 5% to 50 ± 4 %, E:T 10:1; p<0.001). The TCR/CD3 mediated activation is blocked by pre-treatment with cyclosporine A, confirming the role of calcium-regulated phosphatase calcineurin in the CD3-linked degranulation pathway. Interestingly, CIK cells retain functional activity as antigen-specific memory T cells. Indeed in case of CIK cultures obtained from CMV-seropositive donors, CMV-specific CD3+/CD56+ CIK cells can be generated. CMV-specific CIK cells immunopurified by HLA-peptide tetramers are able to specifically recognise and kill autologous but not allogeneic PHA-blasts pulsed with pp65495-503 but not with irrelevant peptide (average lysis 63 ± 8%, E:T 10:1) and to produce IFNgamma following antigenic stimulation (26.4 ± 7%). Similar data are obtained with EBV-specific T cells. Moreover, CIK cells also show non-MHC-restricted cytotoxicity against numerous leukemic target cell lines. The same CMV-specific purified CIK population shows to posses non MHC-restricted cytotoxic properties against several leukemic targets (average lysis 44 ± 8%, E:T 10:1). NKG2D, described as receptor that can trigger TCR-independent cytotoxicity in activated T cells, is expressed on all CIK cells (mean 99%, MFI 251). Although we can show that NKG2D is functional in these cells since cross-linking with anti-NKG2D mAb leads to ERK phophorylation, blocking of this receptor with mAb does not affect the cytolysis of leukaemic targets. NKG2D crosslinking in CIK cells is not sufficient to induce granule esocytosis and INFgamma or TNFalpha production. No correlation is found between expression and surface density of NKG2D ligands on leukaemic cell targets and their susceptibility to CIK-mediated lysis. Unrestricted CIK-mediated cytotoxicity occurs in the absence of measurable degranulation, is not affected by cyclosporin A, but is inhibited by 70% in presence of brefeldin A, a surface upregulation of glycopolypeptide molecules inhibitor, suggesting a role for Fas-ligand family molecules. CIK cells indeed express TNFalpha (mean 16%, MFI 56), FasL (mean 34%, MFI 34) and TRAIL (mean 37%, MFI 49). The role of this death ligands in leukaemic cell killing is currently under investigation. These data clearly show that CD3+/CD56+/CD8+ CIK cells are activated T EMRA cells which have retained their TCR/CD3 complex usage and their antigen specificity but have acquired unrestricted anti-leukaemic activity. The identification of the molecules involved in this killing is still under investigation. These data open up the possibility of multiple clinical use of CIK cultures, including anti-leukaemic and anti-infective usage particularly in immunodeficient patients. Disclosures No relevant conflicts of interest to declare.
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Zheng, Zhuanzhen, Zhang Yuna, Zhang Huimin, Qingchi Liu, Yanping Ma, Weihai Wu, Chuanbao MA, Yuhui Pang, and Jianying LI. "Clinical Study Of DC-CIK (dendritic cells and cytokine-induced killer cells ) Eliminate Minimal Residual Leukemia." Blood 122, no. 21 (November 15, 2013): 1450. http://dx.doi.org/10.1182/blood.v122.21.1450.1450.
