HSV-1 oncolytic virus therapies that specifically kill ALT dependent cancers
Recombinant herpes simplex virus (HSV)-1 capable of selectively replicating in alternative lengthening of telomeres (ALT)-dependent tumor cells are described. The recombinant HSV-1 are ICP0-deficient, such as by complete deletion of the ICP0 gene, or mutation of the ICP0 gene sufficient to diminish or eliminate E3 ubiquitin ligase activity of ICP0. In some cases, the recombinant HSV-1 further include additional gene deletions or mutations, such as those that render the virus glycoprotein C (gC) deficient, or include a heterologous gene, such as a gene encoding an immunostimulatory molecule. Methods of treating ALT-dependent cancer, and methods of selectively killing ALT-dependent tumor cells are also described.
1. A method of treating an alternative lengthening of telomeres (ALT)-dependent cancer in a subject, comprising:
selecting a subject having an ALT-dependent cancer; and
administering to the subject a recombinant herpes simplex virus (HSV)-1 that is infected cell protein 0 (ICP0)-deficient, glycoprotein C (gC)-deficient, or both ICP0-deficient and gC-deficient, thereby treating the ALT-dependent cancer in the subject.
2. The method of claim 1 , wherein the recombinant HSV-1 comprises a disruption in at least one copy of the ICP0 gene that diminishes or eliminates expression of functional ICP0.
3. The method of claim 2 , wherein:
the disruption in the ICP0 gene is a complete deletion of the ICP0 gene;
the disruption in the ICP0 gene is a partial deletion in the ICP0 gene; or
the disruption in the ICP0 gene is an insertion or a point mutation in the ICP0 gene.
4. The method of claim 3 , wherein the partial deletion in the ICP0 gene or the insertion or point mutation in the ICP0 gene is in the RING finger domain coding region, wherein the RING finger domain corresponds to amino acids 116-157 of SEQ ID NO: 25.
5. The method of claim 1 , wherein the recombinant HSV-1 comprises a gC gene with a deletion of the cytosine at position 186 relative to the gC gene of wild-type HSV-1, wherein the gC gene of wild-type HSV-1 comprises the nucleotide sequence of SEQ ID NO: 27.
6. The method of claim 1 , wherein the recombinant HSV-1 comprises a gC gene with a premature termination at the 175 th codon relative to the gC gene of wild-type HSV-1, wherein the gC gene of wild-type HSV-1 comprises the nucleotide sequence of SEQ ID NO: 27.
7. The method of claim 1 , wherein the recombinant HSV-1 further comprises a heterologous gene encoding an immunostimulatory molecule.
8. The method of claim 1 , wherein the recombinant HSV-1 further comprises a disruption in at least one copy of the ICP34.5 gene, the ICP6 gene, and/or the ICP47 gene that diminishes or eliminates expression of functional ICP34.5, ICP6 and/or ICP47.
9. The method of claim 8 , wherein:
the disruption in the ICP34.5 gene, the ICP6 gene, or the ICP47 gene is a complete deletion of the ICP34.5 gene, the ICP6 gene, or the ICP47 gene;
the disruption in the ICP34.5 gene, the ICP6 gene, or the ICP47 gene is a partial deletion in the ICP34.5 gene, the ICP6 gene, or the ICP47 gene; or
the disruption in the ICP34.5 gene, the ICP6 gene, or the ICP47 gene is an insertion or a point mutation in the ICP34.5 gene, the ICP6 gene, or the ICP47 gene.
10. The method of claim 1 , wherein the recombinant HSV-1 comprises a complete deletion of the ICP0 gene and comprises a heterologous gene encoding GM-CSF.
11. The method of claim 10 , wherein the recombinant HSV-1 comprises a genome sequence at least 80% identical to SEQ ID NO: 15 or SEQ ID NO: 23.
12. The method of claim 1 , wherein the recombinant HSV-1 comprises a complete deletion of the ICP0 gene and a partial deletion of the ICP47 gene, and further comprises a heterologous gene encoding GM-CSF.
13. The method of claim 12 , wherein the recombinant HSV-1 comprises a genome sequence at least 80% identical to SEQ ID NO: 16 or SEQ ID NO: 24.
14. The method of claim 1 , further comprising administering an anti-cancer therapy to the subject.
15. The method of claim 1 , wherein the ALT-dependent cancer is a soft tissue sarcoma, a cancer of the central nervous system, or an osteosarcoma.