The aim of the study is to evaluate the safety and anti-tumour activity of MSCTRAIL in addition to chemotherapy in metastatic Non-small cell lung cancer (NSCLC) patients in a Phase I/II clinical trial.
In the phase I study, patients will receive cisplatin and pemetrexed on day one followed by MSCTRAIL cells on day 2. This constitutes one cycle of treatment. Each patient will receive 3 cycles of treatment at 21 day intervals. The aim of phase 1 is to estimate the recommended Phase II dose (RP2D) of MSCTRAIL in combination with pemetrexed/cisplatin chemotherapy.
During the phase II study patients will be randomised to either the intervention or the control arm of the study. All patients in both arms will receive cisplatin and pemetrexed on day one of treatment. Patients randomised to the intervention arm will receive the recommended dose of MSCTRAIL from Phase I on day 2 whilst those in the control arm will receive a placebo. As this is a double blind trial both patients and the clinical team will not know whether they are receiving MSCTRAIL or a placebo product. The aim of phase 2 is to assess tolerability and preliminary efficacy of MSCTRAIL in combination with pemetrexed/cisplatin chemotherapy.

开始日期2019-03-05

申办/合作机构

University College London

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100 项与 Msctrail(University College, London) 相关的转化医学

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100 项与 Msctrail(University College, London) 相关的专利（医药）

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项与 Msctrail(University College, London) 相关的文献（医药）

2020-12-01·Stem Cell Research & Therapy2区 · 医学

Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT

2区 · 医学

ArticleOA

作者: Weil, Benjamin D ; Janes, Sam M ; Sanderson, Tom ; Kalber, Tammy L ; Dickson, John C ; Lowdell, Mark ; Patrick, P Stephen ; Zaw Thin, May ; Edwards, Adam ; Sage, Elizabeth K ; Lythgoe, Mark F ; Kolluri, Krishna K

AbstractBackgroundMSCTRAIL is a cell-based therapy consisting of human allogeneic umbilical cord-derived MSCs genetically modified to express the anti-cancer protein TRAIL. Though cell-based therapies are typically designed with a target tissue in mind, delivery is rarely assessed due to a lack of translatable non-invasive imaging approaches. In this preclinical study, we demonstrate89Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution. Future implementation of this technique should improve our understanding of MSCTRAIL during its evaluation as a therapy for metastatic lung adenocarcinoma.MethodsMSCTRAIL were radiolabelled with89Zr-oxine and assayed for viability, phenotype, and therapeutic efficacy post-labelling. PET-CT imaging of89Zr-oxine-labelled MSCTRAIL was performed in a mouse model of lung cancer following intravenous injection, and biodistribution was confirmed ex vivo.ResultsMSCTRAIL retained the therapeutic efficacy and MSC phenotype in vitro at labelling amounts up to and above those required for clinical imaging. The effect of89Zr-oxine labelling on cell proliferation rate was amount- and time-dependent. PET-CT imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer up to 1 week post-injection, validated by in vivo bioluminescence imaging, autoradiography, and fluorescence imaging on tissue sections.Conclusions89Zr-oxine labelling and PET-CT imaging present a potential method of evaluating the biodistribution of new cell therapies in patients, including MSCTRAIL. This offers to improve understanding of cell therapies, including mechanism of action, migration dynamics, and inter-patient variability.

2019-12-01·Anticancer Research4区 · 医学

Evaluation of Combination Treatment Effect With TRAIL-secreting Mesenchymal Stem Cells and Compound C Against Glioblastoma

4区 · 医学

Article

作者: Ahn, Stephen ; Jeun, Sin-Soo ; Ryu, Chung Heon ; Han, Hye Rim ; Park, Soon A

BACKGROUND/AIMTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis of cancer cells and, when used in combination with other anticancer drugs, is regarded as an effective strategy for anticancer treatment. In this study, we investigated the efficacy of combination treatment with TRAIL-secreting human mesenchymal stem cells (MSC-TRAIL) and compound C, an AMP-activated protein kinase (AMPK inhibitor), on glioblastoma.MATERIALS AND METHODSThe anticancer effect using MSC-TRAIL and compound C on glioma was evaluated in vitro and on in vivo models.RESULTSCombination treatment of MSC-TRAIL and compound C increased apoptosis by enhancing expression of B-cell lymphoma 2 (BCL2)-associated X protein (BAX) and reducing that of anti-apoptotic proteins cellular FLICE-inhibitory protein (FLIP), X-linked inhibitor of apoptosis (XIAP), and BCL2 in glioma. In addition, MSC-TRAIL and compound C combination increased caspase-3 cleavage and apoptotic cells in a mouse glioma model compared with the group treated with the agents alone.CONCLUSIONOur results suggest that MSC-TRAIL and compound C are a novel combination for treatment of glioma.

2016-08-23·Oncotarget

The application of mRNA-based gene transfer in mesenchymal stem cell-mediated cytotoxicity of glioma cells

Article

作者: Wang, Bin ; Sun, Xu-Yong ; Yang, Zhuo-Shun ; Wang, Xiao-Li ; Yuan, Ya-Hong ; Zou, Dan-Dan ; Gui, Hui ; Fang, Juan ; Warnock, Garth L. ; Dai, Long-Jun ; Tang, Xiang-Jun ; Ma, Shi-Nan ; Guo, Xing-Rong ; Tu, Han-Jun ; Zhang, Li

Since the tumor-oriented homing capacity of mesenchymal stem cells (MSCs) was discovered, MSCs have attracted great interest in the research field of cancer therapy mainly focused on their use as carries for anticancer agents. Differing from DNA-based vectors, the use of mRNA-based antituor gene delivery benefits from readily transfection and mutagenesis-free. However, it is essential to verify if mRNA transfection interferes with MSCs' tropism and their antitumor properties. TRAIL- and PTEN-mRNAs were synthesized and studied in an in vitro model of MSC-mediated indirect co-culture with DBTRG human glioma cells. The expression of TRAIL and PTEN in transfected MSCs was verified by immunoblotting analysis, and the migration ability of MSCs after anticancer gene transfection was demonstrated using transwell co-cultures. The viability of DBTRG cells was determined with bioluminescence, live/dead staining and real time cell analyzer. An in vivo model of DBTRG cell-derived xenografted tumors was used to verify the antitumor effects of TRAIL- and PTEN-engineered MSCs. With regard to the effect of mRNA transfection on MSCs' migration toward glioma cells, an enhanced migration rate was observed with MSCs transfected with all tested mRNAs compared to non-transfected MSCs (p<0.05). TRAIL- and PTEN-mRNA-induced cytotoxicity of DBTRG glioma cells was proportionally correlated with the ratio of conditioned medium from transfected MSCs. A synergistic action of TRAIL and PTEN was demonstrated in the current co-culture model. The immunoblotting analysis revealed the apoptotic nature of the cells death in the present study. The growth of the xenografted tumors was significantly inhibited by the application of MSCPTEN or MSCTRAIL/PTEN on day 14 and MSCTRAIL on day 28 (p<0.05). The results suggested that anticancer gene-bearing mRNAs synthesized in vitro are capable of being applied for MSC-mediated anticancer modality. This study provides an experimental base for further clinical anticancer studies using synthesized mRNAs.

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