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Abstract Objective To evaluate the clinical efficacy and safety of allogenic dendritic cells (DCs) and cytokine-induced killer (CIK) cells in the eliminating minimal residual leukemia (MRL). Methods 48 acute leukemia patients with hematological complete remission (CR) but without molecular biological remission (CRM), or patients with minimal residual Leukemia (MRL) were selected from Ping’an Hospital of Shijiazhuang during Jan. 2009 to Jun. 2011. According to the patients’ will, 48 patients divided into combined treatment group and chemotherapy group 24 each. All the patients were in the same general information and disease level. The combined treatment group was treated with DC-CIK and consolidation chemotherapy, and the chemotherapy group was treated with consolidation chemotherapy. PBMCs were collected from healthy donors (the patient's parents or children) to prepare DC-CIK cells. DC-CIK cells were intravenous injected into patients once every 15 days, a total of 4-6 times infusion. The blood routine, bone marrow cells, leukemia related genes, urine and stool routine, liver and kidney biochemistry function, and ECG were observed. Changes of peripheral lymphocyte subsets in patients were detected by flow cytometry. Adverse reactions were examined. Results (1)Eleven cases in the combined treatment group achieved CRM, and the CRM rate was 45.8%; whereas only 2 cases in the chemotherapy group achieved CRM and the CRM rate was 8.3%,the difference was statistically significant(χ2=8.55, P<0.01).(2) Compared with the chemotherapy group, the CFIM (four-color combination flow cytometric immunophenotype of minimal residual leukemia) negative conversion rate of patients in the combined treatment group was significantly raised (66.7% vs 25.0%,χ2=8.39, P<0.01). (3)The negative conversion rate of MRL was higher in the combined treatment group than the chemotherapy group (66.7% vs25.0%, χ2=8.39, P<0.01). (4) After treatment the ratio of CD4+/CD8+ cells was significant increased than before treatment in the combined treatment group (1.3±0.4 vs 0.8±0.4, P<0.05). (5)The complete remission rate (CCR) of patients in the combined treatment group after 3 years was 79.2%, while that in the chemotherapy group was 45.8% (χ2=5.69, P<0.05).(6)No dysfunction of critical organs such as heart, liver and kidney and serious adverse reactions were observed while DC-CIK cells infusion. Conclusion DC-CIK combined with chemotherapy can inhibit leukemia gene, promote the negative conversion rate of CFIM, facilitate the clear of MRL, improve immune function and prolong remission of the patients.No serious adverse reactions were found in patients with DC-CIK infusion. Disclosures: No relevant conflicts of interest to declare.
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Zhou, Liang, Qijiu Chen, Hui Chen, Li Wang, and Jianyong Zhang. "Enhanced Inhibitory Effect of DC-CIK Cells on Lung Adenocarcinoma via Anti-Tim-3 Antibody and Antiprogrammed Cell Death-1 Antibody and Possible Mechanism." Evidence-Based Complementary and Alternative Medicine 2022 (July 31, 2022): 1–11. http://dx.doi.org/10.1155/2022/4097576.
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Objective. To investigate the effect and mechanism of blocking the signaling pathways of the T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and programmed death protein 1 (PD-1) in dendritic cell-cytokine induced killer (DC-CIK) cells on human lung adenocarcinoma A549 cells. Methods. Peripheral blood mononuclear cells (PBMCs) were isolated and induced into mature DC-CIK cells by cytokines in vitro. After blocking the Tim-3 and PD-1 signaling transduction pathways with anti-Tim-3 and anti-PD-1 antibodies, DC-CIK cells were coincubated with A549 cells. The killing effect of DC-CIK cells against A549 cells was measured by a CCK-8 assay. The impact of DC-CIK cells on the invasion and migration ability of A549 cells was detected by the Transwell test. The apoptosis rate of DC-CIK cells and the ratio of CD4+, CD8+, and DC-CIK cell subsets were determined by flow cytometry. The cell proliferation of DC-CIK was detected by the CCK-8 assay. Results. The antibodies of anti-Tim-3 antibody and anti-PD-1 could block Tim-3+ and PD-1+ DC-CIK cells and could significantly increase the killing effect of DC-CIK cells on A549 cells. The number of A549 cells under the microporous membrane of the Transwell chamber was reduced considerably in invasion and migration tests. Anti-Tim-3 and anti-PD-1 antibodies significantly reduced apoptosis of DC-CIK cells. No significant differences were observed in the ratios of CD4+ and CD8+ DC-CIK cell subsets or the proliferation capacity of DC-CIK cells in each group. Conclusion. Blocking the Tim-3 and PD-1 signaling pathways of DC-CIK cells with antibodies can enhance the killing ability of DC-CIK cells in A549 cells and significantly suppress the invasion and migration ability of A549 cells. The potential mechanism may be related to reduced apoptosis of DC-CIK cells.