Academic literature on the topic 'CIK cell'
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Journal articles on the topic "CIK cell"
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Zhou, Liang, Qijiu Chen, Hui Chen, Li Wang, and Jianyong Zhang. "Enhanced Inhibitory Effect of DC-CIK Cells on Lung Adenocarcinoma via Anti-Tim-3 Antibody and Antiprogrammed Cell Death-1 Antibody and Possible Mechanism." Evidence-Based Complementary and Alternative Medicine 2022 (July 31, 2022): 1–11. http://dx.doi.org/10.1155/2022/4097576.
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Objective. To investigate the effect and mechanism of blocking the signaling pathways of the T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and programmed death protein 1 (PD-1) in dendritic cell-cytokine induced killer (DC-CIK) cells on human lung adenocarcinoma A549 cells. Methods. Peripheral blood mononuclear cells (PBMCs) were isolated and induced into mature DC-CIK cells by cytokines in vitro. After blocking the Tim-3 and PD-1 signaling transduction pathways with anti-Tim-3 and anti-PD-1 antibodies, DC-CIK cells were coincubated with A549 cells. The killing effect of DC-CIK cells against A549 cells was measured by a CCK-8 assay. The impact of DC-CIK cells on the invasion and migration ability of A549 cells was detected by the Transwell test. The apoptosis rate of DC-CIK cells and the ratio of CD4+, CD8+, and DC-CIK cell subsets were determined by flow cytometry. The cell proliferation of DC-CIK was detected by the CCK-8 assay. Results. The antibodies of anti-Tim-3 antibody and anti-PD-1 could block Tim-3+ and PD-1+ DC-CIK cells and could significantly increase the killing effect of DC-CIK cells on A549 cells. The number of A549 cells under the microporous membrane of the Transwell chamber was reduced considerably in invasion and migration tests. Anti-Tim-3 and anti-PD-1 antibodies significantly reduced apoptosis of DC-CIK cells. No significant differences were observed in the ratios of CD4+ and CD8+ DC-CIK cell subsets or the proliferation capacity of DC-CIK cells in each group. Conclusion. Blocking the Tim-3 and PD-1 signaling pathways of DC-CIK cells with antibodies can enhance the killing ability of DC-CIK cells in A549 cells and significantly suppress the invasion and migration ability of A549 cells. The potential mechanism may be related to reduced apoptosis of DC-CIK cells.
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Yang, Yang, Yanxia Ma, Zhanzheng Wang, Li Wang, Yubo Zhao, Yang Hui, Chi Zhang, and Feixue Feng. "Compound Kushen Injection Promoted the Killing Effect of Cytokine-Induced Killer Cells Which Was Activated by Dendritic-Colon Cancer Stem Cell Fusion Cells on Colon Cancer Stem Cells." Journal of Biomaterials and Tissue Engineering 10, no. 7 (July 1, 2020): 957–65. http://dx.doi.org/10.1166/jbt.2020.2362.
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Colon cancer stem cells (cCSCs) are highly tumorigenic and resistant to traditional chemotherapeutic drugs. Therefore, they are an essential factor in colorectal cancer (CRC) metastasis and recurrence. Dendritic cells (DCs) could bind to the tumor cells and form the fusion cells (FCs). And these FCs could inhibit the development of malignant tumors. Furthermore, the cytokine induced killer (CIK) cells (CD3+ /CD56+ T lymphocytes) could also apply for the immunotherapy of cancer. And compound Kushen injection (CKI) is a traditional Chinese medicine (TCM) which has been used for the treatment of various tumors. However, whether the dendritic-colon cancer stem cell fusion cells (DC-cCSC FCs) could activate the CIK cells and kill the colon cancer stem cells is unknown. And whether the CKI could enhance the lethal effect is still unclear. In this study, we collected peripheral blood samples from healthy participants to acquire mononuclear cells and induced DC and CIK cells. Meanwhile, the CD44+ cells (cCSCs) were screened from SW480 cells. Next, the DC-cCSC FCs were established for the next experiments. At last, CCK-8 assays were performed to determine the effect of DC-cCSC FCs and CKI on the viability of cCSCs. We found that DC-cCSC FCs enhanced the proliferation of CIK cells and induce the CIK cells to secrete more IL-12. The DC-cCSC FCs enhanced the inhibitory effect of CIK cells on cCSCs. Furthermore, application of CKI enhanced the killing rates of DC-cCSC FCs and CIK cells on cCSCs. CIK cells activated by the DC-cCSC FCs had the lethal effect on the cCSCs. Furthermore, CKI enhanced this lethal effect of DC-cCSC FCs and CIK cells.
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Lee, Jae Hee, Ji Sung Kim, Hong Kyung Lee, Ki Hun Kim, Jeong Eun Choi, A. Young Ji, Jin Tae Hong, Youngsoo Kim, and Sang-Bae Han. "Comparison of cytotoxic dynamics between cytokine-induced killer cells and natural killer cells at the single cell level." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 198.12. http://dx.doi.org/10.4049/jimmunol.198.supp.198.12.
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Abstract Although much has been learned about the cytotoxic mechanisms of cytokine-induced killer (CIK) and natural killer (NK) cells, little is known about how they kill cancer cells at the single-cell level. In the present study, we examined the contact dynamics of CIK and NK cells at the single-cell level by using time-lapse imaging. CIK cells killed MHC-I-negative and -positive cancer cells, but NK cells destroyed MHC-I-negative cells only. Moreover, CIK cells moved in all directions and showed longer tracks than did NK cells. CIK cells showed higher displacement and straightness scores than did NK cells, which indicates long-distance random migration of CIK cells. CIK and NK cells moved at 6.7 mm/min and 4.5 mm/min on average, respectively. These data suggest that CIK cells are likely moving more actively than NK cells. The average threshold number of CIK cells required to kill an individual cancer cell was 6.7 for MHC-I-negative cells and 6.9 for MHC-I-positive cells. That of NK cells was 2.4 for MHC-I-negative cells. Likely due to the higher threshold numbers, killing by CIK cells was delayed in comparison with NK cells: 40% of MHC-negative target cells were killed after 5 h when co-cultured with CIK cells and after 2 h with NK cells. Our data have implications for the rational design of CIK or NK cell–based immunotherapy of cancer patients
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Dehno, Mojgan Naghizadeh, Yutao Li, Hans Weiher, and Ingo G. H. Schmidt-Wolf. "Increase in Efficacy of Checkpoint Inhibition by Cytokine-Induced-Killer Cells as a Combination Immunotherapy for Renal Cancer." International Journal of Molecular Sciences 21, no. 9 (April 27, 2020): 3078. http://dx.doi.org/10.3390/ijms21093078.
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Cytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes that have acquired the expression of several natural killer (NK) cell surface markers following the addition of interferon gamma (IFN-γ), OKT3 and interleukin-2 (IL-2). Treatment with CIK cells demonstrates a practical approach in cancer immunotherapy with limited, if any, graft versus host disease (GvHD) toxicity. CIK cells have been proposed and tested in many clinical trials in cancer patients by autologous, allogeneic or haploidentical administration. The possibility of combining them with specific monoclonal antibodies nivolumab and ipilimumab will further expand the possibility of their clinical utilization. Initially, phenotypic analysis was performed to explore CD3, CD4, CD56, PD-1 and CTLA-4 expression on CIK cells and PD-L1/PD-L2 expression on tumor cells. We further treated CIK cells with nivolumab and ipilimumab and measured the cytotoxicity of CIK cells cocultured to renal carcinoma cell lines, A-498 and Caki-2. We observed a significant decrease in viability of renal cell lines after treating with CIK cells (p < 0.0001) in comparison to untreated renal cell lines and anti-PD-1 or anti-CTLA-4 treatment had no remarkable effect on the viability of tumor cells. Using CCK-8, Precision Count Beads™ and Cell Trace™ violet proliferation assays, we proved significant increased proliferation of CIK cells in the presence of a combination of anti-PD-1 and anti-CTLA-4 antibodies compared to untreated CIK cells. The IFN-γ secretion increased significantly in the presence of A-498 and combinatorial blockade of PD-1 and CTLA-4 compared to nivolumab or ipilimumab monotreatment (p < 0.001). In conclusion, a combination of immune checkpoint inhibition with CIK cells augments cytotoxicity of CIK cells against renal cancer cells.
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Jäkel, Clara E., Stefan Hauser, Sebastian Rogenhofer, Stefan C. Müller, P. Brossart, and Ingo G. H. Schmidt-Wolf. "Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma." Clinical and Developmental Immunology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/473245.
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Metastatic renal cell carcinoma (RCC) seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK) cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable.In vitrostudies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.
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Zhang, Ying, Jörg Ellinger, Manuel Ritter, and Ingo G. H. Schmidt-Wolf. "Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma." Cancers 12, no. 9 (September 1, 2020): 2471. http://dx.doi.org/10.3390/cancers12092471.
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There is growing interest in cytokine-induced killer (CIK) cells on the integrated therapy of patients with RCC, especially those in the late stage or refractory to conventional chemotherapy and radiotherapy. In this review, a total of 15 clinical studies including 681 patients enrolled in CIK cell immunotherapy were outlined. Three-hundred-and-eighty-two patients with RCC were treated with CIK cells alone or in combination with DC vaccination, targeted agents sunitinib or sorafenib, and the PD-1 inhibitor pembrolizumab. Significantly improved 3-year overall survival rate was reported in four trials, whereas remarkably longer median progression-free survival was observed in three studies. Adverse reactions were mild and usually controllable fever and fatigue. Besides, preclinical research progresses were reviewed to increase our understanding about the underlying mechanisms of CIK cell cytotoxicity and identify potential targets to enhance their anti-tumor activity. These studies suggest that CIK cell-based immunotherapy has potential clinical benefits with a good safety profile and could become a promising approach in the combined therapies of RCC patients. However, further large-scale studies are required to evaluate the clinical efficacy of CIK cells and more efforts should be performed to identify the optimal CIK cell-based therapeutic regimen for RCC patients.
