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Published on: May 6, 2015
An evaluation of site-specific immune responses directed against first-generation adenoviral vectors administered by
Edward White1, Alison Bienemann, Hannah Taylor
1Department of Neurosurgery, Frenchay Hospital, Bristol, UK.
Background:
Direct adenoviral vector injections into the brain have been used in clinical trials to treat patients with high-grade gliomas. However, a recent phase 3 trial using first-generation vectors failed to demonstrate significant survival benefits. Malignant gliomas infiltrate extensively through the white matter, making them difficult to treat, and chemotherapy is at best partially effective. Convection enhanced delivery (CED) represents a rationale approach for achieving widespread targeting of infiltrating tumour cells. Previous studies have demonstrated that infusions of particle numbers above a threshold level [10(8) plaque-forming units (pfu)] are associated with a pronounced inflammatory response in rat grey matter, although no such comparisons have been made with CED infusions into the white matter.
Methods:
In the present study, we investigated the distribution and immune response after the administration of 10(7) and 10(9) pfu of a first-generation adenoviral vector (Ad.CMV.EGFP) by CED in both small and large animal models.
Results:
We show that Ad.CMV.EGFP can be efficiently distributed by CED over large volumes of brain. A threshold vector dose of between 10(7) and 10(9) pfu was seen in both rat striatum and white matter, above which transgene expression was lost at 30 days. Furthermore, all adenoviral infusions were associated with evidence of significant tissue damage, as demonstrated by loss of neurones and astrocytes or the presence of extensive astrocytosis.
Conclusions:
These results indicate that CED is capable of mediating widespread adenoviral vector distribution, although these vectors are associated with significant tissue toxicity that may render their safe application in clinical trials unfeasible.
Insights
Convection enhanced delivery (CED) distributes adenoviral vectors widely in the brain, but high doses cause toxicity and reduce transgene expression. This limits the feasibility of using these vectors in clinical trials for brain tumors.
Area of Science:
- Neuro-oncology
- Gene Therapy
- Viral Vector Delivery
Background:
- High-grade gliomas are challenging to treat due to extensive infiltration.
- First-generation adenoviral vectors have shown limited efficacy in clinical trials.
- Convection enhanced delivery (CED) offers a strategy for widespread tumor targeting.
Purpose of the Study:
- To investigate the distribution and immune response of adenoviral vectors delivered via CED.
- To assess the impact of vector dose on transgene expression and tissue toxicity.
Main Methods:
- Administration of 10^7 and 10^9 plaque-forming units (pfu) of Ad.CMV.EGFP via CED in rat models.
- Evaluation of vector distribution, transgene expression at 30 days, and tissue damage.
Main Results:
- CED enabled efficient distribution of adenoviral vectors over large brain volumes.
- A dose threshold between 10^7 and 10^9 pfu was identified, above which transgene expression was lost.
- Adenoviral infusions caused significant tissue damage, including neuronal and astrocyte loss and astrocytosis.
Conclusions:
- CED facilitates widespread adenoviral vector distribution in the brain.
- Significant tissue toxicity associated with adenoviral vectors may limit their clinical application.
- The findings suggest potential safety concerns for CED-based adenoviral vector therapy in clinical trials.
