Enhancing the Antitumor Activity of Oncolytic Adenoviruses by Combining Tumor Targeting with Hyaluronidase Expression or by Increasing the Immunogenicity of Exogenous Epitopes

by Alba Rodríguez García

Institution: Universitat de Barcelona
Year: 2015
Keywords: Oncologia; Oncología; Oncology; Immunoteràpia; Inmunoterapia; Immunotheraphy; Adenovirus; Adenoviruses; Viroterapia; Viroteràpia; Virotherapy; Ciències de la Salut
Record ID: 1124804
Full text PDF: http://hdl.handle.net/10803/290068


Oncolytic adenoviruses represent an appealing therapeutic approach to treat cancer regarding its capability to infect and kill selectively tumor cells without damaging normal tissues. Tumor targeting upon intravenous administration and subsequent intratumoral virus dissemination are key features to improve oncolytic adenovirus therapy. To address these hurdles, in this work we have combined two different genetic modifications previously described by our group in an oncolytic adenovirus backbone with selective replication conditional to pRB pathway deregulation. First, the replacement of the heparan sulfate glycosaminoglycan-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK for tumor-targeting that has shown to prolong blood persistence and significantly enhance the therapeutic index compared with a non­RGDK-modified virus. Second, the expression of hyaluronidase to degrade the extracellular matrix and improve the intratumoral spread of the virus. Preclinical toxicology and biodistribution studies conducted in non-permissive mouse and semi-permissive Syrian hamster models supported the selectivity and safety of this novel virus, ICOVIR-17K. Antitumor efficacy was also demonstrated in different tumor models in immunodeficient mice and immunocompetent hamsters upon different routs of administration. Moreover, the combination of ICOVIR-17K with the chemotherapeutic drug gemcitabine further increased the antitumor activity of the virus. The data presented in this thesis strongly supports ICOVIR-17K as a promising clinical candidate which is currently being tested in phase I clinical trials. Besides direct killing of cancer cells, oncolytic viruses may induce antitumor immune responses. Local inflammation of tumor tissue during an infection by an oncolytic virus provides suitable conditions to trigger antitumor immune responses against the tumor-associated antigens that are released in the immunogenic cell death process caused by these agents. Oncolytic adenoviruses can be used to promote immune responses against tumors by expressing and/or displaying tumor-associated antigens. However, a key limitation of this immunotherapeutic approach is the bias of the response towards the immunodominant viral antigens instead of the less immunogenic tumor antigens. In addition, defects in MHC class I antigen presentation pathway such as the downregulation of the transporter associated with antigen processing (TAP) are frequently associated with immune evasion of tumor cells and further impair the generation of specific immune responses against tumor antigens carried by oncolytic viruses. In this work we present a novel strategy that benefit from the TAP deficiency on tumor cells to enhance the response against those tumor epitopes, which had been attached to the viral protein E3-19K. This protein has a signal sequence that targets it to the endoplasmic reticulum, bypassing the necessity of TAP to transport the epitopes to that compartment. Compared to the display of the epitopes at the adenoviral capsid, this…