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Wang, Jing-Bo, Tong Wu, Jun-Fang Yang, Jian-Ping Zhang, Xing-Yu Cao, Yu-Ming Yin, Yuan Sun, Rong-Mu Luo, Dao-Pei Lu, and Chun-Rong Tong. "Management of Early Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation by Donor’s Dendritic Cell-Primed Cytokine- Induced Killer Cells." Blood 112, no. 11 (November 16, 2008): 829. http://dx.doi.org/10.1182/blood.v112.11.829.829.
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Abstract Leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is one of the main obstacles for survival. Immunosuppressant withdraw, chemotherapy, and donor lymphocyte infusion(DLI) are usually employed for management of recurrence after HSCT, but some patients have poor response to above therapy or have contraindications for DLI due to relapse at early stage after transplant or with active graft-versus-host disease (GVHD). Dendritic cell-primed cytokine-induced killer cells (DC-CIK) have been successfully applied in treatment of minimal residual disease (MRD) in our center for 12 years. In present pilot clinical study, we explore to manage early leukemia relapse after HSCT with donor’s DC-CIK in appropriate patients. The patients who relapsed in hematological (5–20% blasts in BM) or molecular or immunological (MRD>0.1% by flow cytometry) with at least one of the following criteria were included in this clinical trial. 1. No response to DLI; 2. Relapsed within 60 days after HSCT; 3. Relapsed with active GVHD. Total 18 patients (male 9, female 9) with median age 26 (4 to 42) years were eligible to this clinical study. The diagnosis included acute myeloid leukemia (AML 13), acute lymphoblastic leukemia (ALL 4) and chronic myeloid leukemia (CML 1) who failed to reach molecular remission with imatinib before transplant. The types of donor were HLA identical sibling (11), haploidentical family member (5), and unrelated donor (2). Six of 18 patients had either molecular or immunological recurrence, while 12 of 18 cases relapsed hematologically. The median cell dosage of DC-CIK infused was 2.34×109 (0.2–44×109). With DC-CIK treatment, overall 11 of 18 (61.1%) patients achieved complete remission (CR, molecular or immunological or hematological based on the disease status before DC-CIK). Among 6 cases in molecular or immunological recurrence, five of them (83.3%) obtained CR, while 12 patients with early hematological relapse, 6 of them (50%) returned to CR. Seven of 13 patients with AML, and all 4 cases with ALL responded to DC-CIK treatment, while a patient with CML had no therapeutic benefit from it. Among 7 cases without response to DC-CIK, one patient with CML achieved molecular remission with high-dose Imatinib, 1 case obtained CR after DLI later on, 1 patient survived with primary disease so far, and the remaining 4 patients died from leukemia recurrence. In 11 cases who responded to DC-CIK, 10 of them survived with median 359(164 to 1233) days. One patient died from transplant-related complications. Four patients developed GVHD after DC-CIK infusion and controlled completely with Cyclosporin A and Methylprednisolone. Our encouraging results indicate that Donor’s DC-CIK is a safe and effective therapeutic option in management of early leukemia recurrence after allogeneic HSCT, especially for the patients who fail to or ineligible to current standard practice.
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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, and Quan-Li Gao. "Biological Character of RetroNectin Activated Cytokine-Induced Killer Cells." Journal of Immunology Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/5706814.
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Adoptive cell therapy (ACT) using autologous cytokine-induced killer (CIK) cells is a promising treatment for metastatic carcinomas. In this study, we investigated the impact of RetroNectin on the proliferation, phenotype alternation, cytokine secretion, and cytotoxic activity of CIK cells from pancreatic cancer patients. Furthermore, we treated 13 patients with metastatic or locally advanced pancreatic cancer using autologous RetroNectin-activated CIK cells (R-CIK cells) alone or in combination with chemotherapy. Compared with only CD3 activated CIK cells (OKT-CIK cells), R-CIK cells showed stronger and faster proliferative ability, with a lower ratio of spontaneous apoptosis. Moreover, this ability continued after IL-2 was withdrawn from the culture system. R-CIK cells could also secrete higher levels of IL-2 and lower levels of IL-4 and IL-5 versus OKT-CIK cells. There was no difference between OKT-CIK and R-CIK cells in cytotoxic ability against lymphoma cell line K562. In patients who received auto-R-CIK cell infusion therapy, the overall objective response rate was 23.1%. Median survival time (mOS) after first R-CIK cell infusion was 10.57 months; the 1-year survival rate was 38.5%. No serious toxicity was associated with R-CIK cell infusion. In conclusion, RetroNectin may enhance antitumor activity of CIK cells: it is safe for use in treating pancreatic cancer.
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Meng, Juanxia, Mingfeng Zhao, Xiao Chai, Xia Xiao, Juan Mu, Qing Li, Qi Deng, and 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, no. 21 (November 15, 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.
Dissertations / Theses on the topic "CIK cell"
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TURAZZI, NICE. "BAFF RECEPTOR (BAFF-R) CAR-REDIRECTED T CELLS: A NOVEL TOOL TO TREAT HIGH RISK B -CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL)." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/153238.
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La leucemia linfoblastica acuta B (LLA-B) è la leucemia più comune nei bambini (80%), ma ha anche un picco di incidenza in età adulta. Recentemente, gli approcci di immunoterapia diretti contro la molecola CD19 hanno dimostrato un notevole successo nel trattamento della LLA-B recidiva e refrattaria, che rimane una delle principali necessità cliniche. Svantaggi importanti di tali strategie sono la comparsa di recidive CD19-negative e aplasia delle cellule B come risultato della persistenza delle cellule anti-CD19 CAR. In questo contesto, abbiamo ipotizzato che il recettore per il fattore di attivazione delle cellule B (BAFF-R), una proteina transmembrana fondamentale nella maturazione delle cellule B e nella loro sopravvivenza, potrebbe essere una molecola interessante per strategie di targeting, avendo come vantaggio il fatto che questo recettore non è rilevabile nelle cellule B precursori del midollo osseo.
Nel nostro lavoro abbiamo dimostrato che BAFF-R è altamente espresso in tutti i campioni primari di LLA-B sia all'insorgenza che alla ricaduta. Al fine di sviluppare un approccio mediato da un recettore chimerico (CAR) specifico per l’antigene BAFF-R, sono state sviluppate sei tipologie di CAR anti-BAFFR che si differenziano per l'inversione della VH e VL e la lunghezza del dominio cerniera. Cellule killer indotte da citochine (CIK), ingegnerizzate utilizzando un sistema non virale che sfrutta trasposoni Sleeping Beauty (SB), esprimono stabilmente anti-BAFFR.CARs e mantengono il loro caratteristico fenotipo. Tra i CAR generati, il CAR più breve VHVL esercita la massima attività anti-leucemica verso le cellule bersaglio, come NALM-6, con un'attività citotossica in vitro pari al 60%. Abbiamo valutato anche le funzioni effettrici a lungo termine di rilascio di citochine mediante colorazione intracellulare (8,9 ± 2% di cellule producesti IFN-γ e 16,4 ± 5,5% di cellule producesti IL-2). Inoltre, abbiamo anche rilevato una specifica attività citotossica nei confronti di blasti primari di LLA-B (media 65,6 ± 4,5%, n = 9). Combinando le cellule trasdotte Invsh.CAR con le cellule trasdotte CD19.CAR abbiamo rilevato una attività antitumorale superiore nei confronti di tutti le linee target. Infine, utilizzando un campione raccolto da un paziente con recidiva di malattia negativa per l’antigene CD19, abbiamo dimostrato la capacità del INVsh.CAR di lisare blasti CD19-negativi.
Concludendo, questi risultati dimostrano come questo recettore sia un bersaglio sicuro e attraente per un trattamento immunoterapeutico di seconda linea per la LLA-B in caso di recidiva dopo terapia con approcci di targeting dell’antigene CD19 o per un approccio di targeting doppio. Essendo BAFF-R ristretto a cellule B mature e assente in precursori e plasmablast, la nostra strategia potrebbe avere una tossicità inferiore, per quanto riguarda l'emergere di aplasia delle cellule B osservata nei pazienti trattati con le cellule T anti-CD19 CAR.B-cell Acute Lymphoblastic Leukemia (B-ALL) is most common in children (80%), but it has also a peak of incidence in adult age. Recently, immunotherapeutic approaches targeting the CD19 molecule have demonstrated remarkable success in the treatment of relapsed and refractory B-ALL, which remains a major clinical need. Important downsides of these strategies are the emergence of CD19-negative relapses and B-cell aplasia as a result of anti-CD19 CAR T-cell persistence. In this context, we hypothesized that the receptor for B-cell activating factor (BAFF-R), a transmembrane protein fundamental in B-cell maturation and survival, could be an interesting molecule to be targeted, taking the advantage that this receptor is undetectable on bone marrow B-cell precursors. Here we showed that BAFF-R is highly expressed in B-ALL primary samples at the onset and relapse In order to develop a chimeric antigen receptor (CAR) approach targeting BAFF-R molecule, six anti-BAFFR CAR genes that differ for the inversion of the VH and VL and the length of the spacer domain have been generated. Cytokine-induced Killer (CIK) cells, engineered using an improved Sleeping Beauty (SB) transposon system, stably expressed anti-BAFFR.CARs, and maintained their characteristic phenotype. Among the newly constructed CARs, the shortest VHVL CAR exerted the highest anti-leukemic activity towards target cells, such as NALM-6, with an in vitro killing activity of 60%. We also evaluated later effector functions in terms of cytokine release by intracellular staining (8,9±2% of IFN-γ and 16,4±5,5% of IL-2 producing cells). Importantly, we also detected a specific cytotoxic activity towards primary B-ALL blasts (average 65,6±4,5%, n=9). Combining the Invsh.CAR with CD19.CAR we detected a superior antitumor activity towards ALL targets. Furthermore, by using a sample collected from a patient relapsed with CD19 negative disease, we demonstrated the ability of the INVsh.CAR to lysate CD19-negative blasts. Taken together, these findings make this receptor a safe and attractive target for a second line B-ALL immunotherapy in case of relapse after CD19-targeting therapies or for a double targeted approach. Being restricted to mature B cells, but absent in precursors and plasmablasts, our strategy could have an inferior toxicity concerning the emergence of B-cell aplasia observed in patients treated with anti-CD19 CAR-modified T cells.
