The Safety and Efficacy Test of Immuncell-LC to Treat Refractory Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2249585 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Dr. Christopher Contag lab's aim is to, investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients. A promising new direction in cancer therapy is the use of cytokine-induced killer (CIK) cells as broadly active tumoricidal agents. CIK cells derive from blood samples stimulated ex vivo, and these activated immune cells are capable of recognizing and destroying a plethora of tumor targets in vivo. In fact, CIK cells have demonstrated efficacy in clinical trials to treat patients with hepatoma, renal cell cancer, and hematological malignancies. Despite the remarkable clinical promise of this therapy, little is known about the mechanisms that govern CIK cell migration to tumor tissue in vivo. Understanding the trafficking patterns of these potent immune cells is of critical importance to advancing their use in humans. I aim to investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients. RNA from three groups (1,2,3) were sent to Microarray Core E. Group one samples: Splenocytes were obtained from BALB/c mice, and the T cells were isolated using a negative isolation kit (magnetic bead separation). For group 2 and 3 samples: The isolated splenocytes were treated with IFN-gamma overnight. The cells were then added to anti-CD3 coated flasks and stimulated with IL-2. Fresh IL-2 was added to the media every 3 days, and the cells were harvested 12 days post-isolation. The RNA was labeled and hybridized to Glyco_v3 arrays.
2011-04-29 | E-GEOD-28940 | biostudies-arrayexpress
Project description:Dr. Christopher Contag lab's aim is to, investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients. A promising new direction in cancer therapy is the use of cytokine-induced killer (CIK) cells as broadly active tumoricidal agents. CIK cells derive from blood samples stimulated ex vivo, and these activated immune cells are capable of recognizing and destroying a plethora of tumor targets in vivo. In fact, CIK cells have demonstrated efficacy in clinical trials to treat patients with hepatoma, renal cell cancer, and hematological malignancies. Despite the remarkable clinical promise of this therapy, little is known about the mechanisms that govern CIK cell migration to tumor tissue in vivo. Understanding the trafficking patterns of these potent immune cells is of critical importance to advancing their use in humans. I aim to investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients.
2011-04-29 | GSE28940 | GEO
Project description:The Chemotherapeutic Agent, 5,6-Dimethylxanthenone-4-Acetic Acid,
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Project description:Cytokine Induced Killer (CIK) cells are heterogeneous ex vivo expanded T lymphocytes with mixed T-NK phenotype and endowed with a wide MHC-unrestricted antitumor activity against both solid and hematologic malignancies. CIK cells can be easily ex vivo expanded up to clinical relevant rates from circulating peripheral blood mononuclear cells (PBMC), according to a standard protocol involving timed stimulation with IFN- γ (day 0), Ab-antiCD3 OKT3 (day 1) and IL-2 (from day 1 to the end). Nowadays literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. A comprehensive molecular profiling of CIK cells is needed to complete the knowledge of their biologic and functional features. In this perspective we performed a gene expression profile analysis of basal PBMC and ex vivo expanded CIK cells generated from 3 patients with histologic confirmed Gastrointestinal Stromal Tumors (GIST). The principal component analysis (PCA) shows that the CIK cell samples clustered together and were clearly separated from PBMC ones. First, we checked the mRNA expression levels of secreted proteins and we found a significant upregulation of GM-CSF, IL-5, IL-13, and IFN-γ in CIK cells. Moreover, IL-1Ra, IL-1β, IL-6, IL-10, IL-15, IL-8, Eotaxin and MCP-1 are downregulated in CIK cells if compared to PBMC. Noteworthy, among differentially expressed genes (DEGs) we identified other secreted molecules that are upregulated in patient-derived CIK cells, which can contribute to their tumor killing activity: GZMA, GZMB, GZMK, PRF1, IL-32, and LTA. Furthermore, to better characterize the CIK cell phenotype, we studied the surface antigen expression. As expected, we found the downregulation of several myeloid differentiation markers (CD14, CD9, CD93, CSF2RA, CSF2RB, EPB41L3, Receptors for Fc fragments of immunoglobulins, ITGAX, MCEMP1, and TREM1) and B-cell antigens (CD19, CD24, CD79A, CXCR5, and MS4A1). Moreover, microarray data confirmed the upregulation in CIK cells of well-known surface antigens, like CD3D, CD3G, IL2Ra, IL2RG, CD226/DNAM1, ITGAL/LFA-1, KLRK1/NKG2D, NCR3/NKp30, and TRAIL/TNFSF10. Next, in order to identify differentially expressed pathways during CIK cells maturation, we performed a functional analysis by using Ingenuity Pathway Analysis (IPA) software. Among inactivated functions in CIK cells, we found chemotaxis of myeloid cells, phagocytosis, migration of granulocytes and engulfment of leukocytes. Noteworthy, functional gene categories as proliferation of cells, cell death of lymphocytes, cell death of mononuclear leukocytes, apoptosis of B lymphocytes, and quantity of CD4+ T-lymphocytes resulted activated, in agreement with the selection and expansion of CIK cell precursors induced by in vitro treatment of PBMC. Finally, IPA analysis predicted as activated categories cytotoxicity of lymphocytes, cytotoxicity of cells, and cytotoxicity of natural killer cells. In particular, genes involved in cytotoxic mechanism of CIK cells like NCR3/NKp30, KLRK1/NKG2D, TRAIL/TNFSF10, CD226/DNAM1, CD244, CD69, CD96, GZMA, GZMB, PRF1 are differentially expressed. With this work we highlighted previously unknown secretory properties and provided for the first time a comprehensive molecular characterization of CIK cells, opening the possibility to operate on secretory level to improve CIK cell cytotoxic activity against tumors.
