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Publication Number
US-9687515-B2
Publication Date
2017-06-27
Expiration Date
Abstract
The present invention relates to a poxvirus comprising a defective F4L and/or I4L gene, to composition comprising such poxvirus and to the methods and use of such compositions and poxviruses for therapeutic purposes, and more particularly for the treatment of cancer.
Core Innovation
The invention relates to treating cancer, tumors, and diseases resulting from unwanted cell proliferation by administering an oncolytic Orthopox poxvirus. The poxvirus comprises a defective I4L and/or a defective F4L gene together with a defective J2R gene, and the poxvirus is expressly not NYVAC. A composition comprising the poxvirus is also contemplated for administration to a host organism or cell in need.
The disclosed approach further incorporates engineered poxviral nucleic acid of interest to support oncolytic therapy while improving safety, including incorporation of therapeutic genes and suicide gene systems. In particular, cytosine analog prodrugs such as 5-fluorocytosine (5-FC) are converted to cytotoxic 5-fluorouracil (5-FU). Optionally, permease elements are used to support drug uptake in the context of the prodrug system.
Extensive characterization is described for engineered vaccinia vectors that include defective I4L and/or defective F4L, together with functional prodrug-conversion components. The document reports reduced pathogenicity/virulence and oncolytic performance across tumor-relevant cell contexts, including antitumor efficacy in xenograft models using prodrug administration. Combination therapy results are also reported with irinotecan and with oxaliplatin.
Claims Coverage
The independent claims are directed to methods for treating cancer, tumors, and diseases from unwanted cell proliferation using an oncolytic Orthopox poxvirus with specific defective genes combined with a named anticancer drug. Each independent claim centers on a small set of inventive features: the engineered poxvirus gene defect pattern, an explicit exclusion of NYVAC, and co-administration of a specific drug.
Defective Orthopox poxvirus with irinotecan for cancer treatment
Administering to a host organism or cell an oncolytic Orthopox poxvirus comprising a defective I4L and/or a defective F4L gene, and a defective J2R gene, or administering a composition comprising said poxvirus, with the proviso that said poxvirus is not NYVAC, and administering to said host organism or cell irinotecan.
Defective Orthopox poxvirus with oxaliplatin for cancer treatment
Administering to a host organism or cell an oncolytic Orthopox poxvirus comprising a defective I4L and/or a defective F4L gene and a defective J2R gene, or a composition comprising said poxvirus, with the proviso that said poxvirus is not NYVAC, and further comprising administering to said host organism or cell oxaliplatin.
Across the independent claims, the key coverage is the use of an oncolytic Orthopox poxvirus not NYVAC with defective I4L and/or defective F4L together with a defective J2R gene, combined with co-treatment using either irinotecan or oxaliplatin.
Stated Advantages
Improved safety while maintaining oncolytic activity, as described in the document.
Reduced pathogenicity/virulence, as described in the document.
Antitumor efficacy in xenograft models with prodrug.
Documented Applications
Systemic cancer therapy using engineered poxviral oncolytic vectors combined with prodrug conversion components.
Combination therapy with irinotecan and prodrug (5-fluorocytosine), with reported tumor growth inhibition.
Combination therapy with oxaliplatin and prodrug (5-fluorocytosine), with reported tumor growth inhibition.
Antitumor activity in xenograft models including LoVo colon cancer and U87-MG glioblastoma using prodrug.
Use in treating cancers, tumors, and diseases resulting from unwanted cell proliferation, as stated in the independent claims.
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