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ALBERTI, GAIA. "Evaluation of a Tandem CD33-CD146 Chimeric Antigen Receptor (CAR) for the simultaneous targeting of Acute Myeloid Leukemia (AML) blasts and stromal cells in the niche." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/382304.
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La leucemia mieloide acuta (LMA) è la neoplasia ematologica maggiormente diagnosticata nei pazienti adulti (25%) e mentre rappresenta il 15-20% dei casi nei pazienti pediatrici. La chemioterapia convenzionale, che impiega antraciclina e citarabina, rappresenta il trattamento standard per l’LMA, con tassi di remissione completa dal 60% all'80% nei bambini e dal 40% al 60% negli adulti (>60 anni). Sfortunatamente, la ricaduta dopo tale terapia è comune e la sopravvivenza dei pazienti stimata a 5 anni è ancora inferiore al 30%. Risulta quindi di primaria importanza trovare alternative terapeutiche per i pazienti recidivanti e refrattari. Il recente successo clinico, ottenuto nelle leucemie di tipo B, dell'immunoterapia con cellule CAR (chimeric antigen receptor) T ha portato allo sviluppo di nuove strategie terapeutiche nell’ambito dell’LMA. Tuttavia, lo sviluppo del trattamento con cellule CAR T nel contesto dell'LMA è ancora agli albori a causa dell'eterogeneità della malattia, della mancanza di un antigene bersaglio adatto e del ruolo protettivo del microambiente tumorale (TME). Infatti, non esiste ancora un protocollo clinico approvato per il trattamento della leucemia mieloide. Per creare le cellule CAR T abbiamo scelto di utilizzare la piattaforma non virale Sleeping-Beauty (SB) per ingegnerizzare le cellule CIK (cytokine-induced killer). In primo luogo, abbiamo scelto di utilizzare come potenziale strumento per il targeting del TME le cellule CIK ingegnerizzate con anti-CD146.CAR. Di conseguenza, abbiamo ottimizzato 6 diverse molecole CAR aventi un design differente, ottenendo un'espressione ottimale di CD146 nella variante VLVH Long. Abbiamo quindi testato le cellule CD146.CAR-CIK in vitro, ottenendo l’attivazione specifica delle funzioni effettrici (in termini di capacità di killing, produzione di citochine e proliferazione) contro cellule target CD146+. In seguito, abbiamo progettato un Tandem CAR bispecifico (CD33xCD146.CAR-CIKs) che ha mostrato una significativa attività antileucemica in vitro. È stato ampiamente dimostrato che la nicchia midollare contribuisce al supporto e alla protezione delle cellule staminali leucemiche (CSLs). Quindi, per mimare al meglio l’azione del CAR nella nicchia midollare umana, abbiamo testato le cellule CD33xCD146.CAR-CIK contro le linee cellulari stromali CD146+ e le cellule mesenchimali (MSC) primarie sane (HD-) e di derivazione mieloide (LMA-). I dati mostrano una inibizione delle funzioni effettrici delle cellule CAR-CIK e una drastica diminuzione della produzione di citochine e della proliferazione. Inoltre, l'equilibrio tra citochine pro e antinfiammatorie è risultato alterato, infatti la produzione di citochine Th1/Tc1 da parte delle cellule CD146.CAR-CIK è stata inibita dalla co-coltura con cellule stromali, mentre è stato rilevato un aumento delle citochine Th2/Tc2. Questi risultati suggeriscono un potenziale ruolo immunosoppressivo del compartimento stromale nei confronti delle cellule CAR-CIK. Sulla base dell’ effetto immunomodulatorio delle MSC sui linfociti T, abbiamo ipotizzato che la nicchia midollare possa influenzare le funzioni effettrici delle cellule CAR T. Di conseguenza, il targeting del CD146 rappresenta una "proof-of-principles" del fatto che aggredire il microambiente leucemico possa migliorare la terapia CAR T nell’ambito dell’LMA. Per ridurre al minimo la tossicità "off-target ", stiamo cercando di selezionare un antigene bersaglio specifico ed overespresso sulle cellule stromali dell'LMA, che abbia un'espressione minima nello stroma sano e che sia coinvolto nelle interazioni leucemia/nicchia. Il nuovo marker di interesse sarà accoppiato al CD33.CAR nella creazione di un CAR bispecifico, che verrà confrontato con il costrutto CD33xCD146.CAR, valutandone i profili di efficacia e sicurezza sia in vitro che in vivo.Acute myeloid leukemia (AML) is the most frequently diagnosed leukemia in adults (25%) and accounts for 15-20% cases in pediatric patients. Conventional chemotherapy employing anthracycline and cytarabine represents the gold standard treatment for AML, with rates of complete remission from 60% to 80% in children and from 40% to 60% in adults (>60 years). Despite these high rates, relapse after conventional therapy is common and the estimated five-year survival of AML patients is still below 30%. Indeed, there is an urgency to find alternative therapeutic strategies for relapsed and refractory patients. The recent clinical success of chimeric antigen receptor (CAR) T cell immunotherapy in the context of B-cell malignancies has opened a new route of investigation also towards AML. However, the development of CAR T cell therapy in the context of AML is still in its infancy due to heterogeneity of the disease, the lack of a suitable target antigen and the leukemia protective role of the tumor microenvironment (TME) and no approved CAR T cells study exists for AML treatment yet. Non-viral Sleeping-Beauty (SB) transposon platform was employed to redirect cytokine-induce killer (CIK) cell. In this scenario, we firstly characterize non-viral SB engineered CIK cells with anti-CD146.CAR as a potential tool for the targeting of the bone marrow (BM) microenvironment. We optimized the CAR design structure by testing 6 different CAR molecules, achieving a specific and efficient CD146 expression in the VLVH Long variant. CD146.CAR-CIK cells were subsequently tested in vitro, showing an optimal activation of effector functions (in terms of killing activity, cytokines production and proliferation) when they were engaged against CD146+ target cells. Consequently, we developed a bispecific Tandem CAR (CD33xCD146.CAR-CIKs), which displayed anti-leukemic activity in vitro. It has been extensively proven that BM niche contribute to establish a sanctuary in which leukemic stem cells (LSCs) are able to acquire drug-resistant phenotype, therefore, to better mimicking the human BM niche we tested CD33xCD146.CAR-CIK cells against CD146+ stromal cell lines (HS-27A and HS-5) and primary derived healthy (HD-) and patient-derived (AML-) mesenchymal stromal cells (MSCs). Results showed inhibition of the redirected CAR-CIK cells effector functions, resulting in a drastic decrease of cytokines production and proliferation. The balance between pro- and anti- inflammatory cytokines showed that Th1/Tc1 cytokines production by CD146.CAR-CIK cells was inhibited by the co-culture with stromal cells, while increase Th2/Tc2 cytokines was detected when CD146.CAR-CIK cells were co-cultured with stromal target cells. These results suggest a potential immunosuppressive role of the stromal compartment against CAR-CIK cells. According to these results, we hypothesized that BM stromal cells can potentially exert an immunomodulatory effect on T cells, suggesting that the niche microenvironment may be involved in the regulation of CAR T cells therapy effectiveness. Indeed, the targeting of CD146 on stroma represents a “proof-of-principle” that stromal components of leukemic microenvironment may be attractive targets for CAR T based immunotherapy. To minimize “off-tumor” toxicity, we are looking for a specific surface target antigen selectively overexpressed on AML stromal cells, with minimal expression in healthy stroma and possibly involved in leukemia/niche interactions. The newly marker of interest will be coupled to the CD33.CAR and this bispecific CAR will be compared with CD33xCD146.CAR construct, evaluating their efficacy and safety profiles both in vitro and in vivo.
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PIEVANI, ALICE SILVIA. "Cytokine-induced killer (cik) cell cultures for the adoptive immunotherapy of hematological malignancies: characterization and new therapeutic strategies for clinical application." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/20178.
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Cytokine-induced killer (CIK) cells are a heterogeneous population of lymphocytes obtained in vitro within 21 days from mononuclear cells under the influence of cytokines. CIK cells show potent MHC-unrestricted cytotoxicity against a variety of tumor cells, in particular hematological malignancies, and minimal tendency to induce graft-versus-host disease.
