Silvio Hemmi

Adenovirus vectors for cancer gene therapy

The overall aim of my group is to perform basic research on adenoviruses with the ultimate goal to translate this information into improved adenovirus cancer gene therapy vectors. In the recent past, this has includes studies of virus-CD46/CAR-receptor interactions including our more recent work, which showed that based on avidity mechanisms, HAdV-3 and -7 can utilize CD46 as functional attachment receptor, despite a low affinity of the monovalent fiber knob–soluble CD46 interaction.

   My group has experience in generating novel adenovirus vectors harboring modified tropism, including switching to alternative human or mammalian serotypes/species and use of such vectors to express therapeutic genes in vitro and in vivo for the purpose of cancer gene therapy. We were among the first to show that melanoma cells were significantly resistant to infection with standard adenovirus vectors and developed several important modifications to overcome such hurdles. We have since progressed to testing modified adenovirus-mediated therapy against melanoma in experimental mouse models using both replicating and non-replicating adenovirus derivatives. Our BACmid containing the complete HAdV-3 has been used by the group of Akseli Hemminiki (Cancer Therapy Group of the Helsinki University) to generate novel oncolytic adenovirus-based vectors on serotype 3 currently tested in humans.

   More recently, we have obtained preliminary data of adenovirus-host interactions using quantitative transcriptomics analyses of viral, cellular and miRNA gene expression levels and quantitative proteomics of adenovirus-infected cells. We reasoned that a detailed understanding of the regulatory interactions of possible miRNAs derived from adenoviruses or the known cellular miRNAs from human cells with cellular and viral transcripts, respectively, will reveal new regulatory gene expression and modulation mechanisms during adenovirus infection.

   Further, we have recently initiated studies to a better understand basic cell-virus biology of murine adenoviruses. We think that the establishment of murine adenoviruses as an animal model system is an important advance for studying the mechanisms of acute and persistent adenovirus infections in mammals. The long-term goal is the development of the oncolytic vectors in syngeneic mouse systems. This aim is important to test mouse vectors featuring melanoma-specific oncolytic properties similar to human adenovirus vectors that we have developed in the past. A syngeneic model would enable us to address key questions about the efficacy of oncolytic vector in the context of a functional immune system. We hope to improve our understanding of the pathological effects from adenoviruses, and enhance the development of gene therapy vectors.