AbstractFirst-generation adenovirus can be engineered with powerful promoters to drive expression of
therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first
generation adenoviral vectors have either been performed or are ongoing, including an ongoing,
Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the
absence of anti-adenovirus immune responses expression in the brain lasts 6–18
months, systemic infection with adenovirus induces immune responses that inhibit dramatically
therapeutic transgene expression from first generation adenoviral vectors, thus, potentially
compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the
dose that generates an immune response strong enough to eliminate transgene expression from the
CNS. For the systemic immunization to eliminate transgene expression from the brain,
≥1×107 infectious units (iu) of adenovirus need to be used as
immunogen. Furthermore, this immune response eliminates >90% of transgene expression
from 1×107–1×103 iu of vector injected
into the striatum 60 days earlier. Importantly, elimination of transgene expression is
independent of the nature of the promoter that drives transgene expression and is accompanied
by brain infiltration of CD8+ T cells and macrophages. In conclusion, once the
threshold for systemic immunization (i.e. 1×107 iu) is crossed, the
immune response eliminates transgene expression by >90% even from brains that
receive as little as 1000 iu of adenoviral vectors, independently of the type of
promoter that drives expression.
Immune Regulation of Transgene Expression in the Brain: B Cells Regulate an Early Phase of Elimination of Transgene Expression from Adenoviral Vectors