The expanded bulk CIK culture consists of over 90% CD3+ cells, of which the majority coexpress CD56 and the remaining cells are CD56-. CD3+CD56+ “true” CIK cells are terminally differentiated non dividing lymphocytes which could deliver potent MHC-unrestricted cytotoxicity for the immediate destruction of tumor cells. The other less cytotoxic CD3+CD56- cell subset represents a progenitor reservoir that could proliferate and differentiate into CD3+CD56+ CIK cells. CD3+CD56+ CIK cells express activating NK receptors including NKG2D, DNAM-1 and low levels of NKp30. Cell signalling not only through TCR/CD3, but also through NKG2D, DNAM-1 and NKp30, leads to CIK cell activation resulting in granule exocytosis and cytotoxicity. Antibody blocking experiments revealed that NKG2D, DNAM-1 and NKp30 are actually involved in tumor cell recognition and killing. Anti-CMV specific CIK cells could be expanded in standard CIK conditions and mediate both specific, MHC-restricted recognition of a CMV-pulsed autologous target and NK-like non specific cytolytic activity against leukemic cell targets. Antibody 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, two frequently associated complications in transplanted patients.
B-cell non-Hodgkin lymphoma is only partially susceptible to CIK-mediated lysis. The addition of anti-CD20 monoclonal antibodies GA101 or rituximab increased cytotoxicity mediated by CIK cell cultures by 35% and 15%, respectively. This enhancement was mainly due to antibody-dependent cytotoxicity mediated by the 1%-10% NK cells contaminating CIK cultures. The addition of human serum 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 mcg/mL of rituximab, but even more so by GA101, with respect to CIK cultures alone. The combined use of CIK cells with anti-CD20 mAbs could represent a novel immunotherapy protocol for the treatment of B lymphoma patients with resistant disease.
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Bach, Martin. "Der Einfluss muriner mesenchymaler Stammzellen auf murine zytokin induzierte Killerzellen in der Kokultur." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-149957.
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Stimulating lymphocytes with Ifn-γ, anti-CD3, and interleukin-2 promotes the proliferation of a cell population coexpressing T-lymphocyte surface antigens such as CD3, CD8a, and CD25 as well as natural killer cell markers such as NK1.1, CD49, and CD69. These cells, referred to as cytokine-induced killer cells (CIKs), display cytotoxic activity against tumour cells, even without prior antigen presentation, and offer a new cell-based approach to the treatment of malignant diseases. Because CIKs are limited in vivo, strategies to optimize in vitro culture yield are required.
In the last 10 years, mesenchymal stem cells (MSCs) have gathered considerable attention. Aside from their uses in tissue engineering and as support in haematopoietic stem cell transplantations, MSCs show notable immunomodulatory characteristics, providing further possibilities for therapeutic applications. In this study, we investigated the influence of murine MSCs on proliferation, phenotype, vitality, and cytotoxicity of murine CIKs in a coculture system. We found that CIKs in coculture proliferated within 7 days, with an average growth factor of 18.84, whereas controls grew with an average factor of 3.7 in the same period. Furthermore, higher vitality was noted in cocultured CIKs than in controls. Cell phenotype was unaffected by coculture with MSCs and, notably, coculture did not impact cytotoxicity against the tumour cells analysed. The findings suggest that cell–cell contact is primarily responsible for these effects. Humoral interactions play only a minor role. Furthermore, no phenotypical MSCs were detected after coculture for 4 h, suggesting the occurrence of immune reactions between CIKs and MSCs. Further investigations with DiD-labelled MSCs revealed that the observed disappearance of MSCs appears not to be due to differentiation processes.
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Cappuzzello, Elisa. "A DONOR-DEPENDENT SUBSET OF CYTOKINE-INDUCED KILLER (CIK) CELLS EXPRESS CD16 AND CAN BE RETARGETED TO EXERT A POTENT ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC)." Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424343.
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Cancer adoptive cell therapy (ACT) relies on the infusion of immune cell populations mediating direct antitumor effects, such as cytotoxic CD8+ T lymphocytes (CTL), natural killer (NK) cells and Cytokine-Induced Killer (CIK) cells. In this study, we aimed at improving CIK cell potential for adoptive immunotherapy strategies. CIK cells are a heterogeneous population of ex vivo expanded lymphocytes, which share phenotypic and functional features with both NK and T cells. They exert a potent MHC-independent antitumor activity against both hematological and solid malignancies, but not normal tissues and hematopoietic precursors. Several clinical trials have demonstrated the feasibility and the therapeutic efficacy together with low toxicity of CIK cells infusion, supporting CIK cells as a very promising cell population for adoptive immunotherapy. In this work, CIK cells were obtained from PBMCs of healthy donors by the timed addition of IFN-γ, anti-CD3 antibody and IL-2. Analyzing their phenotype, we demonstrated for the first time a relevant expression of CD16 in a donor-dependent manner and, based on this observation, we proved the ability of CIK cells to kill tumors by an Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) mechanism. Indeed, the concurrent administration of clinically therapeutic mAbs, such as trastuzumab or cetuximab, led to a significant improvement of their antitumor activity in vitro against both ovarian and breast cancer cell lines. To formally prove that the CD16 receptor is functional and directly involved in the ADCC, an anti-CD16 blocking antibody was added to the assays. NK cell depletion from bulk cultures confirmed that the ADCC activity is accountable to the CIK CD16+ subpopulation. This novel function of CIK cells, never exploited before, was assessed for therapeutic efficacy in mouse models of human ovarian carcinoma xenografted in NOD/SCID common γ chain knockout (NSG) mice. Co-administration of CIK cells and mAbs significantly increased the survival of tumor-bearing mice, as compared to animals receiving CIK cells alone. CIK cell antitumor activity in vitro was also enhanced by the combination with bispecific antibodies and immunoligands, which are able to target both a tumor-associated antigen and activating receptors expressed by effector cells. Taken together, these data envisage new perspectives for adoptive immunotherapy where antigen-specific retargeting of T cells can be achieved by a combination therapy with clinical-grade monoclonal antibodies already widely used in cancer therapy, and CIK cell populations that are easily expandable in very large numbers, inexpensive, safe and do not require genetic manipulations. In conclusion, this new therapeutic strategy for the ACT treatment of different types of tumors could find wide implementation and application, and be expanded to the use of additional therapeutic antibodies.La terapia cellulare adottiva (Adoptive Cell Therapy, ACT) si basa sulla somministrazione di popolazioni di cellule immunitarie in grado di mediare un effetto antitumorale in modo diretto, ad esempio linfociti T CD8+ citotossici (CTL), cellule natural killer (NK) e cellule killer indotte da citochine (Cytokine-Induced Killer cells, CIK). Lo scopo di questo lavoro è stato quello di incrementare il potenziale delle cellule CIK nelle strategie di immunoterapia adottiva. Le cellule CIK sono una popolazione eterogenea di linfociti espansi ex vivo che condividono caratteristiche fenotipiche e funzionali sia con le cellule NK sia con le cellule T. Queste cellule esercitano una potente citotossicità MHC-indipendente nei confronti di tumori sia ematologici sia solidi, ma non di tessuti normali e precursori ematopoietici. Diversi trial clinici hanno dimostrato l’attuabilità, l’efficacia terapeutica e la bassa tossicità delle infusioni di cellule CIK, supportandole come popolazione cellulare molto promettente per l’immunoterapia adottiva. In questo lavoro, le cellule CIK sono state ottenute da cellule mononucleate del sangue periferico (Pheripheral Blood Mononuclear Cells, PBMCs) di donatori sani mediante l’aggiunta di interferone gamma (Interferon-γ, IFN-γ), anticorpi anti-CD3 e interleuchina 2 (Interleukin-2, IL-2). Analizzando il fenotipo, abbiamo dimostrato per la prima volta una rilevante espressione donatore-dipendente del recettore CD16 e, basandoci su questa osservazione, abbiamo analizzato la capacità delle cellule CIK di uccidere cellule tumorali mediante citotossicità cellulo-mediata anticorpo-dipendente (Antibody-Dependent Cell-mediated Cytotoxicity, ADCC). Infatti, abbiamo osservato che la simultanea somministrazione di anticorpi monoclonali terapeutici, come il trastuzumab e il cetuximab, portano ad un significativo incremento dell’attività antitumorale in vitro delle CIK nei confronti di linee cellulari di tumore ovarico e mammario. Per dimostrare che il CD16 è funzionale ed è direttamente coinvolto nell’ADCC, è stato aggiunto al saggio un anticorpo bloccante anti-CD16. La deplezione delle cellule NK ha confermato che l’ADCC è attribuibile alla sottopopolazione CD16+ delle cellule CIK. Questa nuova funzione delle cellule CIK, descritta qui per la prima volta, è stata valutata per la sua efficacia terapeutica in un modello murino di carcinoma ovarico umano trapiantato in topi NOD/SCID knockout per la catena comune γ (topi NSG). La co-somministrazione di cellule CIK e anticorpi monoclonali ha aumentato significativamente la sopravvivenza dei topi con tumore, in confronto ai topi trattati soltanto con le CIK. Inoltre, l’attività antitumorale in vitro delle cellule CIK è stata incrementata mediante la combinazione con anticorpi bispecifici e immunoligandi, in grado di legare contemporaneamente un antigene associato al tumore e un recettore attivatore espresso dalle cellule effettrici. Complessivamente, questi dati prospettano nuove possibilità per l’immunoterapia adottiva, in cui il reindirizzamento antigene-specifico dei linfociti T può essere ottenuto mediante la combinazione di anticorpi monoclonali di utilizzo clinico, già ampiamente utilizzati per la terapia antitumorale, con popolazioni di cellule CIK, che sono facilmente espandibili, economiche, sicure e non richiedono manipolazioni genetiche. In conclusione, questa nuova strategia terapeutica per trattamento di diversi tipi di tumori mediante terapia cellulare adottiva potrà trovare ampie possibilità di implementazione e applicazione, e potrà essere estesa all’utilizzo di ulteriori anticorpi terapeutici.
