Articles de revues : « CIK cell »

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Zhou, Liang, Qijiu Chen, Hui Chen, Li Wang et 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 (31 juillet 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.

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Yang, Yang, Yanxia Ma, Zhanzheng Wang, Li Wang, Yubo Zhao, Yang Hui, Chi Zhang et 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, n^o 7 (1 juillet 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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Lee, Jae Hee, Ji Sung Kim, Hong Kyung Lee, Ki Hun Kim, Jeong Eun Choi, A. Young Ji, Jin Tae Hong, Youngsoo Kim et 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, n^o 1_Supplement (1 mai 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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Dehno, Mojgan Naghizadeh, Yutao Li, Hans Weiher et 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, n^o 9 (27 avril 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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Jäkel, Clara E., Stefan Hauser, Sebastian Rogenhofer, Stefan C. Müller, P. Brossart et 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 et Ingo G. H. Schmidt-Wolf. « Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma ». Cancers 12, n^o 9 (1 septembre 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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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 et 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, n^o 11 (16 novembre 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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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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Han, Lu, Yi-Man Shang, Yong-Ping Song et 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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Meng, Juanxia, Mingfeng Zhao, Xiao Chai, Xia Xiao, Juan Mu, Qing Li, Qi Deng et Yuming Li. « IL-21 Enhances Anti-Leukemia Effect By Acting On Both CD3+CD56+ CIK Cells and Regulatory T Cells Derived From Umbilical Cord Blood In Vitro ». Blood 122, n^o 21 (15 novembre 2013) : 1051. http://dx.doi.org/10.1182/blood.v122.21.1051.1051.

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Abstract Cytokine-induced killer (CIK) cells are the effective kind of immunocytes participated in biotherapy of tumors and CD3+CD56+ cells display a major role in cytolytic activity against tumors. Recombinant human interleukin-2 (rhIL-2) is one of the most necessary cytokines during induction of CIK cells, however, some extra kinds of cells eapecially regulatory T (Treg) cells may expand during the induction of CIK cells because of the presence of IL-2. As Treg cells may exert a negative effect on function of CIK cells through cell-to-cell contact and some cytokines secreted by Treg cells, so what we need to consider is how to reduce Treg cells in the culture system of CIK cells. Some studies have confirmed that IL-21, which is belonged to a subset of cytokines where the receptors share the common cytokine receptor γ chain, could express an inhibitory influence on proliferation in Treg cells and our previous study has also confirmed its enhancement on proliferation and function of CIK cells. Here we hypothesize that IL-21 not only promotes the proliferation and function of CD3+CD56+ CIK cells, but also depressed Treg cells in the culure system of CIK cells and then result in the enhanced anti-leukemia effect. In this study, we first detected whether Treg cells existed in the culture system of CIK cells. Firstly, CIK cells were obaind from umbilical cord blood mononuclear cells (CBMCs) by the sequential addition of interferon-γ, anti-CD3 antibody , and rh-IL-2. Then the immunophenotype of Treg cells was detected by the flow cytometry through CD4-FITC and Foxp3-PE antibodies double staining. It was found that a certain proportion of Treg cells at about (10.24±1.42)% consisted in the culture system of CIK cells. The second step in this study was to explore the effect of IL-21 acting on CD3+CD56+ CIK cells. Firstly, CD3+CD56+ CIK cells were separated from the culture cells mentioned above by positive selection using Fluorescence-activated Cell Sorter. Cells were then stimulated with IL-21 for a defined period of time and subjected to CCK-8 and LDH assays to measure cellular viability and cytotoxicity against to leukemia cell line—K562 cells, respectively. The CCK-8 assay results showed that OD values in the cells without IL-21 stimulation was 1.08 which was much lower than that in the cells with IL-21 stimulaiton at 1.45 (P<0.01), thus IL-21 could significantly enhance in vitro proliferation of CD3+CD56+ CIK cells. And after 72 hours of stimulation by IL-21, cytotoxicity of CD3+CD56+ CIK cells against K562 cells at an Effector:Target ratio of 20:1 was observed to be (52.99±1.26)%, while the rate in the cells without IL-21 stimulation was (29.31±0.58)% , which was much lower than the cells with IL-21 stimulation (P<0.01). Next, we investigated the effect of IL-21 on both Treg and CIK cells in the culture system. The culture system of CIK cells was established as mentioned above, and then part of these cells were stimulated with IL-21 for 72 hours. Immunophenotype of Treg and CIK cells was detected by flow cytometry. It was found that cells stimulated by IL-21 showed a decreased proportion of CD4+Foxp3+ Treg cells at (1.48±0.06)% compared with the cells without IL-21 stimulation at (10.24±1.42)% (P<0.01). The CD3+CD56+ cells occupied a certain proportion at (39.80±1.80)% in the cells stimulated with IL-21, which was much higher than that in the cells without IL-21 stimulation at (20.46±1.11)% ( P<0.01). Then cytotoxicity of CIK cells was detected by LDH assay and the results showed that IL-21 could extremely strengthen the cytotoxicity of CIK cells to K562 cells, and the cytotoxity index in the cells with IL-21 stimulation at (52.99±1.26)% , which was much higher than that in the cells without IL-21 stimulation at (29.31±0.58)% ( P<0.01). In conclusion, our findings indicate that IL-21 could promote the proliferative and cytotoxic activity of CD3+CD56+ CIK cells, meanwhile it also could suppress the viability of Treg cells in the CIK cells culture system. So a conclusion can be summarized that IL-21 could enhance anti-leukemia effect not only by promoting CD3+CD56+ CIK cells but also by depressing Treg cells derived from umbilical cord blood in vitro. Disclosures: No relevant conflicts of interest to declare.

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Mase, Shintaro, Hideaki Maeba, Toshihiro Fujiki, Rie Kuroda, Raita Araki, Shoichi Koizumi, Akihiro Yachie et Ryosei Nishimura. « Allogeneic Cytokine-Induced Killer Cell-Dependent Eimination of Host Dendritic Cells Leads to Less Graft-Versus-Host Disease. » Blood 120, n^o 21 (16 novembre 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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Yang, Yang, Run-Qing Wang, Yi-Ming Zhong, Ming-Yao Meng, Yi-Yi Zhao, Li-Rong Yang, Lin Li et 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 (8 septembre 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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Rettinger, Eva, Sabine Huenecke, Verena Pfirrmann, Michael Merker, Andre Manfred Willasch, Andrea Jarisch, Jan Soerensen et al. « Repetitive Infusions of Cytokine-Induced Killer (CIK) Cells for Treatment of Impending Relapse in High-Risk Leukemia Patients after Allogeneic Stem Cell Transplantation ». Blood 124, n^o 21 (6 décembre 2014) : 2438. http://dx.doi.org/10.1182/blood.v124.21.2438.2438.

