Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Strategies for Viral Gene Therapy of the GBM
2.1. Viral Vector Types Proposed for Gene Therapy of GBM
2.2. Adenovirus-Based Vectors
2.3. Herpes Simplex Virus-Based Vectors
2.4. Vectors Based on other Viral Backgrounds
2.5. Evaluating Vector Efficacy
3. Discussion
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Name | Structure of Vector | Mechanism of Action | Specificity | Replication Competent |
---|---|---|---|---|
DNX2401 | Ad5 | Lytic viral cycle in targeted cells | Replicate in cells defective in the Rb/p16 tumor suppressor pathway and expressing integrins αvβ3 and αvβ5 | ± |
DNX2440 | Ad5 | Lytic viral cycle in targeted cells and immunomodulatory effect | Replicate in cells defective in the Rb/p16 tumor suppressor pathway and expressing integrins αvβ3 and αvβ5 | ± |
ONYX-015 | chimeric Ad2 and Ad5 | Lytic viral cycle in targeted cells | Replicate in tumor cells with altered p53 pathway | ± |
Ad-hCMV-TK | Ad5 | Converts harmless ganciclovir to toxic product in transduced cells | Transduce CAR-expressing cells. CMV-dependent expression mechanism | − |
ADV/HSV-tk | Ad5 | Converts harmless ganciclovir to toxic product in transduced cells | Transduce CAR-expressing cells. RSV-dependent expression mechanism | − |
Ad-hCMV-Flt3L | Ad5 | Immunomodulatory effect by stimulating both the proliferation of dendritic cells (DCs) and their migration to the tumor site | Transduce CAR expressing cells | − |
Ad-RTS-hIL12 | Ad5 | Immunomodulatory effect by activation of immune system via IL-12 release | Transduce CAR-expressing cells | − |
Ad.hIFN-β | Ad5 | Immunomodulatory effect by activation of immune system via human Interferon-β release | Transduce CAR-expressing cells | − |
VB-111 | Ad5 | Decrease excessive angiogenesis via inhibition of endothelial cells | Transduce CAR-expressing cells, promotor initializes transcription only in endothelial cells undergoing angiogenesis | − |
HSV 1716 | HSV-1 | Lytic viral cycle in targeted cells and indirect T cell-mediated cell death | Replication in PKR-deficient cells | ± |
G207 | HSV-1 | Lytic viral cycle in targeted cells and indirect T cell-mediated cell death | Replication in PKR-deficient and fast dividing cells | ± |
C134 | HSV-1 | Lytic viral cycle in targeted cells and indirect T cell-mediated cell death | Replication in PKR-deficient and fast dividing cells | ± |
rQNestin34.5v.2 | HSV-1 | Lytic viral cycle in targeted cells and indirect T-cell mediated cell death | Replication in PKR-deficient, Nestin-positive and fast dividing cells | ± |
M032-HSV-1 | HSV-1 | Lytic viral cycle in targeted cells, indirect T-cell mediated cell death and immune system stimulation via IL12 release | Replication in PKR-defective and fast dividing cells | ± |
Pelareorep (Reolysin) | Wild-type reovirus | Lytic viral cycle in targeted cells | Replication in ras-positive cells | + |
ParvOryx | Wild-type parvovirus | Lytic viral cycle in targeted cells | Replication in fast dividing cells | + |
NDV-HUJ | Wild-type HUJ strain of Newcastle disease virus | Livin-mediated apoptosis | Replication in fast dividing cells, apoptosis of livin-positive cells | + |
PVSRIPO | Recombinant poliovirus type 1 | Lytic viral cycle in targeted cells | Replication restricted to CD155-expressing non-neuronal cells | + |
Toca 511 | Recombinant Gammaretrovirus | CD-mediated prodrug conversion to cytotoxic drug in transduced cells | Replication in fast dividing cells | + |
TG6002 | Recombinant vaccinia virus | Lytic viral cycle in targeted cells, CD-mediated prodrug conversion | Replication in cells expressing ribonucleotide reductase | + |
MV-CEA | Recombinant measles virus | Lytic viral cycle in targeted cells | Transduce CD46-expressing cells | + |
Vector | A Unique Identification Code Given to Clinical Study Registered on ClinicalTrials.gov | Study Date | Study Type (Safety/Trials in Recurrent GBM/Trials in Newly Diagnosed GBM) | Results/Comments |
---|---|---|---|---|
DNX2401 | NCT00805376 | 2008 | Dose-escalation study in recurrent GBM | Reported in 2018: DNX-2401 is safe, improves clinical outcome. Post-treatment histology examination of biopsy revealed sites of necrosis in GBM [64]. |