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BIONDI, MARTA. "Enhancing AML CAR CIK therapeutic potency increasing the localization of engineered cells in the malignant niche and its selectivity by LSCs specific targeting." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/365153.
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La terapia CAR-T rappresenta un approccio promettente, ma ha riportato una ridotta efficacia nella leucemia mieloide acuta (AML), a causa dell’eterogeneità del tumore, dell’assenza di antigeni target AML-specifici e del ruolo del microambiente leucemico nella protezione dei blasti e delle cellule staminali leucemiche (LSC). La nicchia midollare, nella quale risiedono le LSC, è coinvolta in attività che promuovono la progressione leucemica e sopprimono l’ematopoiesi sana. Quindi ipotizziamo che bersagliare le LSC nascoste nella nicchia potesse migliorare l’efficacia delle CAR-T. Per testare la nostra ipotesi, abbiamo agito su due fronti: 1) promuovere una migrazione efficiente delle CAR-T nella nicchia midollare, 2) selezionare un antigene target ristretto ai blasti leucemici e alle LSC. Prima, abbiamo proposto una strategia per guidare le cellule CD33.CAR CIK (Cytokine-Induced Killer), una sottopopolazione di cellule T effettrici, verso la nicchia leucemica. La chemochina CXCL12, rilasciata dalle cellule mesenchimali stromali (MSC), nella nicchia midollare, e il suo recettore CXCR4, sono coinvolti nella regolazione della migrazione dei leucociti all’interno della nicchia. Quindi, abbiamo ipotizzato che sfruttare questo asse potesse migliorare la capacità di homing delle CD33.CAR-CIK nella nicchia e favorire l’eradicazione della leucemia. Tuttavia i protocolli di manipolazione ex vivo delle CD33.CAR-CIK riducono l’espressione di CXCR4, compromettendo la capacità delle cellule infuse di raggiungere la nicchia. Quindi per implementare la capacità di homing delle CD33.CAR-CIK nel microambiente midollare, abbiamo sviluppato delle CD33.CAR-CIK overesprimenti CXCR4, nella sua forma wild-type o iperattiva mutata. Le CIK ingegnerizzate con i costrutti CD33.CAR-CXCR4 hanno mostrato un consistente aumento dell’espressione di CXCR4, senza riportare alterazioni fenotipiche e nelle funzioni effettrici CAR-associate. Inoltre, rispetto alle CD33.CAR-CIK, le cellule CD33.CAR-CXCR4WT -CIK ed in particolare le CD33.CAR-CXCR4MUT-CIK hanno dimostrato non solo una superiore risposta chemotattica in vitro verso il CXCL12 ed i surnatanti delle MSC, ma anche un aumentato homing in vivo. In seguito, per promuovere lo sviluppo di un approccio CAR-T più efficace e sicuro, abbiamo proposto di re-indirizzare il CAR verso un antigene espresso selettivamente dalle cellule AML, ma assente sulle cellule staminali ematopoietiche (HSC). TIM-3 è un immune checkpoint, svolge un ruolo centrale nella regolazione delle risposte immunitarie nell’AML e costituisce un marcatore selettivo per le LSC, senza essere espresso dalle HSC. Abbiamo disegnato un CAR di terza generazione diretto contro TIM-3, utilizzando la porzione scFv derivante da un anticorpo monoclonale anti-TIM-3. In vitro, le TIM-3.CAR-CIK hanno dimostrato di eliminare sia le linee AML che i blasti primari, senza dare tossicità verso le cellule TIM-3+ sane, come le CIK attivate, i monociti e le cellule NK. Inoltre, le TIM-3.CAR-CIK hanno eliminato in maniera selettiva le LSC (CD34+ CD38-). Infine, le TIM-3.CAR-CIK hanno mantenuto le loro capacità effettrici nonostante multiple ristimolazioni in vitro, gettando le basi per lo studio di questo costrutto in vivo. Complessivamente, entrambi gli approcci, uno implementando l’homing delle CAR-CIK alla nicchia midollare e l’altro conferendo una superiore selettività, potrebbero migliorare l’efficacia della terapia CAR-T nel contesto dell’AML.Chimeric Antigen Receptor (CAR) T-cell therapy has produced remarkable clinical responses in patients affected by acute lymphoblastic leukemia. Unfortunately, CAR T-cells have not been equally successful in acute myeloid leukemia (AML) due to tumor heterogeneity, lack of truly AML-restricted target antigens and the role of leukemia microenvironment in blasts protection and leukemia stem cells (LSCs) maintenance. Specifically, the bone marrow (BM) niche, where LSCs reside, is involved in leukemia promoting activities whilst suppressing normal hematopoiesis. Therefore, we hypothesized that targeting LSCs at their location may enhance the potency and selectivity of CAR-T cells. To address this issue, we have designed two aims: 1) promote rapid and efficient localization of CAR T-cells within the BM niche, 2) select a leukemia-restricted antigen to specifically target AML blasts and LSCs. First, we proposed to harness CD33.CAR-redirected Cytokine-Induced Killer (CIK) cells, an alternative effector T-cell population with acquired NK-like cytotoxic activity as well as minimal alloreactivity, to selectively route their activity to leukemia transformed niche. The chemokine ligand 12 (CXCL12), released by mesenchymal stromal cells (MSCs) within the medullary niche, and its chemokine receptor 4 (CXCR4) are two pivotal players regulating leukocytes trafficking to the BM. In AML, CXCL12 interacts with CXCR4 overexpressed on blasts, promoting their migration and homing in the niche. Hence, taking advantage of this axis might facilitate CD33.CAR-CIK cells homing to the BM and therefore leukemia eradication. However, ex vivo manipulation protocols of CD33.CAR-CIK cells consistently downregulate CXCR4 expression and may affect the capacity of adoptively infused cells to migrate to BM and exert their anti-leukemic action. Therefore, to improve CD33.CAR-CIKs homing in the BM microenvironment we have developed CD33.CAR-CIK cells overexpressing CXCR4, in its wild-type or hyperactive mutant form. Notably, CIK cells engineering with CD33.CAR-CXCR4 constructs led to a consistent increase in CXCR4 expression, without altering CIK cells phenotype and CAR-related effector functions. Interestingly, compared to conventional CD33.CAR-CIK cells, CD33.CAR-CXCR4WT and especially CD33.CAR-CXCR4MUT-CIK cells demonstrated significantly superior in vitro chemotactic response toward CXCL12 and MSC-derived supernatants, and greater in vivo BM homing ability and persistence. Furthermore, to develop an effective anti-AML CAR T-cell therapy, it is fundamental to identify a LSC-specific marker, sparing the normal counterpart of hematopoietic stem cells (HSCs). T-cell immunoglobulin and mucin protein 3 (TIM-3) is an immune checkpoint molecule, it plays a central role in immune responses in AML and it is an LSC-specific marker, lacking expression on HSCs. Therefore, we designed a third-generation anti-TIM-3.CAR using the single-chain fragment variable (scFv) derived from an antagonistic ligand-blocking anti-TIM-3 antibody. In vitro, TIM-3.CAR-CIK cells efficiently killed both AML cell lines and primary AML blasts, but not normal TIM-3+ activated CIK cells, monocytes and NK-cells. Notably, we observed selective elimination of primary LSC-enriched population (CD34+ CD38-). Furthermore, TIM-3.CAR-CIK cells maintained their effector functions despite multiple in vitro restimulations, setting the basis for further exploration in in vivo models. Overall, both approaches, one improving CAR-CIK cells homing to the transformed niche and the other conferring superior safety and selectivity, might improve the efficacy of anti-AML CAR-CIK therapy.
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Weylandt, Karsten-Henrich. "Towards a functional role for human CIC-3 and human CIC-4, two members of the CIC chloride channel family." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341009.
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Zeid, Rhamy. "Characterization and Disruption of Cis Regulatory Elements in Cancer." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493536.
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Enhancers are cis regulatory elements that play key roles in the control of cell-type specific gene expression programs. In cancer, enhancer deregulation plays a key role in maintaining gene regulatory programs that underlie an oncogenic state. This dissertation focuses on understanding and modulating aberrant enhancer activity to identify potential vulnerabilities in human cancers. These studies were empowered by evolving technologies in genome-wide measurements of enhancer factors, computational approaches, and chemical and genetic tools to disrupt enhancer function.
In high-risk pediatric neuroblastoma, the transcription factor MYCN is frequently amplified and treatment options for these patients are largely ineffective thus establishing the need for improved therapeutic options. To identify previously unrecognized dependencies in neuroblastoma, we generated genome-wide maps of the active enhancer gene regulatory landscape leading to the identification of ID1 as an uncharacterized dependency in neuroblastoma. These results outline a strategy to identify alternative therapeutic avenues based on a holistic understanding of aberrant enhancer activity.
While MYCN amplification is the defining feature of high-risk neuroblastoma, a detailed mechanistic understanding of oncogenic transcriptional rewiring has been stalled by a lack of genome-wide binding data.
Here we present the dynamic and temporally resolved landscape of genome-wide MYCN occupancy in neuroblastoma. We find that deregulated MYCN binding at enhancers (termed enhancer invasion) is critical to maintaining the oncogenic station and identify the lineage specific transcription factor TWIST1 as a key collaborator and synthetic lethality of oncogenic MYCN. These data suggest that MYCN enhancer invasion shapes transcriptional amplification in neuroblastoma to promote tumorigenesis.