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Abstract Introduction: Allogeneic stem cell transplantation (SCT) is an established treatment option for patients with high-risk leukemias. But the success of this approach is still limited by patients’ relapse. Evidence was presented, that minimal residual disease (MRD) status in principle could be treated by donor lymphocyte infusion (DLI). However, T cells within DLI raise the risk for severe graft versus host disease (GvHD). Cytokine-induced killer (CIK) cells, mainly T cells sharing in part characteristics of natural killer (NK) cells, demonstrated potent non major histocompatibility complex (MHC)-restricted cytotoxicity against hematological malignancies, but displayed negligible alloreactivity in vitro and caused minimal GvHD in vivo. Here, we report our single center experience of repetitive, dose-escalating CIK cell infusions in 12 leukemia patients with impending (n=10) or overt relapse (n=2) after allogeneic SCT. Patients and Methods: Between August 11, 2011 and July 31, 2014 CIK cell infusions approved by the regulatory authorities (Regierungspräsidium Darmstadt, Germany) were given repetitively on compassionate used basis to 12 patients (<18 years of age, n=11, median age 9, range 1-16 years; >18 years of age, n=1, age 69 years) with haematological malignancies (AML, n=6; ALL, n=5; CML, n=1) and evidence of relapse in the absence of acute GvHD >grade I after allogeneic SCT. CIK cells obtained from peripheral blood mononuclear cells of original stem cell donors were generated within 10 days under good manufacturing practice (GMP)-conditions in the presence of interferong, anti-CD3 antibody, interleukin-2 and -15. Results: Altogether 53 CIK cell infusions (median number 3.5, range 1-10 per patient) from matched unrelated (n=6) or haploidentical (n=6) stem cell donors were offered at a minimum of three weeks after allogeneic SCT and an interval of 4-6 weeks between infusions (median follow up after 1st CIK cell infusion 8, range 3-22 months). Patients with overt relapse underwent cytoreductive chemotherapy before infusions. Based on our cumulative experience starting doses of CIK cell infusions were 5x106 CD3+CD56- CIK cells/kg in pediatric and 1x106 CD3+CD56- CIK cells/kg in adult patients. Regardless of donor type, dose escalation continued until a maximal dose of 100x106 CD3+CD56- CIK cells/kg was reached(median dose 10x106, range 0.1-100x106 CD3+CD56- CIK cells/kg). Acute GvHD grade I occurred in two patients after infusions of 1x106 or 5x106 CD3+CD56- CIK cells/kg. Another two patients developed acute GvHD grade III after infusion of 10x106 CD3+CD56-CIK cells/kg, respectively. In 3 patients with relapsed AML CIK cell infusions provided transient remission, but ultimately all three patients relapsed and succumbed to their diseases 8-9 months after first CIK cell infusion. Two patients with ALL and one patient with AML relapsed 2, 5, and 12 months after first CIK cell infusion, respectively. All patients were offered further anti-leukemic treatment including allogeneic SCT. Two AML patients died due to infections 9 and 12 months after the last CIK cell infusion. Both patients were in complete remission at the time of death. Three high-risk patients with ALL and one CML-patient with impending relapse indicated by MRD or BCR/ABL are still in complete remission. Conclusion: In conclusion, allogeneic CIK cell infusions seemed to be very promising and may improve cell-based immune therapies especially in leukemia patients with impending relapse after allogeneic SCT. Disclosures No relevant conflicts of interest to declare.

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Han, Xiao, Xiaohui Wang, Li Wang, Xianyi Yao, Guangyu Zhao et 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, n^o 10 (1 octobre 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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Pievani, Alice, Camilla Belussi, Christian Klein, Alessandro Rambaldi, Josée Golay et 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, n^o 2 (13 janvier 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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Lu, Xu-zhang, Bao-An Chen, Lin-di Ma, Xiao-hui Cai et Min Zhou. « Role of NKG2D in Cytokine-Induced Killer (CIK) Cells Against Multiple Myeloma Cells ». Blood 118, n^o 21 (18 novembre 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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Pievani, Alice, Gianmaria Borleri, Daniela Pende, Lorenzo Moretta, Alessandro Rambaldi, Josée Golay et 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, n^o 12 (22 septembre 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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Garofano, Francesca, et 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, n^o 11 (27 mai 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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Elia, Angela Rita, Giorgio Inghirami, Paola Circosta, Flavio Cristofani, Nathalie Santoro, Dario Sangiolo, Corrado Tarella et Alessandro Cignetti. « Retargeting of Citokine-Induced Killer (CIK) Cells with Molecularly Engrafted T-Cell Receptors (TCR) : A Preclinical in Vitro and In Vivo Study ». Blood 118, n^o 21 (18 novembre 2011) : 1917. http://dx.doi.org/10.1182/blood.v118.21.1917.1917.

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Abstract Abstract 1917 Cytokine Induced Killer (CIK) cells are a heterogeneous population of T lymphocytes sharing NK phenotype and functional properties: they are CD3+/CD56+ and have a potent MHC-unrestricted antitumor activity. We hypothesized that the therapeutic potential of CIK cells might be increased if they acquired the ability to recognize MHC-restricted tumor associated antigens. To this end, we transduced CIK cells with an HLA-A2 restricted T-Cell Receptor (TCR) directed against the melanocyte associated antigen Mart-1. PBMC were incubated with IFN-γ on day 0 and supplemented with anti-CD3 and IL-2 on day +1 to generate CIK cells. Cultures were transduced at day 4 with concentrated lentiviral particles and successfully expanded over a 4 week period. This allowed to generate CIK cells that contained 11±9% Mart-1 TCR positive cells, as detected by staining with a Mart-1 specific tetramer. Transduced CIK cultures contained 61±19% CD3+/CD56+ cells. Tetramer positive cells were both CD3+/CD56- and CD3+/CD56+ (31±8% and 59±9%, respectively), indicating that both MHC-restricted T-cells and MHC-unrestricted CIK cells could be targeted by lentiviral transduction. TCR-transduced CIK cells specifically recognized tumor cells presenting the relevant peptide and maintained their MHC-unrestricted tumor activity at the same time. The cytotoxic activity of Mart-1 redirected CIK against HLA-A2+ melanoma cell lines was 2.8 fold higher than the untransduced counterparts (62%±9 vs 22±6% lysis at an effector/target ratio of 20:1), while the cytotoxic activity against a Mart-1+/HLA-A2- melanoma cell line was similar in transduced and untransduced CIK cells (24%±8 vs 22±6% lysis), indicating that the increased activity was due to HLA-restricted recognition. This was confirmed by blocking experiments with an HLA-Class I antibody. At the end of the culture, the majority of both unmodified and transduced CIK cells expressed an effector memory phenotype, with few residual central memory cells. In TCR redirected cells there was a slight increase of cells with a naive phenotype compared to unmodified cells (19±5% vs 9±4%). These data suggest that the naive and central memory pool of redirected CIK cells might efficiently expand in vivo and support a long lived memory response, whereas the terminally differentiated pool might mediate short lived but potent MHC-restricted and unrestricted activity. To demonstrate that TCR transduced CIK cells display an increased antitumor activity also in vivo, we have conducted preparative experiments in humanized immunocompromised mice (NOD/scid/γ(c)(−/−), NSG). Results obtained so far have shown that: i) When 5×106 or 10×106 CIK cells (both TCR-transduced and unmodified) were injected intravenously, they stably engrafted NSG mice, homing predominantly to spleen and liver and also, to a lesser extent, to bone marrow and kidney (36±9%, 39±12%, 4±3%, 1.6±3% of human CD3+/CD45+ cells at 3 months in the spleen, liver, bone marrow and kidney, respectively); circulating cells were also detected in the peripheral blood. Engrafted CIK cells maintained high expression of CD8 but progressively downregulated and finally lost CD56 expression. When 10×106 CFSE-marked CIK cells where injected intravenously, they similarly engrafted and proliferated in NSG mice, reaching a peak of proliferation 2–3 weeks after injection; at 4 weeks, the CFSE dye was already completely diluted out. ii) Differently from normal PBMC, CIK cells did not induce any appreciable clinical sign of acute or chronic Graft versus Host Disease (GVHD), as determined by the general appearance of the fur, mobility and weight loss. Mice were observed up to 5 months, and both unmodified and TCR transduced CIK cells displayed the same behavior. iii) NSG accepted the graft of as few as 50.000 matrigel-resuspended melanoma cells that were injected subcutaneously, with the appearance of a measurable mass (>3mm) ten days after inoculation. From these in vivo experiments we conclude that: i) human CIK cells engraft and proliferate in NSG mice; ii) CIK cells do not cause GVHD; iii) the human melanoma cell lines used in vitro can grow in NSG mice. We are now testing whether TCR transduced CIK cells have superior antitumor activity than unmodified CIK in the NSG mice model. Taken together, our data suggest that TCR transfer into CIK cells is feasible and greatly improves their antitumor potential in vitro and possibly in vivo. Disclosures: No relevant conflicts of interest to declare.

