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Tumor-homing cells engineered to produce tumor necrosis factor-related apoptosis-inducing ligand

A technology of apoptosis-inducing ligand and tumor necrosis factor, applied in the direction of tumor necrosis factor, tumor/cancer cell, genetic engineering, etc., can solve problems that cannot be reasonably predicted

Inactive Publication Date: 2007-11-21
DOMPE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, a successful outcome cannot be reasonably predicted, and practical trials are required to confirm the feasibility of this particular consideration

Method used

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  • Tumor-homing cells engineered to produce tumor necrosis factor-related apoptosis-inducing ligand
  • Tumor-homing cells engineered to produce tumor necrosis factor-related apoptosis-inducing ligand
  • Tumor-homing cells engineered to produce tumor necrosis factor-related apoptosis-inducing ligand

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 - triggering apoptosis of lymphoma cell lines in vitro, wherein said lymphoma cell lines are co-cultured with CD34+ cells or NK cells expressing TRAIL after adenovirus-mediated gene transfer

[0034] This example evaluates the effect of co-culture of lymphoma cell lines with CD34+ cells or NK cells, which were engineered to express TRAIL after adenovirus-mediated gene transfer.

[0035] At the beginning of the in vitro experiment, an adenovirus vector expressing TRAIL (Ad-TRAIL) was used to establish the optimal conditions for adenovirus infection of CD34+ cells and NK cells. Then, the progress of TRAIL expression on the surface of CD34+ cells and NK cells was monitored using PE-conjugated anti-TRAIL monoclonal antibody (clone Rik-2). Finally, the ability of membrane-bound TRAIL to induce apoptosis of lymphoma cell lines was evaluated by co-culturing Ad-TRAIL / CD34+ cells or Ad-TRAIL / NK cells with lymphoma cell lines.

[0036] method

[0037] Adenovirus encod...

Embodiment 2

[0070] Example 2 - In vivo evaluation of anticancer activity of CD34+ cells or NK cells engineered to express TRAIL following adenovirus-mediated gene transfer in NOD / SCID mice

[0071] To study the therapeutic ability of Ad-TRAIL / CD34+ cells or Ad-TRAIL / NK cells, NOD / SCID mice were reperfused with TRAIL-sensitive KMS-11 multiple myeloma cell line. Mice were then injected with Ad-TRAIL / CD34+ cells or Ad-TRAIL / NK cells, and mouse survival was used as a readout for the antitumor efficacy of cell-based TRAIL delivery.

[0072] method

[0073] Evaluation of the antitumor activity of Ad-TRAIL / CD34+ cells or Ad-TRAIL / NK cells: 6- to 8-week-old female NOD / SCID mice weighing 20 to 25 g were purchased from Charles River (Milan, Italy). The animals were maintained under standard experimental conditions according to our guidelines. Experimental procedures on animals were approved by the Animal Experimentation Ethics Committee of the Istituto Nazionale Tumori and performed in accordance...

Embodiment 3

[0081] In vitro anti-tumor activity of embodiment 3-CD34 / Ad-TRAIL cells against breast cancer cell lines

[0082] A large proportion of breast cancer cell lines are resistant to TRAIL-induced apoptosis due to multiple mechanisms, including TRAIL masking by TRAIL decoy receptors, loss of R1 and R2 receptor expression, FLIP overexpression, etc. [40] . Based on our previous results that sTRAIL-resistant lymphoma cell lines responded to TRAIL when exposed to mTRAIL, we investigated the sensitivity of two breast cancer cell lines to sTRAIL and mTRAIL.

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PUM

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Abstract

The invention refers to tumor-homing cells expressing the tumor necrosis factor-related apoptosis inducing ligand (TRIAL), particularly to CD34+ and NK cells transduced with adenoviral vectors coding for TRIAL. The cells of the invention are useful for the intravenous treatment of tumors, particularly of lymphoma.

Description

technical field [0001] The present invention relates to tumor-homing cells (tumor-homing cells) expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and the use thereof in anti-tumor therapy. Background of the invention [0002] Dysregulated apoptotic mechanisms play a key role in the pathogenesis and development of lymphoproliferative disorders, leading to longer-than-normal survival of cancer cells and eventual acquisition of chemo-radiation resistance [1]. Therefore, the apoptotic pathway represents an attractive therapeutic target to restore apoptosis sensitivity in malignant cells or to initiate apoptosis agonists [2]. In order to regulate apoptosis genes and proteins, various strategies can be designed to target the intrinsic pathway of apoptosis (Bcl-2, Bcl-X L ), the extrinsic pathway (DR4, DR5, FLIP) or the convergent pathway (cIAP2) [3]. [0003] Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the TNF family of dea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705C12N5/06
CPCA61K2035/124C07K14/4747C12N5/0646C12N2501/48C12N2510/00A61P35/00A61K2239/38A61K2239/31A61K2239/48A61K39/4613A61K39/464438A61K2239/49C12N5/10C12N5/0693C12N15/861C07K14/525
Inventor A·M·詹尼C·卡洛-斯特拉F·科洛塔
Owner DOMPE SPA
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