118 Major synergy between Coxsackievirus A21 (CAVATAK™) and radiotherapy or chemotherapy in bladder cancer

Simpson, G.R.; Annels, NE; Ajaz, Mazhar; Launchbury, F.; Bolton, G.; Melcher, Alan; Harrington, Kevin; Au, Gough G.; Shafren, Darren R.; Pandha, H.

doi:10.1016/s0959-8049(14)70244-8

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“…CVA21 monotherapy has been shown to be well tolerated in patients and to target various tumor types, including melanoma, non-small cell lung cancer, and bladder cancer. 3,5,[37][38][39][40] However, the overall efficacy has been moderate, and efforts to augment clinical outcomes are centered on combination with immunotherapeutics. Preclinical attempts to enhance the potency of CVA21 monotherapy are focused on genetic engineering of the viral genome and methods to enhance delivery.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic Activity of Targeted Picornaviruses Formulated as Synthetic Infectious RNA

Elsedawy

Nace

Russell

et al. 2020

Molecular Therapy - Oncolytics

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Infectious nucleic acid has been proposed as a superior formulation for oncolytic virus therapy. Oncolytic picornaviruses can be formulated as infectious RNA (iRNA), and their unwanted tropisms eliminated by microRNA (miRNA) detargeting. However, genomic insertion of miRNA target sequences into coxsackievirus A21 (CVA21) iRNA compromised its specific infectivity, negating further development as a novel oncolytic virus formulation. To address this limitation, we substituted a muscle-specific miRNA response element for the spacer region downstream of the internal ribosomal entry site in the 5 0 non-coding region of CVA21 iRNA, thereby preserving genome length while avoiding the disruption of known surrounding RNA structural elements. This new iRNA (R-CVA21) retained high specific infectivity, rapidly generating replicating miRNA-detargeted viruses following transfection in H1-HeLa cells. Further, in contrast with alternatively configured iRNAs that were tested in parallel, intratumoral administration of R-CVA21 generated a spreading oncolytic infection that was curative in treated animals without associated myotoxicity. Moreover, R-CVA21 also exhibited superior miRNA response element stability in vivo. This novel formulation is a promising agent for clinical translation.

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