2023-04-07 | GSE97581 | GEO
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Project description:Background. Advanced sarcomas have a severe prognosis, limited therapeutic options, and are seldom sensitive to immunotherapy with checkpoint inhibitors. Novel strategies are urgently needed. Methods. We set up a preclinical approach for testing the combination of chemotherapy (trabectedin) and PARP1 inhibitor (olaparib) to potentiate the HLA-independent cellular immunotherapy with natural killer (NK) or cytokine-induced killer (CIK) lymphocytes. The NK/CIK activators NKG2DLs were studied by qRT-PCR and flow cytometry. Drug-induced transcriptomic events were studied by RNA sequencing and the activation of the cytosolic DNA sensing pathway (cGAS-STING-IRF3-IFNβ) was explored. Focusing on the putative cancer stem cell (CSCs) subpopulation, OCT4 marker was evaluated. IRF3 silencing experiments were done to investigate the role of the cGAS-STING pathway in the control of NKG2DLs. NK/CIK killing activity on both bulk and OCT4-positive cells was tested by viability assay and flow cytometry, respectively. Results. We obtained the enhancement of NK/CIK activity against sarcoma cell lines through an integrated approach based on the combination of trabectedin and olaparib. These drugs upregulated the NKG2DL expression at both mRNA and protein level by inducing the genotoxicity pathway (WP4286) and repressing the cellular response to DNA damage stimulus (GO:0006974). The drug treatment significantly increased the cytosolic DNA content and consequently activated the cGAS-STING-IRF3 pathway and IFNβ production. These molecular events significantly enhanced the antitumor activity of NK and CIK against drug-pretreated sarcoma cells. The OCT4-positive cell fraction was enriched after chemotherapy. Noteworthy, NK/CIK cells efficiently killed both the drug-surviving bulk and CSC subpopulation. Conclusions. Trabectedin+olaparib treatment followed by NK/CIK-based immunotherapy is a promising therapeutic strategy against sarcomas, deserving further investigations.
2025-05-05 | GSE239639 | GEO
Project description:Drosophila carrying Hml-SwitchGal4 were crossed to different uas-constructs (uas-eGFP, uas-PGRP-LC, uas-hop, uas-tkvQD). 3rd instar larvae were either kept as control or SwitchGal4 was activated by hormone feeding for 24h. Afterwards plasmatocytes were extracted and subjected to RNA-seq.
2022-05-31 | E-MTAB-10764 | biostudies-arrayexpress
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| S-EPMC4751873 | biostudies-literature
Project description:Background: Combinations of dendritic and cytokine-induced killer cell (D-CIK) based adoptive immunotherapy and anti-PD-1 antibody may enhance the immune response and stop cancer cells from growing.
Objective: Phase II clinical trial to investigate the safety, clinical activity and toxicity of combinations of D-CIK and anti-PD-1 antibody in patients with treatment-refractory solid tumors.
Methodology: Phase II clinical trial in patients with advanced metastatic hepatocellular carcinoma, renal cell carcinoma,bladder cancer,colorectal cancer,non-small-cell lung cancer,breast cancer and other solid cancers. The D-CIK was isolated from peripheral blood of participants,then activated,expanded and incubated with anti-PD-1 antibody before infusion. The enough number (1.0-1.5 *10^10 cells) of D-CIK were infused back into participants.
| 2223938 | ecrin-mdr-crc