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Liu, Chunyan, Yingying Zheng, Junyi Tang, Dawei Wang, Zhenshen Ma, Shutong Li et Xiaotian Chang. « Stimulation of DC-CIK with PADI4 Protein Can Significantly Elevate the Therapeutic Efficiency in Esophageal Cancer ». Journal of Immunology Research 2019 (3 mars 2019) : 1–11. http://dx.doi.org/10.1155/2019/6587570.

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Background. PADI4 has extensive expression in many tumors. This study applied PADI4 as a tumor marker to stimulate DC- (dendritic cell-) CIK (cytokine-induced killer), an immunotherapy approach. Methods. A PADI4 expression plasmid was transfected into EC-originating ECA-109 cells. PADI4 gene was also inserted into a prokaryotic expression vector to produce recombinant protein. Lysate from PADI4-overexpressing cells or the purified recombinant PADI4 protein was used to load DCs, and the cells were then coincubated with CIK cells. DC and CIK cell phenotypes were determined using flow cytometry. The proliferation and viability of CIK cells were analyzed using trypan blue staining. The cytotoxic effect of DC-CIK cells on cultured ECA-109 cells was determined using CCK8 assays. Tumor-bearing mice were prepared by injection of ECA-109 cells. DC-CIK cells stimulated with lysate from PADI4-overexpressing cells or the PADI4 recombinant protein were injected into the tumor-bearing mice. The tumor growth was measured with magnetic resonance imaging (MRI). Results. Following incubation with lysate from PADI4-overexpressing cells, the ratio of CD40+ DCs increased by 17.5%. Induction of CIK cells with PADI4-stimulated DCs elevated the cell proliferation by 53.2% and the ability of CIK cells to kill ECA-109 cells by 12.1%. DC-CIK cells stimulated with lysate from PADI4-overexpressing cells suppressed tumor volume by 18.6% in the tumor-bearing mice. The recombinant PADI4 protein showed a similar effect on CIK cell proliferation and cytotoxicity as that of the lysate from PADI4-overexpressing cells. Furthermore, the recombinant protein elevated the ratio of CD40+ DCs by 111.8%, CD80+ DCs by 6.3%, CD83+ DCs by 30.8%, and CD86+ DCs by 7.8%. Induction of CIK cells with rPADI4-stimulated DCs elevated the cell proliferation by 50.3% and the ability of CIK cells to kill ECA-109 cells by 14.7% and suppressed tumor volume by 35.1% in the animal model. Conclusion. This study demonstrates that stimulation of DC-CIK cells with PADI4 significantly suppressed tumor growth in tumor-bearing mice by promoting DC maturation, CIK cell proliferation, and cytotoxicity. PADI4 may be a potential tumor marker that could be used to improve the therapeutic efficiency of DC-CIK cells.

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Pengying, L., C. Longbang et H. Xiang. « The antitumor effects of CIK cells combined with docetaxel against drug-resistant lung adenocarcinoma cell line SPC-A1/DTX in vitro and in vivo ». Journal of Clinical Oncology 27, n^o 15_suppl (20 mai 2009) : 3039. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3039.

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3039 Background: Cytokine-induced killer (CIK) cells transfer is now being considered the most promising adoptive cellular therapy strategy. Multidrug resistance (MDR) phenomenon is a major hindrance to the successful chemotherapy of cancer. In this study, the anti-tumor activity of CIK cells combined with docetaxel (DTX) against multidrug resistance SPC-A1/DTX cell line was evaluated in vitro and in vivo. Methods: MTT assay was employed to evaluate the cytotoxic activity of DTX, CIK cells, and DTX plused CIK cells against SPC-A1/DTX cells in vitro. In vivo assay, SPC-A1/DTX cells were injected to nude mice subcutaneously to establish tumor-bearing mice model. On the 14th day, normal saline, docetaxel, CIK cells, and CIK cells combined with docetaxel were administered intraperitoneally respectively. All the nude mice were sacrificed at day 15 after treatment and the tumor were weight out. Results: MTT assay showed that CIK cells possessed a higher antitumor cytotoxic activity against SPC-A1/DTX cells than SPC-A1 cells in vitro (p <0.05). The synergetic anti-tumor activity positively correlated with the E:T ratio and the concertration of docetaxel. The animal data also suggested that CIK cells combined with DTX had a stronger suppressive effect on the tumor growth in vivo. Conclusions: CIK cells plused with docetaxel demonstrated a prominent augmentation of anti-tumor activity against MDR lung adenocarcinoma cell lines both in vitro and in vivo. No significant financial relationships to disclose.

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Introna, Martino, Gianmaria Borleri, Elena Conti, Anna M. Barbui, Raewyn Broady, Erica Dander, Giuseppe Gaipa et al. « Infusion of Donor Derived Cytokine Induced Killer Cells May Induce Clinical Remission with Limited GVHD in Patients Relapsing after Allogeneic Stem Cell Transplantation. » Blood 108, n^o 11 (16 novembre 2006) : 3698. http://dx.doi.org/10.1182/blood.v108.11.3698.3698.

