Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-D<sup>ΔNΔC</sup> Gene Therapy Containing Residual Replication-Competent Adenoviruses

Leikas, Aleksi J.; Laham-Karam, Nihay; Agtereek, Eline; Peltonen, Hanna Marjaana; Selander, Tuomas; Korpisalo, Petra; Holappa, Lari; Hartikainen, Juha; Heikura, Tommi; Ylä‐Herttuala, Seppo

doi:10.1089/hum.2020.299

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…It has been shown that current administration techniques for adenoviral vectors cause systemic off-target distribution [ 17 ], and that the main organ responsible for the vector elimination is the liver [ 18 ]. Even though the time interval between GT and the diagnosis of cancer was two years or more, this concern needs to be carefully monitored in the future trials.…”

Section: Discussionmentioning

confidence: 99%

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

et al. 2021

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In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3–10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36–2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

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Section: Discussionmentioning

confidence: 99%

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

et al. 2021

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“…Vector plasmid DNA was transfected into HEK-293 cells and the resulting recombinant vectors were colony-purified for three rounds prior to cesium chloride gradient purification. The vector titers were quantified spectrophotometrically and tested for sterility and mycoplasma contamination [28] . Expression of the Ad5-RBD and –S vaccine antigens was confirmed in HeLa and A549 cells upon adenoviral infection.…”

Section: Methodsmentioning

confidence: 99%

Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models

Freitag

Fagerlund

Karam

et al. 2023

Vaccine

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“…To our knowledge, KAT301 is the only clinical trial in which the IMP, HEK293propagated replication-deficient HAdV-5 encoding for vascular endothelial growth factor-D ∆N∆C (AdVEGF-D) [100], has been confirmed to be RCA positive using ddPCR after the completion of the trial, despite the initial negative test result [18]. According to the tests conducted on the batches from the same master virus seed stock, the range of RCA in the final phase 1 drug product was retrospectively estimated to be significantly higher than approved by the FDA, 100-200 RCA in 3 × 10 10 tested vp [101].…”

Section: Observations From Cardiovascular Studiesmentioning

confidence: 99%

Adenoviral Gene Therapy Vectors in Clinical Use—Basic Aspects with a Special Reference to Replication-Competent Adenovirus Formation and Its Impact on Clinical Safety

Leikas,

Ylä-Herttuala,

Hartikainen

2023

IJMS

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Adenoviral vectors are commonly used in clinical gene therapy. Apart from oncolytic adenoviruses, vector replication is highly undesired as it may pose a safety risk for the treated patient. Thus, careful monitoring for the formation of replication-competent adenoviruses (RCA) during vector manufacturing is required. To render adenoviruses replication deficient, their genomic E1 region is deleted. However, it has been known for a long time that during their propagation, some viruses will regain their replication capability by recombination in production cells, most commonly HEK293. Recently developed RCA assays have revealed that many clinical batches contain more RCA than previously assumed and allowed by regulatory authorities. The clinical significance of the higher RCA content has yet to be thoroughly evaluated. In this review, we summarize the biology of adenovirus vectors, their manufacturing methods, and the origins of RCA formed during HEK293-based vector production. Lastly, we share our experience using minimally RCA-positive serotype 5 adenoviral vectors based on observations from our clinical cardiovascular gene therapy studies.

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Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-D^ΔNΔC Gene Therapy Containing Residual Replication-Competent Adenoviruses

Cited by 6 publications

References 22 publications

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models

Adenoviral Gene Therapy Vectors in Clinical Use—Basic Aspects with a Special Reference to Replication-Competent Adenovirus Formation and Its Impact on Clinical Safety

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Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-DΔNΔC Gene Therapy Containing Residual Replication-Competent Adenoviruses

Cited by 6 publications

References 22 publications

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Intranasal administration of adenoviral vaccines expressing SARS-CoV-2 spike protein improves vaccine immunity in mouse models

Adenoviral Gene Therapy Vectors in Clinical Use—Basic Aspects with a Special Reference to Replication-Competent Adenovirus Formation and Its Impact on Clinical Safety

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Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-D^ΔNΔC Gene Therapy Containing Residual Replication-Competent Adenoviruses