Reduction of toxicity and improvement of tumor cell infection by oncolytic adenoviruses following systemic administration for the treatment of head and neck cancer

• Applicant: Dr. Lea Krutzke
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Hematology, Oncology ; Virology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537592007

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide, with high mortality and risk of relapses after standard-of-care treatment. Lately, cancer virotherapy using oncolytic viruses has been intensively investigated as alternative new treatment strategy. It is based on viral infection of cancer cells and virus replication-induced cell lysis, followed by the intratumoral spread of viral progeny and infection of neighboring cells. In a further development as cancer immunotherapy, oncolytic virotherapy additionally aims to induce a tumor-directed activation of the immune system due to the virus itself and the release of tumor-associated antigens by virus-induced cell lysis. Currently, human adenoviruses in general and human adenovirus type 5 (HAdV-C5) in particular is intensively investigated as oncolytic virus with promising results. However, its clinical efficacy is limited due to rapid sequestration of viral particles due to off-target cell infection and inactivation by the innate and adaptive immune system. Beyond these sequestration mechanisms, uptake of viral particles by liver-residential macrophages and infection of hepatocytes are particularly effective natural barriers. This strong liver tropism of HAdV-Ct virus particles does not only mitigate effective tumor cell infection, but may also lead to adverse side effects like hepatotoxicity, which is dose-limiting and burdensome or even life-threatening for the patient. Further, the second most severe sequestration mechanism that significantly limits the therapeutic efficacy of oncolytic HAdV-C5 is its high seroprevalence resulting in rapid neutralization and opsonization of particles, especially after systemic administration. Thus to improve the therapeutic efficacy of oncolytic adenoviruses, the overall objective of the proposed project is to understand, characterize and further improve new oncolytic adenoviruses and investigate their therapeutic potential in vitro and in vivo using human xenograft tumor-bearing immunoincompetent mice. To this end, we aim to investigate a recently identified in-house generated genetically surface charge-modified HAdV-C5-based mutant vector, which showed substantially reduced hepatotoxicity in vivo in preliminary work. We will use this vector to unravel and understand the mechanisms of adenovirus induced liver damage. The gathered knowledge will not only be important for adenovirus-based gene therapies in general but favorable features of this mutant virus might be also transferable to other oncolytic adenoviruses of the future. Additionally, we aim to investigate and refine a predefined subselection of 12 out of more than 100 known human adenovirus types different from HAdV-C5 in vitro and in vivo to develop new oncolytic virus candidates with promising characteristics regarding tumor tissue infection, biodistribution profiles, pharmacokinetics, sequestration of particles and safety.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Thomas Barth