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Abstract Cytokine induced killer cells (CIK) are T/NK cells with demonstrated anti-tumoral activity but lack of GVHD reactivity. They are expanded in vitro after stimulation of PBMC with OKT3, IFN-γ and rhIL-2. This phase I study was designed to test the safety and feasibility of repeated infusions of in vitro expanded donor derived CIK cells given to patients relapsed after allogeneic HSCT. The mean number of starting total nucleated cells was 707 × 106 (range 58–1500 × 106). After a median 22 days of culture, a mean percentage of 51% CD3+CD56+ cells (range 40–71%) was obtained corresponding to an absolute mean number of 1421×106 total CIK cells (range 422–2470 × 106). Eleven patients with AML (n=4), HD (n=3), CMML (n=1), pre-B ALL (n=1) and MDS (n=2), all relapsed after sibling (6) or matched unrelated donor (5) HSCT, entered this study. Before CIK administration, 7 patients had received one or more additional salvage treatments including chemotherapy (5), radiotherapy (1) and unmanipulated DLI (6) without any significant tumor response. The median number of CIK infusions was 2 (range 1–7) and the median number of total CIK cells was 14.5 ×106/kg (7.2–51). The infusions were well tolerated and no acute or late infusion-related reactions were registered. Acute GVHD (grade I and II) was observed in 4 patients 30 days after the last CIK infusion, which progressed into extensive chronic GVHD in 2 cases. In 6 patients, no significant clinical response could be registered so that disease progression and death occurred rapidly. In contrast, 5 patients achieved measurable responses: a patient with MDS, who had been treated with CIK cells alone, showed a hematologic improvement but subsequently progressed and died. One patient with HD received local radiotherapy and 7 CIK infusions (total of 51×106/kg CIK cells) which allowed the achievement of a good PR. After almost 1 year (300 days), he progressed and chemotherapy was given with achievement of a very good PR. A second patient with HD received one DLI at day 516 and 1 CIK infusion (12.2×106/kg) at day 537. At day 572, chemotherapy was initiated due to the persistence of disease. At the end of chemotherapy he received 3 additional CIK infusions for a total of 34×106/kg from days 711–752, without signs of aGVHD and is presently in CR at more than 780 days. One patient with CMML had been treated with DLI on day 102 and with a total of 38×106/kg CIK cells, given in four infusions from days 137–530, because of the appearance of mixed chimerism. Full chimerism was achieved 42 days after the first CIK infusion. The patient remains in CR at day 576. A second MDS patient, who had not achieved any significant response after five DLI (days 411–559), obtained a complete hematologic, cytogenetic and molecular remission after a single CIK infusion (7.6 ×106/kg) given at day 603 and remains in CR at day 680. This study shows that the production of allogeneic CIK cells is feasible, their infusion is generally safe and may induce clinical remission in patients relapsing after HSCT.

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Mase, Shintaro, Toshihiro Fujiki, Rie Kuroda, Raita Araki, Hideaki Maeba, Shoichi Koizumi, Akihiro Yachie et Ryosei Nishimura. « Allogeneic Cytokine-Induced Killer Cells Eliminate Host Dendritic Cells Due To The Enhanced Killing Activity By IFN-Gamma, Leading To Less Graft-Versus-Host Disease ». Blood 122, n^o 21 (15 novembre 2013) : 4495. http://dx.doi.org/10.1182/blood.v122.21.4495.4495.

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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. It was reported previously that IFN-gamma was a critical cytokine for preventing GVHD because CIK cells generated from IFN-gamma knock out mice caused lethal GVHD. One possible mechanism of protective effect against GVHD was that a large amount of IFN-gamma secreted by CIK cells could promote Fas-mediated apoptosis of recipient antigen activated donor T cells. However 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 hypothesize that CIK cells eliminate host DCs as same as kill tumor cells, and then reduce GVHD severity. To test this, 51Cr release assay was performed using BM derived DCs as target cells. We showed that allogeneic CIK cells had cytolytic activity against DCs, in marked contrast killing activity of IFN-gamma deficient CIK cells was much less compared to that of WT CIK cells (p< 0.05). Expression level of surface markers including NKG2D and CD8/CD4 ratio was not different between WT and IFN-gamma KO CIK cells. To further explore the mechanism why IFN-gamma deficient CIK cells reduced killing activity against DCs, IFN-gamma neutralizing antibody was added into killing mixture with WT CIK cells. However killing activity of WT CIK cells against DCs with IFN-gamma antibody did not changed compared to that of WT CIK alone. These results suggested that IFN-gamma itself did not affect killing activity directly, but IFN-gamma was essential cytokine to enhance killing activity during the culture of CIK cells. Next concern was whether CIK cells eliminated host DCs in vivo or not, we compared the residual number of host-type splenic DCs between the mice receiving bone marrow (BM) cells plus WT CIK cells and IFN-gamma deficient CIK cells. As shown in the figure below, the number of host DCs in the spleen in the mice receiving WT CIK cells was significantly lower compared to those of the mice receiving IFN-gamma KO CIK cells (p<0.05). In conclusion, allogeneic CIK cells eliminated host DCs due to the enhanced killing activity by IFN-gamma, leading to much less GVHD. Disclosures: No relevant conflicts of interest to declare.

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Nishimura, Ryosei, Jeanette Baker, Andreas Beilhack, Robert Zeiser, Janelle A. Olson, Emanuela I. Sega, Mobin Karimi et Robert S. Negrin. « In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity ». Blood 112, n^o 6 (15 septembre 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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Mehta, BA, IG Schmidt-Wolf, IL Weissman et RS Negrin. « Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells ». Blood 86, n^o 9 (1 novembre 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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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 (octobre 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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Laport, Ginna G., Kevin Sheehan, Robert Lowsky, Judith A. Shizuru, Keith Stockerl-Goldstein, Laura J. Johnston, David Miklos, Sally Arai, Jeanette Baker et Robert S. Negrin. « Cytokine Induced Killer (CIK) Cells as Post-Transplant Immunotherapy Following Allogeneic Hematopoietic Cell Transplantation. » Blood 108, n^o 11 (16 novembre 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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Guo, Rui, Haiyan Piao, Gang Shi, Guirong Zhang et Rui Zhang. « Analysis of the efficacy of CIK therapy in adjuvant treatment of colorectal cancer. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : e15022-e15022. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15022.

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e15022 Background: In the past decade, cell-based immunotherapy has been reported to improve the clinical outcomes by altering tumor immune responses, improving prognosis and overall survival rates in cancer patients.This retrospective study aimed to evaluate the efficacy of cytokine-induced killer (CIK) cell infusion as an adjuvant therapy in patients with colorectal cancer. Methods: A total of 370 patients with colorectal cancer admitted to Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute from March 2013 to April 2015 were retrospectively analyzed.All patients were treated with surgery for primary lesions, and then adjuvant chemotherapy was determined according to the guidelines. Among these patients, 201 patients received CIK therapy (CIK group),while the other 169 patients who had similar demographic and clinical characteristics did not receive a CIK cell infusion therapy (non-CIK group). Then we followed up these patients. Data were analyzed by Kaplan-Meier. Results: Our results showed that the 1,3,5-year overall survival (OS) rate for the CIK group versus the non-CIK group was 98.46 versus 93.61%, 85.4 versus 71.61%, 79.39 versus 67.9%, respectively. The OS was significantly longer in CIK group than in non-CIK group (P = 0.009). Meanwell, the OS of stage II and III colorectal cancer was significant in CIK group than in non-CIK group (P = 0.02 and 0.02). But the OS was not significant in Stage I and IV colorectal cancer (P = 0.347 and 0.285). We analyzed the patients between chemotherapy plus CIK therapy group and chemotherapy only group. We find that the OS has significant difference in two groups (P < 0.001). Conclusions: CIK therapy can improve the efficacy of adjuvant therapy in patients with colorectal cancer. But multicenter, large-sample randomized controlled trials are still needed to confirm it.

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Jäkel, Clara E., Annabelle Vogt, Maria A. Gonzalez-Carmona et 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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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 (17 mars 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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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, n^o 1_Supplement (1 avril 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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Mase, Shintaro, Ryosei Nishimura, Rie Kuroda, Hideaki Maeba, Kazuhito Naka, Raita Araki, Yasuhiro Ikawa, Shoichi Koizumi et Akihiro Yachie. « Cytokine-Induced Killer Cells Facilitate Immune Reconstitution After Allogeneic BMT In Mice. » Blood 116, n^o 21 (19 novembre 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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Yen, C. M., Y. Y. Fu et M. Y. Yang. « P06.06.B standardization of therapy and manufacturing using tumor-associated antigen-stimulated autologous dendritic cells co-cultured with cytokine-induced killer cells in cancer immunotherapy ». Neuro-Oncology 24, Supplement_2 (1 septembre 2022) : ii39. http://dx.doi.org/10.1093/neuonc/noac174.130.

