Concepts in Oncolytic Adenovirus Therapy
Abstract
:1. Introduction
2. The Four Main Concepts for Conditionally Replicating Adenoviruses Used in Actual Clinical Trials
2.1. Specific Cellular Promoters Control E1A and Adenoviral Replication
2.2. Modifications in E1A Control Specificity of Replication
2.2.1. E1A Deletions: Delta 24
2.2.2. E1A 13S Deletion: Dl520, Ad-Delo3-RGD (XVir-N-31)
2.2.3. E1B55K Deletion: Dl1520 (ONYX-015), Oncorine (H101)
3. Oncolytic Adenoviruses and the Immune System
4. Arming of Adenoviral Vectors to Improve Their Therapeutic Effect
4.1. Strategies to Include Transgenes in Adenoviral Vectors
4.2. Transgenes That Confer Improved Therapeutic Effect
5. Delivery and Tropism of Oncolytic Adenoviruses
5.1. Genetic Modifications to Alter the Tropism of Adenoviruses for Clinical Use
5.2. Modification of Natural Tropism
5.3. Delivery Strategies
6. Clinical Trials with Oncolytic Adenoviruses
6.1. Clinical Vectors with Specific Cellular Promoters That Control E1A
6.2. Clinical Vectors with E1A Deletion: Ad5-Delta-24
6.3. Clinical Vectors with Specific Cellular Promoters That Control E1A-Delta-24
6.4. Clinical Vectors with E1B55K Deletions
6.5. Clinical Vectors Based on Direct Evolution
7. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Concept: Promoter | Indication | Clinical Trials.gov No. | Vector Name | Construct | Additional Features | Pre-Clinical | I | II | III | Combination | Application of AdV | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
E2F1- promoter | Bladder Cancer | NCT00109655 | CG0070 | Ad5-E2F-E1A-GMCSF | GM-CSF | 2005 | Intravesical | |||||
NCT02365818 | 2015 completed | Intravesical | ||||||||||
NCT04452591 | 2020 recruiting | Intravesical | ||||||||||
NCT04610671 | 2020 recruiting | Nivolumab | Intravesical | |||||||||
NCT04387461 | 2020 recruiting | Pembrolizumab | Intravesical | |||||||||
hTERT- promoter | Hepatocellular Carcinoma | NCT02293850 | OBP-301 | Ad5-hTERT-E1A-IRES-E1B | 2014 unknown | Intratumoural | ||||||
Melanoma | NCT03190824 | 2017 active | Intratumoural | |||||||||
Solid Tumours | NCT03172819 | 2017 active | Pembrolizumab | Intratumoural | ||||||||
Esophageal Cancer | NCT03213054 | 2017 recruiting | Radiation | Intratumoural | ||||||||
Esophagogastric Adenocarcinoma | NCT03921021 | 2019 recruiting | Pembrolizumab | Intratumoural | ||||||||
Head and Neck Squamous Cell Carcinoma | NCT04685499 | 2020 recruiting | Pembrolizumab | Intratumoural | ||||||||
Esophageal and Gastroesophageal Junction Adenocarcinoma | NCT04391049 | 2020 not recruiting | Paclitaxel, Carboplatin, Radiation | Intratumoural | ||||||||
Survivin- promoter | Glioma | NCT03072134 | CRAd-S-pk7 | NSC-CRAd-Survivin-pk7 | pk7 | 2017 active | Intratumoural | |||||
CgA- promoter | Neuroendocrine Tumours | NCT02749331 | AdVince | CgA -PTD-miR122 | PTD-peptide, miRNA 122 | 2016 recruiting | Intraarterial |
Concept: Promoter & Δ24 | Indication | Clinical Trials.gov No. | Vector Name | Construct | Additional Features | Preclinical | I | II | III | Combination | Application of AdV | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
AFP promoter | Hepatocellular Carcinoma | NCT04612504 | SynOV1.1 | Ad5-AFP-delta24-RGD | GM-CSF | 2020 recruiting | Atezolizumab | Intratumoural | ||||
E2F1 promoter | Melanoma | NCT01864759 | ICOVIR-5 | Ad5-E2F-delta24-RGD | 2013 completed | Intravenous | ||||||
Solid Tumours | NCT01844661 | Mesenchymal allogenic cells | 2013 completed | Intravenous | ||||||||