- | NCT01582516 | 2012 | Dose-escalation study in recurrent GBM | No posted results. |
- | NCT01956734 | 2013 | Safety and efficacy study in recurrent GBM DNX2401 + TMZ vs. TMZ alone | Reported in 2017: The safety objective of the trial was achieved with no severe toxicities related to DNX-2401 [65]. |
- | NCT02197169 | 2014 | Safety and efficacy study in recurrent GBM, DNX2401 + IFN vs. DMX2401 alone | Reported in 2017: DNX-2401 was well tolerated as monotherapy. The addition of interferon did not improve survival [66]. |
- | NCT02798406 | 2016 | Safety and efficacy study in recurrent GBM, DNX2401 + pembrolizumab | No posted results. |
DNX2440 | NCT03714334 | 2018 | Safety and efficacy study in recurrent GBM, DNX2440 alone | No posted results. |
ONYX-015 | Was not registered at ClinicalTrials.gov | - | Dose-escalation study | Reported in 2004: None of the 24 patients experienced serious adverse events related to ONYX-015 [67]. |
ADV/HSV-tk | NCT00589875 | 2008 | Study of AdV-tk + valacyclovir Gene therapy in combination with standard radiation therapy for malignant glioma | Reported in 2016: Addition of ADV/HSV-tk to SoC improves outcome [68]. |
- | NCT00870181 | 2009 | Safety and efficacy of intravenous-administered ADV/HSV-tk in recurrent GBM vs. surgery or systemic chemotherapy or palliative care | Reported in 2016: ADV/HSV-tk is safe and can provide benefits [69]. |
- | NCT03603405 | 2018 | Safety and efficacy study of standard treatment + ADV/HSV-tk in newly diagnosed GBM | No results posted. |
- | NCT03596086 | 2018 | Safety and efficacy of ADV/HSV-tk in recurrent GBM | No results posted. |
Ad-hCMV-Flt3L + 4. Ad-hCMV-TK (combination) | NCT01811992 | 2013 | Dose-escalation study in newly diagnosed GBM + standard treatment | Reported in 2019: Examination of tumor samples reveals increase in the infiltration of inflammatory cells. Preliminary data suggest that virotherapy can improve outcomes [70]. |
Ad-RTS-hIL12 | NCT02026271 | 2014 | Safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with oral veledimex (the activator of RTS promoter) in patients with recurrent or progressive GBM | Reported in 2019: The clinical trial demonstrated tolerability of veledimex-induced hIL-12 expression [71]. |
- | NCT04006119 | 2019 | Safety and efficacy of intratumoral Ad-RTS-hIL-12 and oral veledimex in combination with cemiplimab-rwlc in patients with recurrent or progressive GBM | No results posted. |
Ad.hIFN-β | Was not registered | - | Dose-escalation study | Reported in 2008: The most common adverse events were considered by the investigator as being unrelated to treatment [38]. |
VB-111 | NCT01260506 | 2010 | Dose-escalation study of VB-111 in combination with bevacizumab in recurrent GBM. | Reported in 2013: VB-111 was safe and well tolerated in patients with recurrent GBM with repeat doses of up to 1 × 1013 VPs. Tumor responses were seen [72]. |
- | NCT02511405 | 2015 | Comparison of VB-111 plus bevacizumab to bevacizumab in patients with recurrent GBM | Reported in 2020: Upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes [73]. |
HSV 1716 | Was not registered | - | Safety and feasibility of intratumoral administration of HSV1716 | Reported in 2000: HSV1716 is safe when injected into sites around the post-resection tumor cavity [74]. |
- | Was not registered | - | Efficacy of HSV1716 | Reported in 2002: HSV1716 replicates in HGG without causing toxicity [75]. |
- | Was not registered | - | Efficacy of HSV1716 | Reported in 2004:Study demonstrates that HSV1716 injections can provide benefits [76]. |
G207 | Was not registered | - | Dose-escalation study | Reported in 2000: No viral-related toxicity; evidence of antitumor activity. While adverse events were noted in some patients, no toxicity or serious adverse events could unequivocally be ascribed to G207 [77]. |
- | NCT00028158 | 2001 | Dose-escalation study. Doses 1E9, 3E9 and 1E10 pfu were tested | Reported in 2009:No encephalitis; evidence of antitumor activity and viral replication [78]. |