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Abstract Background The application of DC-CIK in the field of cancer immunotherapy has been shown to be an effective treatment. However, the cost of DC-CIK treatment is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are the main limitations. Material and Methods Our experiments used tumor lysate instead of tumor cell line as tumor-associated antigen source with DCs co-culture. We provide the most efficient method for obtaining autologous DC-CIK cells from peripheral blood. Flow cytometry was used to evaluate DCs activation, CBA assay was used to quantify cytokines secreted by CIK cells, and the antitumor activity of DC-CIK was evaluated in vitro by K562 cell line. Results We demonstrate that the manufacturing process of employing frozen Peripheral Blood Mononuclear Cells (PBMCs) can balance patient’s comfort and economic benefits. DC-CIK can effectively upgrade the immunological specificity of CIK cells to tumors in the presence of tumor-associated antigen. In vitro experiments showed that when the number of DC: CIK cells was co-cultured in 1:20 ratio on the 14th day, the amount of cytokine secreted by CIK cells was the largest, and the anti-tumor immune effect was the most potent. When the number of CIK: K562 cells was in 25:1 ratio, the cytotoxic activity of CIK on K562 cells was the highest. Conclusion We developed an efficient activated fashion of DC:CIK, established the optimal ratio of DC-CIK immunologic activity and the best cytotoxic model of CIK to K562 cells.

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Yen, Chun-Ming, et Yun-Yen Fu. « IMMU-02. STANDARDIZATION OF THERAPY AND MANUFACTURING USING TUMOR-ASSOCIATED ANTIGEN-STIMULATED AUTOLOGOUS DENDRITIC CELLS CO-CULTURED WITH CYTOKINE-INDUCED KILLER CELLS IN CANCER IMMUNOTHERAPY ». Neuro-Oncology 24, Supplement_7 (1 novembre 2022) : vii131. http://dx.doi.org/10.1093/neuonc/noac209.500.

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Abstract BACKGROUND The application of DC-CIK in the field of cancer immunotherapy has been shown to be an effective treatment. However, the cost of DC-CIK treatment is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are the main limitations. METHODS Our experiments used tumor lysate instead of tumor cell line as tumor-associated antigen source with DCs co-culture. We provide the most efficient method for obtaining autologous DC-CIK cells from peripheral blood. Flow cytometry was used to evaluate DCs activation, CBA assay was used to quantify cytokines secreted by CIK cells, and the antitumor activity of DC-CIK was evaluated in vitro by K562 cell line. RESULTS We demonstrate that the manufacturing process of employing frozen Peripheral Blood Mononuclear Cells (PBMCs) can balance patient’s comfort and economic benefits. DC-CIK can effectively upgrade the immunological specificity of CIK cells to tumors in the presence of tumor-associated antigen. In vitro experiments showed that when the number of DC: CIK cells was co-cultured in 1:20 ratio on the 14th day, the amount of cytokine secreted by CIK cells was the largest, and the anti-tumor immune effect was the most potent. When the number of CIK: K562 cells was in 25:1 ratio, the cytotoxic activity of CIK on K562 cells was the highest. CONCLUSION We developed an efficient activated fashion of DC:CIK, established the optimal ratio of DC-CIK immunologic activity and the best cytotoxic model of CIK to K562 cells.

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Hamilton, C. A., M. M. Zhang, J. K. Chan, M. K. Cheung, S. H. Thorne, J. Baker, C. H. Contag et R. S. Negrin. « A preclinical study of cellular immunotherapy redirected by bispecific antibodies in uterine cell lines and primary cancer cells ». Journal of Clinical Oncology 24, n^o 18_suppl (20 juin 2006) : 15044. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.15044.

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15044 Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. We determined the cytotoxic activity of CIK cells against endometrioid and serous papillary (UPSC) uterine cancer cell lines and evaluated the ability of Trastuzumab and Her2xCD3 bispecific antibodies to enhance CIK-mediated cytotoxicity in Her2/neu expressing uterine cancer cells. Methods: The cytotoxicity of CIKs was quantified by 4-hour 51Cr release assays against uterine cell lines HEC-1A (endometrioid) and SPEC-2 (UPSC). Bispecific antibodies against Her2/neu (BSAbHer2) were designed using chemical conjugation methods. Results: Using FACS analysis, we found that the population of CD3+ CD8+ T cells increased from 24% to 56% over 21 days, while the CD3+ CD56+ T cells increased from 7% to 14%. Immunofluorescence microscopy revealed that both cell lines overexpressed Her2/neu. Cytotoxicity assays were performed at effector to target (E:T) ratios of 10:1, 20:1, 40:1 and 100:1 with increasing E:T ratio correlating directly with mean percent specific lysis. At the 100:1 E:T ratio, the mean percent lysis of CIKs against HEC-1A and SPEC-2 cells was 38.8% (±0.21) and 35% (±3.4), respectively. Trastuzumab did not affect the cytotoxic activity of CIKs. However, BSAbHer2 redirection significantly enhanced the cytotoxicity of CIKs against HEC-1A and SPEC-2 cells with a mean percent lysis of 66.3% (±1.0) and 50% (±2.7), respectively. Anti-NKG2D antibodies significantly reduced CIK activity by 49% and 47% in HEC-1A and SPEC-2 cells, respectively. The effects of CIK on advanced uterine cancers were demonstrated using our in vivo bioluminescence imaging system. Conclusion: CIK cells have cytotoxic activity both endometriod and UPSC cell lines. Redirection by BSAbHer2 significantly increased CIK-cell mediated cytotoxicity against Her2/neu expressing cell lines. The mechanism of CIK cytotoxicity appears to be partly mediated by the NKG2D receptor. No significant financial relationships to disclose.

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Wang, Yao, Hanren Dai, Hong Li, Haiyan Lv, Tao Wang, Xiaobing Fu et 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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Vu, Binh Thanh, Nguyet Thi-Anh Tran, Tuyet Thi Nguyen, Quyen Thanh-Ngoc Duong, Phong Minh Le, Hanh Thi Le et 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, n^o 2 (27 mai 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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Xiao, Zheng, Cheng-qiong Wang, Ming-hua Zhou, Na-na Li, Yong-ping Sun, Yu-zhi Wang, Shi-yu Liu et al. « The Antitumor Immunity and Tumor Responses of Chemotherapy with or without DC-CIK for Non-Small-Cell Lung Cancer in China : A Meta-Analysis of 28 Randomized Controlled Trials ». Journal of Immunology Research 2018 (13 décembre 2018) : 1–18. http://dx.doi.org/10.1155/2018/9081938.

