In vitro and in vivo delivery of novel anticancer fusion protein MULT1E/FasTI via adenoviral vectors

Kotturi, Hari; Li, J; Branham‐O'Connor, Melissa; Yu, Xianzhong; Wagner, Thomas E.; Wei, Yanzhang

doi:10.1038/cgt.2009.69

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…In our previous studies, we created a fusion gene consisting of the extracellular domain of MULT1 and the transmembrane and introcellular domains of mouse Fas and demonstrated that fusion protein MULT1E/mFasTI activates NK cells and induces apoptosis of tumor cells expressing the protein in vitro and in vivo. 13 The limitation of fusion protein MULT1E/mFasTI is that it can only activate the NK cells that are engaged with the tumor cells expressing the protein and it cannot activate other NK cells in the tumor environment. The bi-functional protein created in this study, however, can provide a local high dose of IL-12, which is able to activate NK cells in the local tumor environment so that the therapy may be more effective.…”

Section: Discussionmentioning

confidence: 99%

“…Double enzyme digestion was performed on the purified fragment using BamHI and XhoI. The plasmid pcDNA3.1(+)MULT1E/Neo, created earlier in our lab, 13 was digested with BamHI and XhoI allowing for the insertion of mIL-12 directly downstream of MULT1E in frame. The linearized plasmid was excised and gel purified using a gel purification kit (Qiagen).…”

Section: Construction Of Pcdna31(+)mult1e/mil-12/neo Vectormentioning

confidence: 99%

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MULT1E/mIL-12: a novel bifunctional protein for natural killer cell activation

Tietje

et al. 2014

Gene Ther

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Natural killer (NK) cells have the potential to be effective killers of tumor cells. They are governed by inhibitory and activating receptors like NKG2D, whose ligands are normally upregulated in cells that are stressed, like cancer cells. Advanced cancer cells, however, have ways to reduce these ligands' expression, leaving them less detectable by NK cells. Along with these receptors, NK cells also require activating cytokines, like interleukin 12 (IL-12). The goal of this study is to develop a novel bi-functional fusion protein for enhanced NK cell activation. The proposed protein combines the extracellular domain of the NKG2D ligand Mouse UL-16-binding protein-like transcript 1 (MULT1E) and mouse IL-12 (mIL-12). It is hypothesized that when expressed by tumor cells, the protein will activate NK and other killer cells using the NKG2D receptor, and deliver mIL-12 to the NK cells where it can interact with the IL-12R and enhance cytotoxicity. The fusion protein, when expressed by engineered tumor cells, indeed activated NK cells in vitro as assayed by increased production of interferon-γ and cytotoxicity and significantly reduced tumor growth in vivo. Although the study is preliminary, the data suggest that the MULT1E/mIL-12 bi-functional fusion protein is an effective activator of NK cells for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Construction Of Pcdna31(+)mult1e/mil-12/neo Vectormentioning

confidence: 99%

MULT1E/mIL-12: a novel bifunctional protein for natural killer cell activation

Tietje

et al. 2014

Gene Ther

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“…Tumor cells expressing MULT1E-FasTI proliferated significantly more slowly compared to tumor cells without the fusion protein in mouse. Kotturi et al [ 68 ] packaged this fusion gene in an adenoviral delivery vector and directly injected the viral particles into the tumors in mice. This treatment induced the apoptosis of the tumor cells in vivo and significantly delayed the tumor growth.…”

Section: Strategies Of Fusion Proteinsmentioning

confidence: 99%

Fusion Proteins of NKG2D/NKG2DL in Cancer Immunotherapy

Ding

Yang

Wei

2018

IJMS

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NKG2D (natural killer group 2, member D) is an important activating receptor in natural killer (NK) cells and some T cells. NKG2D ligands (NKG2DLs) are specifically expressed on most tumor cells. The engagement of these ligands on tumor cells to NKG2D on NK cells will induce cell-mediated cytotoxicity and have target cells destroyed. This gives NKG2D/NKG2DLs great potential in cancer therapeutic application. The creation of NKG2D/NKG2DL-based multi-functional fusion proteins is becoming one of the most promising strategies in immunotherapy for cancer. Antibodies, cytokines, and death receptors have been fused with NKG2D or its ligands to produce many powerful fusion proteins, including NKG2D-based chimeric antigen receptors (CARs). In this article, we review the recent developments of the fusion proteins with NKG2D/NKG2DL ligands in cancer immunotherapy.

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“…Pulmonary metastasis studies showed that most of the mice completely rejected tumor cells expressing MULT1E/FasTI. [27] We then tried to use an adenoviral gene delivery system to deliver this fusion protein and demonstrated that adenoviral vector can efficiently deliver the MULT1E/FasTI fusion protein into TC-1 cells both in vitro and in vivo as assayed by RT-PCR, FACS analysis, caspase 3 activity and decreased in vivo tumor growth [28].…”

Section: Mult1e/fastimentioning

confidence: 99%

Reshaping the Immunosuppressive Tumor Microenvironment: The Fusion Protein Strategy

Wei¹

2016

CCLSJ

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Advanced tumor cells often create immunosuppressive tumor microenvironment to block immune system's attack in defense. The conversion of the environment from immunosuppressive to immune active holds hopes for effective cancer immunotherapies. Fusion proteins coupled with appropriate delivery approaches represent a promising strategy for this conversion. In the last decade, a variety of fusion cytokine proteins (GPI-anchored IL-2/IL-12, RGD/Fc, MULT1E/FasTI, MULT1E/IL-12, and IL-12/FasTI) have been created and tested for their anti-cancer activities in a series of in vitro and in vivo studies. The efforts are going on to develop effective method to deliver the fusion proteins specifically into tumors.

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In vitro and in vivo delivery of novel anticancer fusion protein MULT1E/FasTI via adenoviral vectors

Cited by 7 publications

References 28 publications

MULT1E/mIL-12: a novel bifunctional protein for natural killer cell activation

MULT1E/mIL-12: a novel bifunctional protein for natural killer cell activation

Fusion Proteins of NKG2D/NKG2DL in Cancer Immunotherapy

Reshaping the Immunosuppressive Tumor Microenvironment: The Fusion Protein Strategy

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