A Comparative Study of Neural and Mesenchymal Stem Cell-Based Carriers for Oncolytic Adenovirus in a Model of Malignant Glioma

Ahmed, Atique U.; Tyler, Matthew A.; Thaçi, Bart; Alexiades, Nikita G.; Han, Yu; Ulasov, Ilya V.; Lesniak, Mac Iej S

doi:10.1021/mp200161f

Cited by 122 publications

(139 citation statements)

References 42 publications

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“…For targeted delivery, neural stem cells (NSCs) have been well studied and applied [25,26]. However, isolation and use of NSCs are limited by ethics concerns, and MSCs have been proposed as an alternative type of therapeutic stem cells.…”

Section: Introductionmentioning

confidence: 99%

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

Akimoto

Kimura

Nagano

et al. 2013

Stem Cells and Development

162

119

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Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCBMSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when ATMSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms-promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCBMSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application.

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Section: Introductionmentioning

confidence: 99%

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

Akimoto

Kimura

Nagano

et al. 2013

Stem Cells and Development

162

119

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“…Success of this strategy depends on efficient ex vivo cellular loading with virus, intracellular virus amplification, effective cellular targeting of tumor sites following systemic administration, and successful virus hand-off at the tumor site. A variety of primary leukocytes, [42][43][44] immortalized cell lines, 45 and progenitor cells 41,[46][47][48] have all undergone preclinical evaluation for this purpose, with varying degrees of therapeutic success. In reality, many of the potential candidates are technically difficult to isolate, culture, or expand ex vivo.…”

mentioning

confidence: 99%

Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity

Castleton

Dey

Beaton

et al. 2014

Blood

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Key Points• Human BM-MSCs can be used to successfully deliver systemic oncolytic measles virotherapy to ALL tumor targets.• This approach permits circumvention of preexisting anti-measles humoral immunity and enhanced therapeutic outcomes.Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL. (Blood. 2014;123(9):1327-1335) IntroductionAdult acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy with complete remission rates following initial induction therapy of 85% to 95%. [1][2][3][4][5][6][7][8] Despite cycles of combined immunosuppressive and myelosuppressive chemotherapeutics, longterm survival is achieved in fewer than half of adults, 9 and few patients with relapsed disease survive. 10 The ability to quantify and monitor minimal residual disease in the majority of patients with ALL, provides a basis-already recognized by the regulatory authorities-for early intervention with novel therapeutics prior to overt disease relapse, 11 which would be the optimal setting for novel biological therapies.Oncolytic viruses (OVs) preferentially infect and lyse transformed cells, leaving normal cells relatively unharmed. They lack crossresistance with existing therapies, and the acceptable safety profile of OVs has been demonstrated in numerous trials. [12][13][14][15][16] Vaccine-strain live, attenuated MV (MV-Edm) has shown tumor-specific replication and antitumor activity in a range of malignancies, [17][18][19][20][21][22][23][24][25][26][27][28][29][30] with published phase 1 clinical trials showing safety and some therapeutic promise in cutaneous T-cell lymphoma 31 and ovarian cancer. 32 Sophisticated manipulations of the vaccine MV genome can aid tumor targeting [33][34][35][36][37] and assist with in vivo tracking. 21,38,39 Despite this, the necessity to shield MV from neutralizing antibody during systemic delivery has not been appropriately addressed 40,41 but is likely to preclude repeat dosing regimes and impact adversely on therapy.There has been in...

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“…The interaction between MSCs and tumor cells, and the potential risk of MSC transformation into malignant cells remain controversial (58)(59)(60). MSCs and NSCs have similar tumor tropism and infiltrative potential across the BBB (61). Intracranially implanted MSCs have demonstrated tropism for experimental gliomas, where MSCs were able to successfully deliver therapeutic substances, thereby contributing to the increased survival of glioma-bearing model animals (14,15).…”

Section: Types Of Cell Vectormentioning

confidence: 99%

Use of genetically engineered stem cells for glioma therapy

2015

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Abstract. Glioblastoma, the most common and most malignant type of primary brain tumor, is associated with poor prognosis, even when treated using combined therapies, including surgery followed by concomitant radiotherapy with temozolomide-based chemotherapy. The invasive nature of this type of tumor is a major reason underlying treatment failure. The tumor-tropic ability of neural and mesenchymal stem cells offers an alternative therapeutic approach, where these cells may be used as vehicles for the invasion of tumors. Stem cell-based therapy is particularly attractive due to its tumor selectivity, meaning that the stem cells are able to target tumor cells without harming healthy brain tissue, as well as the extensive tumor tropism of stem cells when delivering anti-tumor substances, even to distant tumor microsatellites. Stem cells have previously been used to deliver cytokine genes, suicide genes and oncolytic viruses. The present review will summarize current trends in experimental studies of stem cell-based gene therapy against gliomas, and discuss the potential concerns for translating these promising strategies into clinical use.

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A Comparative Study of Neural and Mesenchymal Stem Cell-Based Carriers for Oncolytic Adenovirus in a Model of Malignant Glioma

Cited by 122 publications

References 42 publications

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity

Use of genetically engineered stem cells for glioma therapy

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