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Objective. DC-CIK therapy included DC-CIK cells and Ag-DC-CIK cells. To further confirm whether DC-CIK reconstructs the antitumor immunity and improves the tumor responses and reveals its optimal usage and combination with chemotherapy, we systematically reevaluated all the related studies.Materials and Methods. All studies about DC-CIK plus chemotherapy for NSCLC were collected from the published and ongoing database as CBM, CNKI, VIP, Wanfang, ISI, Embase, MEDLINE, CENTRAL, WHO-ICTRP, Chi-CTR, and US clinical trials (established on June 2017). We evaluated their methodological bias risk according to the Cochrane evaluation handbook of RCTs (5.1.0), extracted data following the predesigned data extraction form, and synthesized the data using meta-analysis.Results. We included 28 RCTs (phase IV) with 2242 patients, but most trials had unclear bias risk. The SMD and 95% CI of meta-analysis for CD3+T cells, CD3+CD4+T cells, CD3+CD8+T cells, CD4+/CD8+T cell ratio, CIK cells, NK cells, and Treg cells were as follows: 1.85 (1.39 to 2.31), 0.87 (0.65 to 1.10), 1.04 (0.58 to 1.50), 0.75 (0.27 to 1.22), 3.87 (2.48 to 5.25), 1.51 (0.99 to 2.03), and −2.31(−3.84 to −0.79). The RR and 95% CI of meta-analysis for ORR and DCR were as follows: 1.38 (1.24 to 1.54) and 1.27 (1.20 to 1.34). All differences were statistically significant between DC-CIK plus chemotherapy and chemotherapy alone. Subgroup analysis showed that only DC-CIK cells could increase the CD3+T cells, CD3+CD4+T cells, CD3+CD8+T cells, and CD4+/CD8+T cell ratio. In treatment with one cycle or two cycles and combination with NP or GP, DC-CIK could increase the CD4+/CD8+T cell ratio. All results had good stability.Conclusions. DC-CIK therapy can simultaneously improve the antitumor immunity and tumor responses. DC-CIK therapy, especially DC-CIK cells, can improve antitumor immunity through increasing the T lymphocyte subsets, CIK cell, and NK cells in peripheral blood. The one cycle to two cycles may be optimal cycle, and the NP or GP may be optimal combination.

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Nishimura, Ryosei, Jeanette Baker, Andreas Beilhack et Robert Negrin. « Allogeneic Cytokine-Induced Killer Cells Traffick to GVHD Target Tissue but Cause Less GVHD, While Retaining Tumor Cytotoxicity and Facilitating Bone Marrow Engraftment. » Blood 108, n^o 11 (16 novembre 2006) : 3169. http://dx.doi.org/10.1182/blood.v108.11.3169.3169.

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Abstract Cytokine-induced-killer cells (CIK), generated from splenocytes in mice and PBMC in human by the timed addition of IFN-γ, anti-CD3 MAbs and IL-2, express both T cell and NK cell markers and have cytotoxic activity against autologous and allogeneic tumors. We previously showed that adoptive transfer of allogeneic CIK in a murine model did not cause severe acute GVHD, leading to full survival. However the precise mechanism of reduced GVHD and retained GVT activity is not fully understood. To this end, we first evaluated the trafficking patterns of luciferase-transgenic CIK in a major MHC mismatched BMT model. In vivo bioluminescence imaging (BLI) showed that both CIK and fresh splenocytes homed to and proliferated initially in secondary lymphoid organs including the spleen, followed by infiltration of the gut and skin by day 7. All mice receiving fresh splenocytes died by day 10. Signal from gut mucosa in animals receiving allogeneic CIK cells was transient, however signals from other sites such as mesenteric lymph nodes were high and persistent. By day 21 allogeneic CIK reinfiltrated intestinal tissue without causing severe GVHD. To further investigate potential changes in the expression of surface molecules in vivo, we transplanted GFP positive fresh splenocytes and GFP positive CIK cells into major mismatched irradiated hosts, and then on day 7 analyzed activation markers, homing molecules, apoptosis related genes, and peripheral tolerance induction molecules such as CTLA-4 and PD-1 by FACS. No significant differences were noted between CIK and splenocytes. However we found that the cell division rate of CIK cells in vivo was much slower than those of splenocytes utilizing a CFSE based cell proliferation assay. This might lead to less GVHD in mice receiving CIK cells. Next we evaluated whether CIK retained tumor killing activity in vivo using A20 luciferase lymphoma cells into lethally irradiated MHC major mismatched receipients subcutaneously. We visualized the reduction of tumor by BLI. GFP positive CIK, which were extracted on day 7 following their transplantation into MHC-mismatched allogeneic recipients, retained tumor cytotoxicity in vitro. Finally, to study whether CIK facilitate BM engraftment, we quantified the absolute number of cells from the peripheral blood in MHC major-mismatched nonmyeloablative BMT. On day 30 mice receiving CIK showed rapid BM engraftment, especially in CD4 (p=0.0007) and CD8 (p<0.0001) subpopulations. In conclusion, allogeneic CIK homed to and expanded in GVHD target organs without causing acute GVHD, retained tumor killing activity and promoted BM engraftment.

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Baker, Jeanette, Kevin Sheehan, Gina Monterola, Nancy Staines et Robert S. Negrin. « Human CIK Maintain Their In Vitro and In Vivo Anti-Tumor Ability after Cryopreservation. » Blood 106, n^o 11 (16 novembre 2005) : 1062. http://dx.doi.org/10.1182/blood.v106.11.1062.1062.

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Abstract Adoptive cellular therapy holds promise for improving the outcome of hematopoietic cell transplantation (HCT). At present, donor lymphocyte infusion post-HCT is efficacious for only a limited number of diseases, yet can induce significant graft versus host disease (GVHD). To improve the outcome of this approach, it would be beneficial to identify populations of T cells that retain graft versus tumor (GVT) effects with reduced propensity for GVHD. We have previously described studies of murine expanded Cytokine Induced Killer (CIK) cells which are ex vivo activated and expanded T cells that express both T and NK markers. CIK cells mediate cytotoxicity both in vivo and in vitro in a non- MHC restricted NKG2D dependent manner. Human CIK cells were expanded from PBMC from 9 healthy donors, cultured with IFNg, CD3 and IL-2 and maintained in AastromRepliCell® biochambers for 21–28 days. We aimed to determine whether cryopreservation of the CIK affects viability, cytotoxicity and phenotype. Cells were cryopreserved immediately after harvest at 10x106/ml and stored in liquid nitrogen vapor phase. CIK viability was not compromised with cryopreservation and cells thawed at 1, 2, 4, 8, 10 and 28 weeks after freezing were 96% viable (range 95%–99%). Immediately upon thawing, CIK cells showed diminished cytotoxicity against the B cell lymphoma cell lines DB and SUDHL4 with 6–10% killing at the 40:1 E:T ratio. However, thawed CIK cells regained their pre-freeze cytotoxic activity against these targets within 5 hours of being placed in reactivation medium containing IL-2 at 300 IU/ml. Reactivation of the CIK cells was extended up to 48 hours but showed no further increase in cytotoxicity beyond that attained at 5 hours; nor did increasing the IL-2 concentration to 1500 IU/ml in the reactivation medium improve CIK cell activity over the same time course. Cell viability declined during reactivation, decreasing from an average 96% upon thawing to 60% over 48 hours. Thawed CIK cells placed in reactivation medium maintained their cytotoxic activity up to 14 days in vitro. The cytotoxicity of reactivated CIK cells was assessed in vivo using SCID mice inoculated IP with 1x106 human ovarian cancer UCI-101 cells expressing the firefly luciferase gene. The mice were treated weekly with 2x107 cryopreserved and thawed human CIK cells that were re-cultured for 5 hours before injection. Following each administration of CIK cells, there was a reduction of tumor signal. Weekly treatments resulted in a better survival outcome for the mice receiving CIK cells as compared to PBS control mice. This study demonstrates that human CIK cells may be reactivated after cryopreservation and regain their cytotoxic potential. These finding have important implications for the application of these cells as adoptive cellular therapy.