The development of small molecule inhibitors of the bromodomain and extra-terminal (BET) family of proteins provides a pharmacological strategy to inhibit enhancer activity. The efficacy of BET inhibition in several cancers has prompted efforts to predict and understand mechanisms of resistance to BET inhibition. Here, we use a newly developed class of small molecules to pharmacologically induce targeted degradation of the BET family. In triple negative breast cancer, we demonstrate that targeted BET family degradation effectively overcomes BET inhibitor resistance. These studies suggest BET degradation as a strategy to overcome BET inhibitor resistance and further disrupt and dissect enhancer activity in cancer.Medical Sciences
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Ganakammal, Satishkumar Ranganathan. "CIS REGULATORY MODULE DISCOVERY IN TH1 CELL DEVELOPMENT." Thesis, Proceeding ISB '10 Proceedings of the International Symposium on Biocomputing ACM New York, NY, USA ©2010 table of contents ISBN: 978-1-60558-722-6 doi>10.1145/1722024.1722039, 2010. http://hdl.handle.net/1805/2678.
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Indiana University-Purdue University Indianapolis (IUPUI)Immune response enables the body to resist foreign invasions. The Inflammatory response is an important aspect in the immune response which is articulated by elements such as cytokines, APC, T-cell and B-cell, effector cell or natural killer. Of these elements, T-cells especially T-helper cells; a sub class of T-cells plays a pivotal role in stimulating the immune response by participating in various biological reactions such as, the transcription regulatory network. Transcriptional regulatory mechanisms are mediated by a set of transcription factors (TFs), that bind to a specific region (motifs or transcription factor binding sites, TFBS), on the target gene(s) controlling the expression of genes that are involved in T-helper cell mediated immune response. Eukaryotic regulatory motifs, referred to as cis regulatory modules (CRMs) or cistrome, co-occur with the regulated gene’s transcription start site (TSS) thus, providing all the essential components for building the transcriptional regulatory networks that depends on the relevant TF-TFBS interactions. Here, we study IL-12 stimulated transcriptional regulators in STAT4 mediated T helper 1 (Th1) cell development by focusing on the identification of TFBS and CRMs using a set of Stat4 ChIP-on-chip target genes. A region containing 2000 bases of Mus musculus sequences with the Stat4 binding site, derived from the ChIP-on-chip data, has been characterized for enrichment of other motifs and, thus CRMs. Our experiments identify some potential motifs, (such as NF-κB and PPARγ/RXR) being enriched in the Stat4 binding sequences compared to neighboring background sequences. Furthermore, these predicted CRMs were observed to be associated with biologically relevant target genes in the ChIP-on-chip data set by meaningful gene ontology annotations. These analyses will enable us to comprehend the complicated transcription regulatory network and at the same time categorically analyze the IL-12 stimulated Stat4 mediated Th1 cell differentiation.
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Calzone, Laurence. "Mathematical Modeling of the Budding Yeast Cell Cycle." Thesis, Virginia Tech, 2000. http://hdl.handle.net/10919/31988.
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The cell cycle of the budding yeast, Saccharomyces cerevisiae, is regulated by a complex network of chemical reactions controlling the activity of the cyclin-dependent kinases (CDKs), a family of protein kinases that drive the major events of the cell cycle. A previous mathematical model by Chen et al. (2000) described a molecular mechanism for the Start transition (passage from G1 phase to S/M phase) in budding yeast. In this thesis, my main goal is to extend Chen's model to include new information about the mechanism controlling Finish (passage from S/M phase to G1 phase). Using laws of biochemical kinetics, I transcribed the hypothetical molecular mechanism into a set of differential equations. Simulations of the wild-type cell cycle and the phenotypes of more than 60 mutants provide a thorough understanding of how budding yeast cells exit mitosis.Master of Science
Books on the topic "CIK cell"
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Almeida, Maria Inez Barros de. Panorama visto do Rio: Cia. Tônia-Celi-Autran. [Rio de Janeiro]: Ministério da Cultura, Instituto Nacional de Artes Cênicas, 1987.
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Cueto, J. A. del. Stability of CIS/CIGS modules at the outdoor test facility over two decades: Preprint. Golden, CO: National Renewable Energy Laboratory, 2008.
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Yakov, Gluzman, and Cold Spring Harbor Laboratory, eds. Eukaryotic transcription: The role of cis- and trans-acting elements in initiation. Cold Spring Harbor, N.Y: Cold Spring Harbor Laboratory, 1985.
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1948-, Stone Michael, and Mitchell Chris, eds. The cell: Inside the 9/11 plot and why the CIA and FBI failed to stop it. New York: Hyperion, 2002.
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1948-, Stone Michael, and Mitchell Chris 1964-, eds. The cell: Inside the 9/11 plot, and why the FBI and CIA failed to stop it. Waterville, Me: Thorndike Press, 2002.
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Delahoy, Alan Edward. CIS photovoltaic technology: Final technical report 12 January 1997 - 15 April 1998. Golden, CO (1617 Cole Boulevard, Golden 80401-3393): National Renewable Energy Laboratory, 1998.
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Kushida, Michelle Mayumi. Identification of CIS-active targets of MHC class 1 transcritional downregulaton in tumour cells. Ottawa: National Library of Canada, 1996.
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Dolfi, Anna, ed. Non finito. Opera interrotta e modernità. Florence: Firenze University Press, 2015. http://dx.doi.org/10.36253/978-88-6655-729-6.
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Non finito, opera interrotta… difficile trovare una definizione, circoscrivere il tema, distinguere il caso dall’intenzionalità. Certo pochi ‘generi’ e/o declinazioni hanno come il non finito bisogno di ciò che è esterno all’opera e che in qualche modo la completa, collocandola in posizione privilegiata per la sintonia con la nostra inquieta modernità. Non stupisce che in letteratura siano naturaliter ‘sospesi’ – oltre a ciò che è stato brutalmente interrotto – gli epistolari, i diari, le cronache della malattia e della sofferenza; né che l’incompiutezza accompagni gli scritti che rinviano a grumi irrisolti, traumi nascosti, taciute malinconie. Dettata da scelta o da gradi distinti di incapacità, la tentazione del non finito, del non finire, insegue, incalza, illude… Ce ne parlano le scritture del privato, gli abbozzi, i progetti, le carte che testimoniano il cammino necessario all’opera per arrivare alla sua forma. Questo libro, ricco e suggestivo, ideato e curato da Anna Dolfi, inscritto – come il suo oggetto – all’insegna dell’incompiuto, del non finibile, si interroga su alcuni dei tanti esempi possibili, lungo un arco diacronico che va alla letteratura alle arti figurative, al teatro, al cinema: da Leonardo a Blake, da Ariosto a Stendhal, da Dossi a Gadda, da Kafka a Borges, dalla Sarraute alla Morante, dagli sconosciuti scriventi affetti da ‘cancroregina’ all’ultimo Pirandello messo in scena da Tiezzi, fino al Fellini dell’impossibile Mastorna ... Al centro del volume una sezione con le pagine del dattiloscritto ed i quaderni di appunti inediti di/per La scelta di Giuseppe Dessí conduce ai limiti dello spazio bianco, là dove la chambre claire fissa con pochi, rarefatti segni, quanto si cela oltre la scrittura.
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Ranky, Paul G. Flexible manufacturing cells and systems in CIM: A practical and consistent approach centered around powerful methodologies and technologies leading to the creation of wealth by applying Computer Integrated Manufacturing. Guildford, Surrey: CIMware, 1990.
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La Familia De Pascual Duarte Camilo Jose Cela. Editorial Diana - Mexico, 1991.
Find full textBook chapters on the topic "CIK cell"
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Pirincci Ercan, Deniz, and Frank Uhlmann. "Analysis of Cell Cycle Progression in the Budding Yeast S. cerevisiae." In Methods in Molecular Biology, 265–76. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1538-6_19.
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AbstractThe cell cycle is an ordered series of events by which cells grow and divide to give rise to two daughter cells. In eukaryotes, cyclin–cyclin-dependent kinase (cyclin–Cdk) complexes act as master regulators of the cell division cycle by phosphorylating numerous substrates. Their activity and expression profiles are regulated in time. The budding yeast S. cerevisiae was one of the pioneering model organisms to study the cell cycle. Its genetic amenability continues to make it a favorite model to decipher the principles of how changes in cyclin-Cdk activity translate into the intricate sequence of substrate phosphorylation events that govern the cell cycle. In this chapter, we introduce robust and straightforward methods to analyze cell cycle progression in S. cerevisiae. These techniques can be utilized to describe cell cycle events and to address the effects of perturbations on accurate and timely cell cycle progression.
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Rodríguez-Otero, Paula, and Jesús F. San Miguel. "Post-CAR-T Cell Therapy (Consolidation and Relapse): Multiple Myeloma." In The EBMT/EHA CAR-T Cell Handbook, 173–76. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-94353-0_34.
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AbstractAdoptive cell therapy with BCMA-directed autologous CAR-T cells has shown very encouraging results in end-stage relapse and refractory multiple myeloma (MM), with overall response rates ranging between 73% and 96.9%, complete response (CR) rates between 33% and 67.9%, and MRD negativity in 50–74% of patients in the two largest phase 2 studies of ide-cel (idecabtagene autoleucel, KarMMa) and cilta-cel (ciltacabtagene autoleucel, CARTITUDE 1) reported thus far (Madduri et al. 2020; Munshi et al. 2021). Unfortunately, responses are usually not maintained, and no plateau has yet been seen in the survival curves. The median progression-free survival (PFS) in the KarMMa study of ide-cel was 8.8 months (95% CI, 5.6–11.6) among all 128 patients infused, increased to 12.1 months (95% CI, 8.8–12.3) among patients receiving the highest dose (450 × 106 CAR + T cells) and increased to 20.2 months (95% CI, 12.3–NE) among those achieving a CR. In the CARTITUDE-1 study, with a median follow-up of 12.4 months, the median PFS has not yet been reached, and the 12-month PFS rate was 76.6% (95% CI; 66.0–84.3). The absence of a clear plateau in PFS differs from what has been observed in DLBCL or B-ALL with currently approved CD-19-directed CAR-T cells, where (albeit with a shorter PFS and lower rates of CR) patients remaining free from relapse beyond 6 months are likely to enjoy prolonged disease control or even be cured.