- | NCT00157703 | 2005 | De-escalation study. First patients received the highest dose (1E10 pfu). and if excessive toxicity had occurred, the dose would be reduced for the following patients | As reported in 2014: Treatment was well tolerated with signs of improving outcomes [79]. |
C134 | NCT03657576 | 2018 | Dose-escalation study in recurrent/progressive GBM, anaplastic astrocytoma, or gliosarcoma | No results posted. |
rQNestin34.5v.2 | NCT03152318 | 2017 | Dose-escalation study of in patients with recurrent GBM | No results posted. |
M032-HSV-1 | NCT02062827 | 2014 | Dose escalation in recurrent/progressive GBM, anaplastic astrocytoma or gliosarcoma | No results posted. |
Pelareorep (Reolysin) | NCT02444546 | 2015 | Dose-escalation study of Pelareorep in combination with sargramostim in recurrent/progressive GBM | No results posted. |
- | NCT00528684 | 2007 | Dose-escalation study of Pelareorep in recurrent GBM | Reported in 2008: The intratumoral administration of the genetically unmodified reovirus was well tolerated using these doses and schedule in patients with recurrent GBM [80]. |
ParvOryx | NCT01301430 | 2011 | Dose-escalation study of ParvOryx in patients with progressive or recurrent GBM | Reported in 2012 and 2017: No dose-limiting toxicity was reported but clinical response did not depend on the dose or mode of ParvOryx administration. No statistical confirmation of efficacy [81,82]. |
NDV-HUJ | Was not registered | - | Dose-escalation study of NDV-HUJ | Reported in 2006: Toxicity was minimal with Grade I/II constitutional fever being seen in five patients. Maximum tolerated dose was not achieved [83]. |
- | NCT01174537 | 2010 | Safety and efficacy of single dose intravenously administered | No results posted. |
PVSRIPO | NCT02986178 | 2016 | Safety and efficacy of single dose PVSRIPO administered intratumorally in patients with recurrent GBM | No results posted. |
- | NCT03973879 | 2019 | Safety and efficacy of single dose PVSRIPO administered intratumorally with atezolizumab treatment in patients with recurrent GBM | Withdrawn. |
- | NCT01491893 | 2011 | Dose-escalation study of PVSRIPO administered intratumorally in patients with recurrent GBM | Reported in 2018: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential [84]. |
Toca 511 | NCT04105374 | 2019 | Toca 511, Toca FC and standard of care vs. standard of care in newly diagnosed GBM | Withdrawn. |
- | NCT02414165 | 2015 | Toca 511/Toca FC vs. Lomustine, Temozolomide, or Bevacizumab in recurrent GBM | Reported in 2020: administration of Toca 511 and Toca FC, compared with SoC, did not improve overall survival (11.10 months vs. 12.22 months, respectively) or other end points [85]. |
- | NCT01470794 | 2011 | Dose-escalation study of Toca 511/Toca FC administered by injections into resection cavity wall in patients with recurrent GBM | Reported in 2016, 2016, 2018: Toca 511/Toca FC is safe and can provide durable complete response in some patients [86,87,88]. |
- | NCT01156584 | 2010 | Dose-escalation study of Toca 511/Toca FC administered by intratumoral injections in patients with recurrent GBM | Reported in 2015, 2016:Safe and well tolerated [87,88,89]. |
- | NCT01985256 | 2013 | Dose-escalation study of Toca 511/Toca FC administered by intravenously in patients with recurrent GBM | Reported in 2016: Injections were well tolerated [87]. |
TG6002 | NCT03294486 | 2017 | Dose-escalation study of TG6002 in patients with recurrent GBM | No results posted. |
MV-CEA | NCT00390299 | 2006 | Dose-escalation study of MV-CEA in patients with recurrent GBM | No results posted. |
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Mozhei, O.; G. Teschemacher, A.; Kasparov, S. Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma. Cancers 2020, 12, 3724. https://doi.org/10.3390/cancers12123724
Mozhei O, G. Teschemacher A, Kasparov S. Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma. Cancers. 2020; 12(12):3724. https://doi.org/10.3390/cancers12123724
Chicago/Turabian StyleMozhei, Oleg, Anja G. Teschemacher, and Sergey Kasparov. 2020. "Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma" Cancers 12, no. 12: 3724. https://doi.org/10.3390/cancers12123724