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Pan, Qiu-Zhong, Qing Liu, Yu-Qing Zhou, Jing-Jing Zhao, Qi-Jing Wang, Yong-Qiang Li, Yan Tang et al. « CIK cell cytotoxicity is a predictive biomarker for CIK cell immunotherapy in postoperative patients with hepatocellular carcinoma ». Cancer Immunology, Immunotherapy 69, n^o 5 (14 février 2020) : 825–34. http://dx.doi.org/10.1007/s00262-020-02486-y.

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Yang, Chan-Keng, Chien-Hao Huang, Ching-Hsun Hu, Jian-He Fang, Tse-Ching Chen, Yung-Chang Lin et Chun-Yen Lin. « Immunophenotype and antitumor activity of cytokine-induced killer cells from patients with hepatocellular carcinoma ». PLOS ONE 18, n^o 1 (4 janvier 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, Rie Kuroda, Raita Araki, Toshihiro Fujiki, Hideo Yagita, Akihiro Yachie, Shoichi Koizumi et Ryosei Nishimura. « Allogeneic Cytokine-Induced Killer Cells Kill Dendritic Cells Efficiently Resulting in Less Graft-Versus-Host Disease ». Blood 118, n^o 21 (18 novembre 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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Perriello, Vincenzo Maria, Maria Caterina Rotiroti, Ilaria Pisani, Gaia Alberti, Giulia Pianigiani, Roberta Rossi, Valerio Ciaurro et al. « CD123 and CD33 Co-Targeting By Balanced Signaling on CAR-CIK Cells Reduces Potential Off-Target Toxicity While Preserving the Anti-Leukemic Activity of Acute Myeloid Leukemia ». Blood 138, Supplement 1 (5 novembre 2021) : 1699. http://dx.doi.org/10.1182/blood-2021-150487.

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Abstract Acute Myeloid Leukemia (AML) still represents an unmet clinical need for adult and pediatric high-risk patients. Adoptive cell therapy by chimeric antigen receptor (CAR) T cells demonstrated a high therapeutic potential in B-acute lymphoblastic leukemia, but translation in AML is limited by the absence of an ideal tumor-specific antigen. CD123 (known as IL-3 receptor alfa) and CD33 satisfy several features of ideal target antigens as they are expressed in almost all AML patients (mainly overexpressed in NPM1 and FLT-3 mutated AML), and conserved at disease relapse . Despite that, CD33 expression on hemopoietic stem/progenitor cells (HSPC) induced prolonged myelotoxicity after anti-CD33 CAR-T cell therapy and CD123 expression on endothelium was responsible for severe capillary leak syndrome after anti-CD123 CAR therapy. With the aim to improve selectivity for CD123+/CD33+ AML cells while minimizing toxicity against healthy cells, we probe a dual targeting model by Cytokine Induced Killer (CIK) cells co-expressing a first generation low affinity anti-CD123 IL-3 zetakine (IL3z.CAR) and an anti-CD33 as costimulatory receptor without activation signaling domains (CD33.CCR). This trans-signaling strategy could allow: 1) low toxicity profile against CD123+ endothelial cells and HSPC, due to a reduced cell activation given by the suboptimal first-generation CAR signal; 2) no or low myelotoxicity against CD33+ HSPC cells, due to absence of CIK cell activation upon the sole costimulatory signal engagement; 3) full CAR-CIK activation only against double expressing CD123 + / CD33 + leukemic cells. Fresh and frozen peripheral blood mononuclear cells were transduced with retroviral vectors during the CIK cell differentiation process . The functional activity of CAR-CIK cells was assessed in vitro by means of short- and long- term cytotoxicity and cytokine production assays upon challenge with different CD123/CD33 positive AML cell lines (THP-1 and KG-1) or with a CD123 positive human endothelial cell line (TIME). To assess the myelotoxicity against HSPC, CD34+ cells were sorted after 24h co-culture with CAR-CIK cells and mixed with methylcellulose-based semisolid medium to evaluate Colony Forming Units (CFU) after 14 days through an automated imaging and counting system for hematopoietic colonies (Stemvision). The in vivo anti-leukemic activity was evaluated by monitoring luciferase-expressing KG1 AML cell line growth over time in NSG mice treated with 3 infusions of all different CAR-CIK conditions. Dual CAR-CIK cells (IL-3z.CAR/CD33.CCR) display a potent and specific in vitro anti-leukemic efficacy against all the AML cell lines tested, compared to single targeting IL-3z.CAR and non-transduced CIK cells. To further minimize toxicities against healthy cells exploiting differences in CD123 antigen density between leukemic and healthy cells, we generated a low affinity dual CAR decreasing the IL3z.CAR binding affinity to CD123, by site-directed mutagenesis. Low affinity dual CAR-CIK cells show irrelevant cytotoxicity against the TIME endothelial cell line, comparable to non-transduced CIK cells, while preserving the efficacy against THP1 and KG1 AML cell lines. As a confirm of the reduced reactivity against endothelial cells, low affinity dual CAR-CIK cells produce the same levels of IL-2 and IFNγ either alone or in the presence of TIME cell line. Low affinity dual CAR-CIK cells also preserve the in vitro CFU-E, CFU-GM and CFU-GEMM colony forming capacity as compared to wild type (wt) dual CAR-CIK and wt IL-3z.CAR-CIK cells, highlighting the possibility to find a therapeutic window to minimize toxicity on healthy cells. The anti-leukemic activity of low affinity dual CAR-CIK cells has been confirmed also in vivo, with a significant suppression of leukemic growth against KG1 AML cell line. Mice treated with 3 infusions of low affinity dual CAR-CIK cells exhibited a significant better anti-leukemic profile, when compared to IL-3-single targeting CAR-CIK cells in terms of tumor growth and overall survival. These preclinical data demonstrate a powerful antitumor efficacy mediated by low affinity dual targeting IL-3z.CAR/CD33.CCR CIK cells against AML targets without any relevant in vitro toxicity on HSPC and endothelial cells, offering a proof-of-concept strategy to increase selectivity for CD123+/CD33+ AML cells whilst reducing the risk of "on-target off-tumor toxicity". Disclosures Perriello: Novartis: Other: Advisory Board. Martelli: Abbvie, Amgen, Celgene, Janssen, Novartis, Pfizer, Jazz Pharmaceuticals: Honoraria. Falini: Rasna Therapeutics: Honoraria. Biondi: Novartis: Honoraria; Bluebird: Other: Advisory Board; Incyte: Consultancy, Other: Advisory Board; Amgen: Honoraria; Colmmune: Honoraria.

