Abstract
Promising results have been reported from numerous studies with replication-selective oncolytic adenoviral mutants as novel treatments for a variety of cancers. Most of these studies were performed in cancer cell lines, dissociated tumor tissue, or animal models, and the predictive utility for efficacy and safety in the clinical setting is unclear. Indeed, the outcome of many clinical trials with viral mutants that demonstrated high efficacy preclinically has so far been disappointing, necessitating better test models. To this end, we developed a methodology using primary human cancer specimens for evaluation of cytotoxicity ex vivo including colorectal liver metastasis, ovarian, breast, colon, and prostate carcinomas. Under optimized culture conditions, primary human tumor tissue remained viable for up to 48 h, enabling evaluation of viral mutants in tissue with intact morphology. This assay may have great utility to investigate novel viral mutants and to identify treatment sensitive cancers by assessing specific oncolytic mutants in individual cases.
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References
Parato, K. A., Senger, D., Forsyth, P. A., and Bell, J. C. (2005) Recent progress in the battle between oncolytic viruses and tumours, Nat Rev Cancer5, 965–976.
Liu, T. C., Galanis, E., and Kirn, D. (2007) Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress, Nat Clin Pract Oncol4, 101–117.
de Vrij, J., Willemsen, R. A., Lindholm, L., and Hoeben, R. C., GIANT consortium (2010) Adenovirus-Derived Vectors for Prostate Cancer Gene Therapy, Hum Gene Ther 21(7), 795–805.
Matthews, K., Noker, P. E., Tian, B., Grimes, S. D., Fulton, R., Schweikart, K., Harris, R., Aurigemma, R., Wang, M., Barnes, M. N., Siegal, G. P., Hemminki, A., Zinn, K., Curiel, D. T., and Alvarez, R. D. (2009) Identifying the safety profile of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in anticipation of a phase I clinical trial in patients with recurrent ovarian cancer, Clin Cancer Res15, 4131–4137.
Freytag, S. O., Stricker, H., Peabody, J., Pegg, J., Paielli, D., Movsas, B., Barton, K. N., Brown, S. L., Lu, M., and Kim, J. H. (2007) Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer, Mol Ther15, 636–642.
Öberg, D., Yanover, E., Sweeney, K., Adam, V., Costas, C., Lemoine, N.R., and Halldén, G. (2010) Improved potency and selectivity of an oncolytic E1ACR2 and E1B19K deleted adenoviral mutant (Ad∆∆) in prostate and pancreatic cancers. Clin Canc Res16, 541–53.
Russell, W. C. (2009) Adenoviruses: update on structure and function, J Gen Virol90, 1–20.
Thomas, M. A., Spencer, J. F., Toth, K., Sagartz, J. E., Phillips, N. J., and Wold, W. S. (2008) Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model, Mol Ther16, 1665–1673.
Thomas, M. A., Spencer, J. F., and Wold, W. S. (2007) Use of the Syrian hamster as an animal model for oncolytic adenovirus vectors, Methods Mol Med130, 169–183.
Steel, J. C., Morrison, B. J., Mannan, P., Abu-Asab, M. S., Wildner, O., Miles, B. K., Yim, K. C., Ramanan, V., Prince, G. A., and Morris, J. C. (2007) Immunocompetent syngeneic cotton rat tumor models for the assessment of replication-competent oncolytic adenovirus, Virology369, 131–142.
Wang, Y., Hallden, G., Hill, R., Anand, A., Liu, T. C., Francis, J., Brooks, G., Lemoine, N., and Kirn, D. (2003) E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models, Nat Biotechnol21, 1328–1335.
Kasuya, H., Pawlik, T. M., Mullen, J. T., Donahue, J. M., Nakamura, H., Chandrasekhar, S., Kawasaki, H., Choi, E., and Tanabe, K. K. (2004) Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen, Cancer Res64, 2561–2567.
Kirby, T. O., Rivera, A., Rein, D., Wang, M., Ulasov, I., Breidenbach, M., Kataram, M., Contreras, J. L., Krumdieck, C., Yamamoto, M., Rots, M. G., Haisma, H. J., Alvarez, R. D., Mahasreshti, P. J., and Curiel, D. T. (2004) A novel ex vivo model system for evaluation of conditionally replicative adenoviruses therapeutic efficacy and toxicity, Clin Cancer Res10, 8697–8703.
Marsman, W. A., Buskens, C. J., Wesseling, J. G., Offerhaus, G. J., Bergman, J. J., Tytgat, G. N., van Lanschot, J. J., and Bosma, P. J. (2004) Gene therapy for esophageal carcinoma: the use of an explant model to test adenoviral vectors ex vivo, Cancer Gene Ther11, 289–296.
Wang, Y., Thorne, S., Hannock, J., Francis, J., Au, T., Reid, T., Lemoine, N., Kirn, D., and Hallden, G. (2005) A novel assay to assess primary human cancer infectibility by replication-selective oncolytic adenoviruses, Clin Cancer Res11, 351–360.
O’Reilly, D., Muller, L., and Luckow, V. (1994) Virus Methods, in Bculovirus expression vectors: A laboratory manual, pp 132–134, Oxford University Press, Oxford.
Acknowledgments
This work was supported by grants from the Barts & The London Charity and Cancer Research UK (C633-A6253/A6251). The author would like to thank the patients and surgical teams at the Hammersmith Hospital, London and the Veterans Admini-stration Hospital, Palo Alto for their cooperation, and Steve Thorne, Yaohe Wang, Vipul Bakta, Celina Costas, and Suresh Radhakrishnan for their contributions in developing this method.
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Halldén, G. (2012). Adenoviral Gene Expression and Replication in Human Tumor Explant Models. In: Kirn, D., Liu, TC., Thorne, S. (eds) Oncolytic Viruses. Methods in Molecular Biology, vol 797. Humana, Totowa, NJ. https://doi.org/10.1007/978-1-61779-340-0_5
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DOI: https://doi.org/10.1007/978-1-61779-340-0_5
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