Glioma | NCT04758533 | 2021 not recruiting | Intravenous | |||||||||
Advanced Solid Tumours Pancreatic Adenocarcinoma | NCT02045602 | VCN-01 | Ad5-E2F-delta24-RGD -PH20 | Hyaluronidase (PH20) | 2014 completed | Gemcitabine, Abraxane | Intravenous | |||||
Pancreatic Adenocarcinoma | NCT02045589 | 2014 completed | Gemcitabine, Abraxane | Intravenous | ||||||||
Refractory Retinoblastoma | NCT03284268 | 2017 recruiting | Intravitreal | |||||||||
Squamous cell Carcinoma of Head and Neck | NCT03799744 | 2019 recruiting | Durvalumab | Intravenous | ||||||||
Pancreatic Cancer | NCT02705196 | LOAd-703 | Ad5/35-E2F-delta24 | CD40L, 4-1BBL | 2016 recruiting | Gemcitabine, Nab-Paclitaxel, Atezolizumab | Intratumoural | |||||
Pancreatic Cancer/Ovarian, biliary, colorectal Cancer | NCT03225989 | 2017 completed | Standard chemotherapy or Gemcitabine | Intratumoural | ||||||||
Colorectal Cancer | NCT03555149 | 2018 recruiting | Standard chemotherapy | Intratumoural | ||||||||
Melanoma | NCT04123470 | 2019 recruiting | Atezolizumab | Intratumoural |
Concept: | Indication | Clinical Trials.gov No | Vector Name | Construct | Additional Features | Preclinical | I | II | III | Combination | Application of AdV | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Δ24 | Ovarian Cancer, Primary Peritoneal Cancer | NCT00562003 | Ad5-Delta 24RGD | 2017 completed | Intraperitoneal | |||||||
Brain Cancer | NCT00805376 | DNX-2401 | Ad5-Delta 24RGD | 2018 completed | Intratumoural | |||||||
Glioblastoma | NCT01582516 | 2012 completed | Intratumoural | |||||||||
Glioblastoma or Gliosarcoma | NCT01956734 | 2013 completed | Temozolomide | Intratumoural | ||||||||
Brain Cancer | NCT02798406 | 2016 completed | Pembrolizumab | Intratumoural | ||||||||
Glioblastoma or Gliosarcoma | NCT02197169 | 2014 completed | Interferon-gamma | Intratumoural | ||||||||
Gliomas | NCT03178032 | 2017 active, not recruiting | Radiotherapy, chemotherapy | Intratumoural | ||||||||
Gliomas | NCT03896568 | Ad5-Delta 24RGD | Mesenchymal stem cells as carriers | 2019 recruiting | Intraarterial | |||||||
Gliomas | NCT03714334 | DNX-2440 | Ad5-delta24-RGD-OX40L | CMV-OX40L-BGHpA repl. E3 | 2018 recruiting | Intratumoural | ||||||
Glioblastoma and multiple Solid Tumours | NCT04714983 | 2021 recruiting | Intratumoural | |||||||||
Solid Tumours | NCT01598129 | ONCOS-102 | Ad5/3-delta24-GMCSF | GM-CSF | 2012 completed | Cyclophosphamide | Intratumoural and intravenous | |||||
Melanoma | NCT03003676 | 2016 active, not recruiting | Cyclophosphamide, Pembrolizumab | Intratumoural | ||||||||
Colorectal, Ovarian, Appendiceal Cancer | NCT02963831 | 2017 active, not recruiting | Durvalumab | Intraperitoneal | ||||||||
Colorectal, Ovarian, Appendiceal Cancer | NCT03514836 | 2018 active, not recruiting | Durvalumab | Intratumoural | ||||||||
Prostate Cancer | NCT04097002 | ORCA-010 | Ad5-delta24-RGD | E3/19K-T1 protein | 2019 recruiting | Intratumoural | ||||||
Melanoma | NCT04217473 | TILT 123 | Ad5/3-delta24-TNFα-IRES-IL2 | TNFα-IRES-IL2 in E3 | 2020 recruiting | Intratumoural | ||||||
Melanoma, Solid Tumours | NCT04695327 | 2021 recruiting | Intratumoural | |||||||||
Diverse HER2 positive Solid Tumours | NCT03740256 | CAdVec | Ad5-Delta 24 | HER2-specific autol. CAR T cells | 2018 recruiting | Helper dependent Ad expressing PD-1 minibody | Intratumoural |