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Qian, Shenxian, Pengfei Shi, Yaping Xie, Ying Xu, Daquan Gao, Lirong Liu, Xilian Huang, Kuang Chen et 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, n^o 21 (6 décembre 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 (13 novembre 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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Li, Yang, Shaoliang Huang, Jianpei Fang, Xuchao Zhang, Jing Wei, Wenge Huang et Yanfeng Wu. « Using the NOD/SCID Mice Model of Human Erythroleukemia for Evaluating the Cytotoxicity Activity of CB-CIK/NK Cells Stimulated by K562-DCs Fusion Vaccines. » Blood 106, n^o 11 (16 novembre 2005) : 5240. http://dx.doi.org/10.1182/blood.v106.11.5240.5240.

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Abstract CD3+CD56+ cytokine-induced killer (CIK) cells are prospective effectors for adoptive immunotherapy, CIK/NK cells incubated with K562-dendritic cells (DCs) fusion vaccines have more higher cytotoxicity activity. In this study, the efficacy and the safety of application of cord blood (CB) derived CIK/NK cells stimulated by K562-dendritic cells (DCs) fusion vaccines were evaluated in vivo by the NOD/SCID mice model of human erythroleukemia (K562 line, CD13+). DCs and CIK/NK cells were inducted by combination of cytokines from CB MNCs, DCs were fused with inactivated K562 tumor line by PEG (mw1500). 5 days before the harvest of CIK/NK cells, 1×105 K562-DCs fusion vaccines were co-cultured with 1×106 CB-CIK/NK cells to prepare for the K562-DCs fusion vaccines stimulated CIK/NK cells. NOD/SCID mice divided into six groups, eight in one group. Mice in A,B and C groups were inoculated with 1×106 K562 cells by tail vein. 24 hours later, 1×107 K562-DCs fusion vaccines stimulated CIK/NK cells and 1×107 unstimulated CIK/NK cells were transfued into the mice of group A and B, respectively. Group D and E were K562-DCs fusion vaccines stimulated CIK/NK cells and no-stimulated CIK/NK cells control, transfued by 1×107 stimulated CIK/NK cells and 1×107 no-stimulated CIK/NK cells, respectively. Group F is a normal control that no any inoculation were taken. None of the NOD/SCID mice in group C that inoculated with 1×106 K562 cells survived longer than 39 days, hepatosplenomegalic mass was seen in five mice. Death in group A and B were only one and two, respectively, at day 65 and day 56, 62. There was no tumour mass can be seen in group A and B, and the survial were more than 70 days. Both survival time of group A(69.38±1.77 days) and B(67.25±5.34 days) were longer than that of group C(30.38±4.57 days) significantly (P<0.01). The tumor marker (CD13) in periperal blood, live and lung of CIK/NK cells treated NOD/SCID mice (group A and B) significantly less than group C(P<0.01). There was no difference of CD56 positive in periperal blood of group A and B survival mice between that of the control (group D and E). These result indicated that K562-DCs fusion vaccines stimulating CB-CIK/NK cells have a potent anti-tumour activity in vivo and without any side-effect.

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Schlimper, Claudia, Andreas A. Hombach, Hinrich Abken et 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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Linn, Yeh Ching, Tsyr jong Lim, Madelaine Niam, Garnet Suck, Yeow Tee Goh, William Hwang, Yvonne Loh, Lee Hui Ng, Hao Xiang Yong et 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, n^o 11 (16 novembre 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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Rodeghiero, Francesco, Cristina Zanon, Matteo Stocchero, Elena Albiero, Silvia Castegnaro, Katia Chieregato, Domenico Madeo et Giuseppe Astori. « The Ex-Vivo Expansion of Cytokine Induced Killer (CIK) Cells Can Be Optimized Predicting Cell Expansion Dynamics by Means of Multivariate Statistical Data Analysis ». Blood 120, n^o 21 (16 novembre 2012) : 4125. http://dx.doi.org/10.1182/blood.v120.21.4125.4125.

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Abstract Abstract 4125 Introduction and Aims. CIK cells are CD3+/CD56+ T lymphocytes known for their antitumour effect against several haematological malignancies and solid tumours. CIK cells are obtained ex-vivo by stimulating peripheral blood mononucleated cells (MNC) with IFN-gamma (day 0), IL-2, anti-CD3 monoclonal-antibody (day 1) and IL2 every 3 days from day 1 to the 21st when maximum expansion of CD3+/CD56+ is expected as firstly described by Negrin. The percentage of CIK cells at the end of expansion represents a criteria for batch release: if CIK cells are less than 40% of the bulk population at the end of the culture, the batch should be considered suboptimal for transplantation. We have analyzed cell expansion dynamics of 30 samples evaluating the composition of cells constituting the bulk. In 11 samples (37%) CIK percentage reached plateau on day 17 instead of day 21, and then started to decrease rapidly. We believe that it is fundamental for the operator to predict in advance the harvest day in which CIK cells reach the maximal concentration in the bulk. Thus, the aim of this study was to introduce a new approach to control and optimize the expansion process based on multivariate statistical data analysis in order to improve its quality. Methods. Multivariate Batch Statistical Process Control (BSPC) and regression models based on Bidirectional-Orthogonal Projections to Latent Structures (O2PLS) were applied for monitoring the expansion process. Phenotypical analysis of cell populations was performed by flow cytometry by measuring the following different cellular subsets (11 variables): total T lymphocytes (CD3+), T-Helper lymphocytes (CD3+4+), T-cytotoxic lymphocytes (CD3+8+), CIK cells (CD3+56+), NK cells (CD3–56+), T lymphocytes (CD3+56-), monocytes (CD14+), B lymphocytes (CD19+), granulocytes (CD33+) and the undifferentiated subset CD3–56-. BSPC allowed us to produce suitable control charts while to estimate the level of CIK cells on days 17 and 21 we built different O2PLS regression models using as predictors the descriptions of the cellular population of the previous days. The chained use of the obtained regression models enabled us to predict in advance unsatisfactory expansions. Results. The expansions having a percentage of CIK cells ≥40% were used to build different types of control charts. In particular, the charts based on DModX and on T2 resulted predictive in the detection of unsatisfactory expansions. Indeed the expansions having CIK <40% on day 17 or on day 21 showed at least one time point out of the control limits for the two charts (Figure 1). Three O2PLS regression models were calculated. By considering the first three time points of expansion (day 0, day 4 and day 7), we obtained a regression model to estimate the CIK percentage on day 21 highly predictive (in Figure 2 we report the behavior of the model during cross validation). The interpretation of the model in terms of single measured variable pointed out that to estimate CIK percentage on day 21, only four out of eleven variables could be considered significant markers able to predict growth kinetic of CIK population during expansion. These variables are: the % of CIK cells on day 7, % of cytotoxic T lymphocytes on day 4 and % of NK at the beginning of the culture. Other two independent regression models were built to estimate CIK percentage on day 17 and on day 21 respectively These models used data collected until day 14 and resulted more accurate than the screening model. To validate the procedure based on the chained use of these three regression models, we tested it on three new batches. All new batches were correctly estimated as optimal or suboptimal at the end of the culture. Discussion. Multivariate statistical data analysis has been shown to be useful in generating suitable control charts and predictive models for biological experiments usually full of variables. In our study we showed that it is possible to predict the composition of the harvested population by considering the description of the cellular bulk population at the very early stages of the expansion realizing in advance if a batch will achieve acceptance criteria for release or not. The proposed approach is promising both for improving the quality of the process and for saving time and resources. Furthermore, the developed models are dynamics since they can be constantly refined by adding new data. Disclosures: No relevant conflicts of interest to declare.

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