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Joubès, Jérôme, Christian Chevalier, Denes Dudits, Erwin Heberle-Bors, Dirk Inzé, Masaaki Umeda, and Jean-Pierre Renaudin. "CDK-related protein kinases in plants." In The Plant Cell Cycle, 63–76. Dordrecht: Springer Netherlands, 2000. http://dx.doi.org/10.1007/978-94-010-0936-2_6.
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Nelms, Keats A. "Cis-Acting Elements That Regulate Immunoglobulin Gene Transcription." In Cell Biology and Biotechnology, 157–76. New York, NY: Springer New York, 1993. http://dx.doi.org/10.1007/978-1-4684-9418-1_12.
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Jackman, Mark. "Baculoviral Expression and Partial Purification of Cyclin/CDK Complexes." In Animal Cell Culture Techniques, 131–48. Berlin, Heidelberg: Springer Berlin Heidelberg, 1998. http://dx.doi.org/10.1007/978-3-642-80412-0_9.
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Ball, Kathryn L. "p21: structure and functions associated with cyclin-CDK binding." In Progress in Cell Cycle Research, 125–34. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4615-5371-7_10.
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Vogel, Lee, and Blandine Baratte. "Suc1: cdc2 affinity reagent or essential cdk adaptor protein?" In Progress in Cell Cycle Research, 129–35. Boston, MA: Springer US, 1996. http://dx.doi.org/10.1007/978-1-4615-5873-6_13.
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Soos, T. J., M. Park, H. Kiyokawa, and A. Koff. "Regulation of the cell cycle by CDK inhibitors." In Results and Problems in Cell Differentiation, 111–31. Berlin, Heidelberg: Springer Berlin Heidelberg, 1998. http://dx.doi.org/10.1007/978-3-540-69686-5_5.
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Mir, Manzoor Ahmad, and Tabish Javeed. "Novel CDK Inhibitors in Breast Cancer." In Therapeutic potential of Cell Cycle Kinases in Breast Cancer, 253–67. Singapore: Springer Nature Singapore, 2023. http://dx.doi.org/10.1007/978-981-19-8911-7_12.
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Vervaet, A., M. Burgelman, I. Clemminck, and M. Casteleyn. "Screen Printing of CIS Films for CIS-CdS Solar Cells." In Tenth E.C. Photovoltaic Solar Energy Conference, 900–903. Dordrecht: Springer Netherlands, 1991. http://dx.doi.org/10.1007/978-94-011-3622-8_230.
Full textConference papers on the topic "CIK cell"
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Jin, Younggeon, Juyoun Jin, Kyeung Min Joo, Se Jeong Lee, Mi-young Jo, Yonghyun Kim, and Do-Hyun Nam. "Abstract LB-326: Synergistic therapeutic effects of cytokine-induced killer (CIK) cell and temozolomide against glioblastoma." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-lb-326.
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Wang, Shuo, and Jun Ren. "Abstract 4227: Safety of dendtritic cell and cytokine-induced killer(DC-CIK) cell based immunotherapy in patients with solid tumor: A large retrospective study in China." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-4227.
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Ren, Jun, Guoliang Qiao, Xiaoli Wang, Xinna Zhou, and Lefu Huang. "Abstract A42: CD8+PD-1+ cells population were associated with the superiority of DC/CIK cell immunotherapy combined S-1 in patients with advanced pancreatic and gastric cancer." In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; October 1-4, 2017; Boston, MA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/2326-6074.tumimm17-a42.
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Rodins, Juris, Vadims Korhovs, Talivaldis Freivalds, Indulis Buikis, and Tatjana Ivanova. "Influence of Strong Static Magnetic Field on Human Cancer HT 1080 Cells." In European Conference on Biomedical Optics. Washington, D.C.: Optica Publishing Group, 2001. http://dx.doi.org/10.1364/ecbo.2001.4432_242.
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The aim of this study was to investigate strong uniform magnetic field influence on the human cancer cells HT 1080. The cells were treated with magnetic field of intensity 1,16 Tesla and with anticance agent – cis-platinum 0.025 mg/ml or vincristinum 2-3 ng/ml. The intact and the treated cell samples were incubated in a medium with acridine orange (AO). The magnetic field after 15 minutes of influence significantly increased cytoplasmic red fluorescence. Increased AO accumulation in lysosomes suggested to cancer cell metabolic activity stimulation.
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Campana, Kimberly A., Eric Y. Shin, Beverly Z. Waisner, and Sherry L. Voytik-Harbin. "3D Cell Shape and Cell Fate are Regulated by the Dynamic Micro-Mechanical Properties of the Cell-ECM Interface." In ASME 2007 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2007. http://dx.doi.org/10.1115/sbc2007-176626.
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Mechanobiology is an interdisciplinary field that focuses on predicting and understanding cellular responses to mechanical loads. The extracellular matrix (ECM) represents a macromolecular framework that naturally imparts structural support and spatial organization for resident cells. The ECM also participates in the communication and transfer of mechanical loads to cells, in part, via integrin attachment to the cytoskeleton (CSK). Recently, using a tissue model in which cells are embedded in a 3D collagen ECM, we have shown that fundamental cell behaviors, including morphology, proliferation, contractility, and ECM remodeling properties, can be modulated by varying 3D microstructural organization and mechanical properties of the surrounding collagen fibrils[1]. While these and other results demonstrate the critical role played by the ECM in regulating cell behavior, the mechanical-based mechanisms underlying these critical cell-ECM interactions have yet to be fully elucidated [2].
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Czajkowski, Walt, and Jim Cirasuolo. "Computer Integrated Optical Fabrication Cells." In Optical Fabrication and Testing. Washington, D.C.: Optica Publishing Group, 1988. http://dx.doi.org/10.1364/oft.1988.wb3.
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Computer integrated manufacturing and flexible machining cells are making big inroads in the enthusiastic revival of american industry. Improved productivity, efficiency and costs along with an increased awareness of quality and ownership are key ingredients associated with marriage and implementation of the CIM/product cell concept.
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Jung, Jun K., Ka Yaw Teo, J. Craig Dutton, and Bumsoo Han. "Development of Quantum Dot Mediated Cell Image Deformetry for Microscale Tissue Deformation Measurement." In ASME 2007 International Mechanical Engineering Congress and Exposition. ASMEDC, 2007. http://dx.doi.org/10.1115/imece2007-41690.
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Since biological tissues are composed of cells, extracellular matrix, and interstitial fluid, freezing of biological tissues induces complex cell-fluid-matrix interaction. Quantitative understanding of this cell-fluid-matrix interaction is crucial to the design and optimization of a wide variety of cryomedicine applications. However, quantitative measurement of the interaction is extremely challenging due to the lack of reliable non-invasive measurement techniques during freezing and thawing. In the present study, a new measurement technique was developed to dynamically measure microscale tissue deformation during freezing/thawing and its feasibility was demonstrated. In this method, which is named “Cell Image Deformetry” (CID), engineered tissues with pre-labeled cells with quantum dots are imaged under a fluorescence microscope. Then, the tissue deformation is evaluated by cross-correlating cell locations between sequential microscopic images with known time intervals based on the particle image velocimetry (PIV) data processing technique.
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Li, Weisi, K. R. Crompton, and Jason Ostanek. "Experimental Measurement of CID- and Vent-Activation in Cylindrical Lithium-Ion Batteries." In ASME 2021 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2021. http://dx.doi.org/10.1115/imece2021-68046.
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Abstract Two pressure-activated safety devices, a current interrupt device (CID) and a vent mechanism, are commonly built into the cap structure of cylindrical 18650 lithium-ion cells to isolate the cell electrically and relieve internal cell pressure prior to case rupture, respectively, in an abuse or thermal runaway event. The activation pressure for these two mechanisms, and how it varies with temperature, is an important parameter for the thermal runaway models incorporating electrolyte evaporation, gas generation and venting. This paper presents a method to extract the geometry of four commercial 18650 lithium-ion vent cap assemblies and measure the CID- and vent-activation pressures with a customized experimental setup. The experimental data were collected at ambient temperature and 100 °C. The CID-activation pressures of the MTI, LG MJ1, K2, and LG M36 caps were 1.058 ± 0.053, 1.293 ± 0.119, 0.997 ± 0.292 and 1.393 ± 0.113 MPa at ambient temperature and 0.920 ± 0.076, 1.066 ± 0.068, 0.834 ± 0.057 and 1.083 ± 0.077 MPa at 100°C, respectively. The vent-activation pressures of the MTI, LG MJ1, K2, and LG M36 caps were 2.308 ± 0.196, 2.202 ± 0.083, 2.190 ± 0.372 and 2.363 ± 0.199 MPa at ambient temperature and 1.919 ± 0.132, 1.866 ± 0.084, 1.781 ± 0.355 and 1.799 ± 0.284 MPa at 100°C, respectively. The experimental setup may be used in future studies to measure activation pressures of future cylindrical cells. The CAD model of the caps may be used to develop a finite element model (FEM) to simulate the CID- and vent-activation pressure and a computational fluid dynamics (CFD) model to design more reliable and effective CID and vent mechanisms.
