Viral vectors for cancer therapy
The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding an immunomodulatory polypeptide (e.g., a pro-inflammatory cytokine such as a human IL-2 or IL-12 polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for the treatment of cancer, such as lung cancer); and articles of manufacture or kits thereof.
1. A pharmaceutical composition comprising:
(a) a herpes simplex virus comprising a recombinant herpes simplex virus genome, wherein the recombinant herpes simplex virus genome comprises a polynucleotide encoding an Interleukin (IL)-2 polypeptide and a polynucleotide encoding an IL-12 polypeptide; and
(b) a pharmaceutically acceptable excipient,
wherein the recombinant herpes simplex virus genome does not comprise a polynucleotide encoding a Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) polypeptide; and
wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in an Infected Cell Polypeptide (ICP) 22 herpes simplex virus gene.
2. The pharmaceutical composition of claim 1 , wherein the herpes simplex virus is replication defective.
3. The pharmaceutical composition of claim 1 , wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome or a recombinant herpes simplex virus type 2 (HSV-2) genome.
4. The pharmaceutical composition of claim 1 , wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome.
5. The pharmaceutical composition of claim 1 , wherein the recombinant herpes simplex virus genome further comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP27, ICP47, thymidine kinase (tk), Long Unique Region (UL) 41, and UL55.
6. The pharmaceutical composition of claim 1 , wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in one or both copies of the ICP4 gene.
7. The pharmaceutical composition of claim 1 , wherein the herpes simplex virus is not oncolytic.
8. The pharmaceutical composition of claim 1 , wherein the herpes simplex virus has reduced cytotoxicity as compared to a corresponding wild-type herpes simplex virus.
9. The pharmaceutical composition of claim 1 , wherein the IL-2 polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 3.
10. The pharmaceutical composition of claim 1 , wherein the IL-12 polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 85.
11. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, epicutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intramuscular, intraosseous, intracardial, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, intratumoral, local, or inhaled administration.
12. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for intratumoral administration.
13. The pharmaceutical composition of claim 1 , wherein the recombinant herpes simplex virus genome comprises the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within the same viral gene locus.
14. The pharmaceutical composition of claim 13 , wherein the viral gene locus is an ICP4 viral gene locus.
15. The pharmaceutical composition of claim 1 , wherein the recombinant herpes simplex virus genome comprises the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within different viral gene loci.
16. The pharmaceutical composition of claim 1 , wherein the IL-2 polypeptide and the IL-12 polypeptide are human polypeptides.
17. A pharmaceutical composition consisting essentially of:
(a) a population of herpes simplex viruses, wherein the population of herpes simplex viruses is either all replication defective or all replication competent, and wherein the population of herpes simplex viruses comprises recombinant herpes simplex virus genomes comprising a polynucleotide encoding an IL-2 polypeptide and a polynucleotide encoding an IL-12 polypeptide; and
(b) a pharmaceutically acceptable excipient;
wherein the recombinant herpes simplex virus genome comprises an inactivating mutation in an ICP22 herpes simplex virus gene.
18. The pharmaceutical composition of claim 17 , wherein the polynucleotide encoding the IL-2 polypeptide and the polynucleotide encoding the IL-12 polypeptide are comprised within the same recombinant herpes simplex virus genome.
19. The pharmaceutical composition of claim 17 , wherein the population of herpes simplex viruses is replication defective.
20. The pharmaceutical composition of claim 17 , wherein the recombinant herpes simplex virus genomes are recombinant HSV-1 genomes or recombinant HSV-2 genomes.
21. The pharmaceutical composition of claim 17 , wherein the recombinant herpes simplex genomes are recombinant HSV-1 genomes.
22. The pharmaceutical composition of claim 17 , wherein the recombinant herpes simplex virus genomes further comprise an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP27, ICP47, tk, UL41, and UL55.
23. The pharmaceutical composition of claim 17 , wherein the recombinant herpes simplex virus genomes comprise an inactivating mutation in one or both copies of the ICP4 gene.
24. The pharmaceutical composition of claim 17 , wherein the population of herpes simplex viruses is not oncolytic.
25. The pharmaceutical composition of claim 17 , wherein the population of herpes simplex viruses has reduced cytotoxicity as compared to a corresponding population of wild-type herpes simplex viruses.
26. The pharmaceutical composition of claim 17 , wherein the IL-2 polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 3.
27. The pharmaceutical composition of claim 17 , wherein the IL-12 polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 85.
28. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is suitable for topical, transdermal, subcutaneous, epicutaneous, intradermal, oral, intranasal, intratracheal, sublingual, buccal, rectal, vaginal, intravenous, intraarterial, intramuscular, intraosseous, intracardial, intraperitoneal, transmucosal, intravitreal, subretinal, intraarticular, peri-articular, intratumoral, local, or inhaled administration.
29. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is suitable for intratumoral administration.
30. The pharmaceutical composition of claim 17 , wherein the recombinant herpes simplex virus genomes comprise the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within the same viral gene locus.
31. The pharmaceutical composition of claim 30 , wherein the viral gene locus is an ICP4 viral gene locus.
32. The pharmaceutical composition of claim 17 , wherein the recombinant herpes simplex virus genomes comprise the polynucleotide encoding the IL-12 polypeptide and the polynucleotide encoding the IL-2 polypeptide within different viral gene loci.