Concept: | Indication | Clinical Trials.gov No. | Vector Name | Construct | Additional Features | Preclinical | I | II | III | Combination | Application of AdV |
---|---|---|---|---|---|---|---|---|---|---|---|
ΔE1A 13S | Glioblastoma | 2016-000292-25 (EudraCT no.) | XVir-N-31 | Ad5 E1A13S/E1B19K/E3 deletions, Fibre RGD | 2021 active, not recruiting | Intratumoural | |||||
ΔE1B 55K | Nasopharyngeal Carcinoma | no number | Ad5 E1B55K/E3 deletions | 2005 approved by the State Food and Drug Administration of China | Cisplatin, 5-Fluorouracil, Adriamycin | Intratumoural | |||||
Refractory Malignant Ascites | NCT04771676 | Oncorine (H101) | 2021 recruiting | Intraperitoneal | |||||||
Lung Cancer | NCT02579564 | 2015 active, not recruiting | Gemcitabine, Vinorelbine, Paclitaxel, Pemetrexed, Endostar, Cisplatin | Intrathoracic | |||||||
Hepatocellular Carcinoma | NCT03780049 | 2018 recruiting | Oxaliplatin, 5-Fluorouracil, Leucovorin | Intraarterial | |||||||
Prostate Cancer | NCT02555397 | Ad5-yCD/ mutTKSR39rep-hIL12 | E1B55K deletion | yCD, mutTk, IL-12 * | 2015 unknown | Intraprostatic | |||||
Metastatic Pancreatic Cancer | NCT03281382 | 2017 unknown | 5-Fluorocytosine (5-FC), chemotherapy | Intratumoural |
Other Approaches | Indication | Clinical Trials.gov No. | Vector Name | Construct | Additional Features | Preclinical | I | II | III | Combination | Application of AdV | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Evolution | Solid Tumours | NCT02053220 | Enadenotucirev (Colo-Ad1) | Ad3/11 Chimera | 2014 completed | Intravenous | ||||||
Solid Tumours of Epithelial Origin | NCT02028442 | 2014 completed | Intravenous | |||||||||
Ovarian Cancer | NCT02028117 | 2014 completed | Intravenous | |||||||||
Colorectal Cancer, Squamous Cell Carcinoma of the Head and Neck, Epithelial Tumours | NCT02636036 | 2015, active not recruiting | Nivolumab | Intravenous | ||||||||
Rectal Cancer | NCT03916510 | 2019 recruiting | Capecitabine, radiation | Intravenous | ||||||||
Epithelial Tumours | NCT03852511 | NG-350A | Anti-CD40 Ab | 2019 recruiting | Intratumoural, intravenous | |||||||
Epithelial Tumours | NCT04053283 | NG-641 | FAP/CD3, CXCL9, CXCL10, IFNa | 2019 recruiting | chemotherapy, checkpoint inhibitors | Intratumoural, intravenous | ||||||
Squamous Cell Carcinoma of the Head and Neck | NCT04830592 | NG-641 | 2021 active, not recruiting | Pembrolizumab | Intravenous |
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Mantwill, K.; Klein, F.G.; Wang, D.; Hindupur, S.V.; Ehrenfeld, M.; Holm, P.S.; Nawroth, R. Concepts in Oncolytic Adenovirus Therapy. Int. J. Mol. Sci. 2021, 22, 10522. https://doi.org/10.3390/ijms221910522
Mantwill K, Klein FG, Wang D, Hindupur SV, Ehrenfeld M, Holm PS, Nawroth R. Concepts in Oncolytic Adenovirus Therapy. International Journal of Molecular Sciences. 2021; 22(19):10522. https://doi.org/10.3390/ijms221910522
Chicago/Turabian StyleMantwill, Klaus, Florian Gerhard Klein, Dongbiao Wang, Sruthi Vasantamadhava Hindupur, Maximilian Ehrenfeld, Per Sonne Holm, and Roman Nawroth. 2021. "Concepts in Oncolytic Adenovirus Therapy" International Journal of Molecular Sciences 22, no. 19: 10522. https://doi.org/10.3390/ijms221910522
APA StyleMantwill, K., Klein, F. G., Wang, D., Hindupur, S. V., Ehrenfeld, M., Holm, P. S., & Nawroth, R. (2021). Concepts in Oncolytic Adenovirus Therapy. International Journal of Molecular Sciences, 22(19), 10522. https://doi.org/10.3390/ijms221910522