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Published on: November 24, 2014
Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy
Gunnel Halldén1, Richard Hill, Yaohe Wang
1Viral and Genetic Therapy Program, Cancer Research U.K. Molecular Oncology Unit and Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom. davidhkim@sbcglobal.net
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.
Insights
Oncolytic adenoviruses show promise for cancer treatment. New immunocompetent mouse models reveal viral replication and immune responses are key to adenovirus efficacy against tumors.
Area of Science:
- Oncolytic virotherapy
- Cancer research
- Immunology
Background:
- Oncolytic adenoviruses are a promising cancer therapy.
- Lack of immunocompetent models limits understanding of immune response and viral E3 genes.
- Need for effective models to study adenovirus replication and efficacy.
Purpose of the Study:
- To screen murine carcinoma cell lines for adenovirus (Ad5) susceptibility.
- To establish immunocompetent murine xenograft models for oncolytic adenovirus studies.
- To investigate the role of viral replication and host immunity in Ad5 efficacy.
Main Methods:
- Screened nine murine carcinoma cell lines for Ad5 uptake, replication, and cytopathic effects.
- Developed subcutaneous xenografts in immunocompetent mice.
- Injected xenografts with Ad5, saline, or control particles to assess intratumoral gene expression, replication, and antitumoral effects.
Main Results:
- Seven of nine murine cell lines showed Ad5 infectability and cytopathic effects similar to human lines.
- Productive Ad5 replication occurred in several lines, with varying levels.
- Ad5 demonstrated significant antitumoral efficacy in both replication-permissive and poorly permissive xenografts.
- Efficacy against poorly permissive tumors was greater in immunocompetent mice than athymic mice.
Conclusions:
- Murine xenograft models are suitable for studying oncolytic adenovirus therapy.
- Host immune response significantly impacts Ad5 efficacy, particularly in poorly permissive tumors.
- These models can elucidate viral and host immune mechanisms in oncolytic adenovirus antitumoral effects.
