Abstract

Selective replication of oncolytic viruses in tumor cells provides a promising approach for the treatment of human cancers. One of the limitations observed with oncolytic viruses currently used in the treatment of solid tumors is the inefficient spread of virus throughout the tumor mass following intratumoral injection. Data are presented showing that oncolytic adenoviruses expressing the relaxin gene and containing an Ad5/Ad35 chimeric fiber showed significantly enhanced transduction and increased virus spread throughout the tumor when compared with non-relaxin-expressing, Ad5-based viruses. The increased spread of such viruses throughout tumors correlated well with improved antitumor efficacy and overall survival in two highly metastatic tumor models. Furthermore, nonreplicating viruses expressing relaxin did not increase metastases, suggesting that high level expression of relaxin will not enhance metastatic spread of tumors. In summary, the data show that relaxin may play a role in rearranging matrix components within tumors, which helps recombinant oncolytic adenoviruses to spread effectively throughout the tumor mass and thereby increase the extent of viral replication within the tumor. Expressing relaxin from Ad5/Ad35 fiber chimeric adenoviruses may prove a potent and novel approach to treating patients with cancer.

Highlights

  • Oncolytic adenovirus therapies use a unique method of tumor destruction by selective viral replication and lysis of tumor cells and represent a novel approach for treating solid tumors [1]

  • The presence of the hGM-CSF gene in these viruses does not alter the relative potency of these vectors in the studies reported here because human granulocyte macrophage colony-stimulating factor (GM-CSF) is not active in mice and, in addition, all of the studies are done in immunodeficient mice

  • The inability of Ad5-based oncolytic viruses to consistently transduce a broad range of tumor cells and efficiently spread throughout solid tumors seems to hamper their effectiveness in clinic [1, 33]

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Summary

Introduction

Oncolytic adenovirus therapies use a unique method of tumor destruction by selective viral replication and lysis of tumor cells and represent a novel approach for treating solid tumors [1]. The antitumor efficacy of these oncolytic adenoviruses is, frequently limited due to variable expression levels of the coxsackievirus-adenovirus receptor (CAR) on tumor cells [2,3,4,5], a cell surface receptor used by Ad5-based viruses to bind and enter cells [6]. By switching the Ad5 fiber knob with the Ad35 knob that recognizes the highly abundant CD46 receptor on tumor cells [7], viral entry was significantly improved and correlated well with enhanced antitumor activity of Ad5/35 chimeric viruses when compared with Ad5-based viruses [6,7,8]. The fiber chimeric viruses significantly increase virus entry into tumor cells, the inability of the virus to efficiently spread throughout a big tumor mass still remains a major obstacle to the development of.

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