Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy

Abstract

Oncolytic replication-selective adenoviruses constitute a rapidly expanding experimental approach to the treatment of cancer. However, due to the lack of an immunocompetent and replication-competent efficacy model, the role of the host immune response and viral E3 immunoregulatory genes remained unknown. We screened nine murine carcinoma lines for adenovirus (Ad5) uptake, gene expression, replication, and cytopathic effects. In seven of these murine cell lines the infectability and cytopathic effects were similar to those seen with human carcinoma lines. Surprisingly, productive viral replication was demonstrated in several lines; replication varied from levels similar to those for some human carcinoma lines (e.g., CMT-64) to very low levels. Seven of these lines were grown as subcutaneous xenografts in immunocompetent mice and were subsequently injected directly with Ad5, saline, or a replication-deficient control adenovirus particle to assess intratumoral viral gene expression, replication, and antitumoral effects. E1A, coat protein expression, and cytopathic effects were documented in five xenografts; Ad5 replication was demonstrated in CMT-64 and JC xenografts. Ad5 demonstrated significant efficacy compared to saline and nonreplicating control Ad particles in both replication-permissive xenografts (CMT-64, JC) and poorly permissive tumors (CMT-93); efficacy against CMT-93 tumors was significantly greater in immunocompetent mice compared to athymic mice. These murine tumor xenograft models have potential for elucidating viral and host immune mechanisms involved in oncolytic adenovirus antitumoral effects.

Combination of gemcitabine and Ad5/3-Δ24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer

“…Although human adenoviruses do not productively replicate in murine cells, E1A expression and protein production does ensue. 33 Theoretically, this could sensitize normal cells to gemcitabine-mediated damage. Although the capsid modification used here increases the tropism of the virus to tumor cells, it has little effect on the biodistribution in general and the liver transduction in particular.…”

Infectivity enhancement for adenoviral transduction of canine osteosarcoma cells

“…One approach employs certain permissive murine tumor cell lines grown in immunocompetent animals to study human adenovirus replication. [7][8][9] However, the inefficient replication of human adenovirus in these cell lines, as well as the artificial establishment of these tumors as subcutaneous syngeneic grafts, raises concerns as to how well this model supports human adenovirus replication and how accurately the tumor grafts represent their natural human counterparts. An alternative approach that we have pursued is to use syngeneic Ad vectors in their natural host system.…”

Functional interactions of antiapoptotic proteins and tumor necrosis factor in the context of a replication-competent adenovirus

“…Of note, the roles of TNF and an intact immune response were determined. To accomplish this we took advantage of a novel immunocompetent tumor model that we recently described in which intratumoral adenovirus replication occurs 31 and the fact that murine liver is semipermissive for human adenovirus replication. 32 …”