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Jamieson, G. A., and G. Grignani. "GENERATION OF ADP BY HUMAN AND MURINE TUMOR CELLS IS SPECIFIC BUT IS UNRELATED TO METASTATIC POTENTIAL." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643204.
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The ability of tumor cells to activate platelets may facilitate the metastatic process. It has been generally assumed that the production of ADP by tumor cells is due to non-specific damage during harvesting in vitro or, in vivo, by frictional interactions with the capillary wall. The present work shows that tumor cell ADP arises not from cell damage but by a specific process under metabolic control. The human 253J urinary carcinoma cell line activated heparinized human platelets by an ADP-dependent mechanism based on inhibition by CP/CPK and the identification of aggregating concentrations (1 uM) of ADP in the cell-free supernatant by HPLC. Tumor cell damage during harvesting was shown not to be a factor since (i) the amount of ADP secreted was unrelated to the appearance of LDH, (ii) was similar when measured in confluent monolayers, in tumor cells after detachment and resuspension or following crossover studied in HBSS and MEM, and (iii) was constant at varying tumor cell concentrations. Metabolic control of ADP generation or transport was indicated by the fact that it was reduced 50 in tumor cells treated with p-chloromercuribenzene sulfonate and was completely abolished in those treated with iodoacetic acid. In order to determine whether this metabolically controlled generation of ADP was related to metastatic potential, we carried out identical experiments with the FI (low) and F10 (high) metastatic variants of the Bl6 murine melanoma line. The amounts of ADP produced by the B16 cells were about twice as great as with the human 253J cells but there was no significant difference between the amounts of ADP generated by FI and F10 variants. These studies demonstrate that ADP production by tumor cells is a discrete process under metabolic control but is not directly related to the metastatic potential of individual tumor cell lines.
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Wongkajornsilp, Adisak, Khin Su Su Htwe, Nathawadee Sawatpiboon, Sunisa Duangsa-ard, and Kanda Kasetsinsombat. "Abstract 4141: The induction of iNKT cells and CIK cells toward anti-tumor phenotypes." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4141.
Full textReports on the topic "CIK cell"
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Chejanovsky, Nor, and Bruce A. Webb. Potentiation of pest control by insect immunosuppression. United States Department of Agriculture, July 2004. http://dx.doi.org/10.32747/2004.7587236.bard.
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Our original aims were to elucidate the mechanisms through which the immunosuppressive insect virus, the Campoletis sonorensis polydnavirus (CsV) promotes replication of a well-characterized pathogenic virus, the Autographa californica multiple nucleopolyhedrovirus (AcMNPV) in hosts that are mildly or non-permissive to virus replication. According to the BARD panels criticism we modified our short-term goals (see below). Thus, in this feasibility study (one-year funding) we aimed to show that: 1. S. littoralis larvae mount an immune response against a baculovirus infection. 2. Immunosuppression of an insect pest improves the ability of a viral pathogen (a baculovirus) to infect the pest. 3. S. littoralis cells constitute an efficient tool to study some aspects of the anti- viral immune response. We achieved the above objectives by: 1. Finding melanized viral foci upon following the baculoviral infection in S . littoralis larvae infected with a polyhedra - positive AcMNPV recombinant that expressed the GFP gene under the control of the Drosophila heat shock promoter. 2. Studying the effect of AcMNPV-infection in S . littoralis immunosuppressed by parasitation with the Braconidae wasp Chelonus inanitus that bears the CiV polydna virus, that resulted in higher susceptibility of S. littoralis to AcMNPV- infection. 3. Proving that S. littoralis hemocytes resist AcMNPV -infection. 4. Defining SL2 as a granulocyte-like cell line and demonstrating that as littoralis hemocytic cell line undergoes apoptosis upon AcMNPV -infection. 5. Showing that some of the recombinant AcMNPV expressing the immuno-suppressive polydna virus CsV- vankyrin genes inhibit baculoviral-induced lysis of SL2 cells. This information paves the way to elucidate the mechanisms through which the immuno- suppressive polydna insect viruses promote replication of pathogenic baculoviruses in lepidopteran hosts that are mildly or non-permissive to virus- replication by: - Assessing the extent to which and the mechanisms whereby the immunosuppressive viruses, CiV and CsV or their genes enhance AcMNPV replication in polydnavirus- immunosuppressed H. zea and S. littoralis insects and S. littoralis cells. - Identifying CiV and CsV genes involved in the above immunosuppression (e.g. inhibiting cellular encapsulation and disrupting humoral immunity). This study will provide insight to the molecular mechanisms of viral pathogenesis and improve our understanding of insect immunity. This knowledge is of fundamental importance to controlling insect vectored diseases of humans, animals and plants and essential to developing novel means for pest control (including baculoviruses) that strategically weaken insect defenses to improve pathogen (i.e. biocontrol agent) infection and virulence.
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Grafi, Gideon, and Brian Larkins. Endoreduplication in Maize Endosperm: An Approach for Increasing Crop Productivity. United States Department of Agriculture, September 2000. http://dx.doi.org/10.32747/2000.7575285.bard.
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The focus of this research project is to investigate the role of endoreduplication in maize endosperm development and the extent to which this process contributes to high levels of starch and storage protein synthesis. Although endoreduplication has been widely observed in many cells and tissues, especially those with high levels of metabolic activity, the molecular mechanisms through which the cell cycle is altered to produce consecutive cycles of S-phase without an intervening M-phase are unknown. Our previous research has shown that changes in the expression of several cell cycle regulatory genes coincide with the onset of endoreduplication. During this process, there is a sharp reduction in the activity of the mitotic cyclin-dependent kinase (CDK) and activation of the S-phase CDK. It appears the M-phase CDK is stable, but its activity is blocked by a proteinaceous inhibitor. Coincidentally, the S-phase checkpoint protein, retinoblastoma (ZmRb), becomes phosphorylated, presumably releasing an E2F-type transcriptional regulator which promotes the expression of genes responsible for DNA synthesis. To investigate the role of these cell cycle proteins in endoreduplication, we have created transgenic maize plants that express various genes in an endosperm-specific manner using a storage protein (g-zein) promoter. During the first year of the grant, we constructed point mutations of the maize M-phase kinase, p34cdc2. One alteration replaced aspartic acid at position 146 with asparagine (p3630-CdcD146N), while another changed threonine 161 to alanine (p3630-CdcT161A). These mutations abolish the activity of the CDK. We hypothesized that expression of the mutant forms of p34cdc2 in endoreduplicating endosperm, compared to a control p34cdc2, would lead to extra cycles of DNA synthesis. We also fused the gene encoding the regulatory subunit of the M- phase kinase, cyclin B, under the g-zein promoter. Normally, cyclin B is expected to be destroyed prior to the onset of endoreduplication. By producing high levels of this protein in developing endosperm, we hypothesized that the M-phase would be extended, potentially reducing the number of cycles of endoreduplication. Finally, we genetically engineered the wheat dwarf virus RepA protein for endosperm-specific expression. RepA binds to the maize retinoblastoma protein and presumably releases E2F-like transcription factors that activate DNA synthesis. We anticipated that inactivation of ZmRb by RepA would lead to additional cycles of DNA synthesis.
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Lee, Byeong-Chei. Csk Homologous Kinase, a Potential Regulator of CXCR4-mediated Breast Cancer Cell Metastasis. Fort Belvoir, VA: Defense Technical Information Center, August 2010. http://dx.doi.org/10.21236/ada538886.
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Lee, Byeong-Chel. Csk Homologous Kinase, a Potential Regulator of CXCR4-Medicated Breast Cancer Cell Metastasis. Fort Belvoir, VA: Defense Technical Information Center, August 2011. http://dx.doi.org/10.21236/ada554270.
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Olsen, L. C. Alternative Heterojunction Partners for CIS-Based Solar Cells; Final Report: 1 January 1998--31 August 2001. Office of Scientific and Technical Information (OSTI), January 2003. http://dx.doi.org/10.2172/15003609.
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Zagozdzon, Radoslaw, and Hava Avraham. Effects of Csk Homologous Kinase Overexpression on HER2/Neu-Mediated Signal Transduction Pathways in Breast Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, April 2005. http://dx.doi.org/10.21236/ada436916.
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Zagozdzon, Radoslaw, and Hava Avraham. Effects of CSK Homologous Kinase Overexpression on HER2/Neu-Mediated Signal Transduction Pathways in Breast Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, April 2003. http://dx.doi.org/10.21236/ada416967.
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Zagozdzon, Radoslaw, and Hava Avraham. Effects of CSK Homologous Kinase Overexpression on HER2/Neu-Mediated Signal Transduction Pathways in Breast Cancer Cells. Fort Belvoir, VA: Defense Technical Information Center, April 2004. http://dx.doi.org/10.21236/ada425671.
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Olsen, L. C. Alternative heterojunction partners for CIS-based solar cells: Annual subcontract report, 29 December 1997--28 December 1998. Office of Scientific and Technical Information (OSTI), February 2000. http://dx.doi.org/10.2172/754633.
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Korai, Bernard, and Ibrahima Bocoum. Outils d'information sur l'alimentation, les produits bioalimentaires et les risques alimentaires au Québec. CIRANO, 2022. http://dx.doi.org/10.54932/cgan3344.
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Cette étude se propose d’analyser les facteurs contribuant à la qualité de l’information alimentaire et nutritionnelle au Québec, et la manière dont celle-ci affecte le niveau de littératie alimentaire des populations. Certaines pistes de réflexion sont, par ailleurs, suggérées afin de promouvoir les habitudes de saine alimentation.