Vaccine compositions comprising an amphipathic compound, a neoantigen and a hydrophobic carrier, and methods of use thereof
The present application relates to vaccine compositions comprising an amphipathic compound, a neoantigen and a hydrophobic carrier. Further described are methods and use of the vaccine composition for inducing an antibody immune response and/or a cell-mediated immune response to the neoantigen, as well as methods and uses of the vaccine compositions in the treatment of cancer.
1. A vaccine composition comprising:
(a) a lipid molecule mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol;
(b) a neoantigen;
(c) mannide oleate in mineral oil solution;
(d) a T-helper epitope; and
(e) a polyI:C polynucleotide adjuvant,
wherein the composition is water-free or substantially free of water, wherein substantially free of water comprises less than about 10% water on a weight/weight basis of the total weight of the carrier,
wherein the composition generates an enhanced cell-mediated immune response that is at least 2-fold greater than when the neoantigen is formulated in an aqueous-based vaccine formulation, and wherein the enhanced cell-mediated immune response is provided by only a single immunization with the composition.
2. The composition of claim 1 , wherein a composition that is substantially free of water comprises less than about 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% water on a weight/weight basis of the total weight of the carrier.
3. The composition of claim 1 , wherein the neoantigen is a neoantigenic peptide or a polynucleotide encoding a neoantigenic peptide.
4. The composition of claim 3 , wherein the neoantigenic peptide is 5 to 50 amino acids in length.
5. The composition of claim 3 , wherein the neoantigenic peptide comprises one or more neoepitopes.
6. The composition of claim 5 , wherein the one or more neoepitopes are selected from: an MHC class I T-cell neoepitope of 9 to 11 amino acids in length; an MHC class II T-cell neoepitope of 13 to 17 amino acids in length; or a B-cell neoepitope of 5 to 20 amino acids in length.
7. The composition of claim 1 , wherein the neoantigen comprises the amino acid sequence PSKPSFQEFVDWENVSPELNSTDQPFL (SEQ ID NO: 2).
8. The composition of claim 1 , wherein the neoantigen is a weakly immunogenic antigen.
9. The composition of claim 1 , wherein the composition comprises a low dose amount of the neoantigen.
10. The composition of claim 1 , wherein the neoantigen is sufficiently hydrophobic, or is made sufficiently hydrophobic, such that the neoantigen is miscible in the hydrophobic carrier.
11. The composition of claim 10 , wherein the neoantigen is made sufficiently hydrophobic by the presence of the amphipathic compound, wherein:
the amphipathic compound is closely associated with the neoantigen to make the neoantigen miscible in the hydrophobic carrier; and/or
the amphipathic compound forms a sheet or vesicular structure, partially or completely surrounding the neoantigen.
12. The composition of claim 1 , wherein the T-helper epitope is PADRE comprising the amino acid sequence AKXVAAWTLKAAA (SEQ ID NO: 6); Tetanus toxoid peptide F21E comprising the amino acid sequence FNNFTVSFWLRVPKVSASHLE (SEQ ID NO: 7); or modified Tetanus toxin peptide A16L comprising the amino acid sequence AQYIKANSKFIGITEL (SEQ ID NO: 1).
13. The composition of claim 1 , wherein the T-helper epitope is
a universal T-helper epitope from tetanus toxoid comprising the amino acid sequence AQYIKANSKFIGITEL (SEQ ID NO: 1).
14. The composition of claim 1 , which generates an enhanced cell-mediated immune response that is at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold or at least 10-fold greater than when the neoantigen is formulated in an aqueous-based vaccine formulation.
15. The composition of claim 14 , wherein the enhanced cell-mediated immune response is provided by a low dose amount of the neoantigen in the composition, wherein the low dose amount is about 50% of the dose amount in the aqueous-based vaccine formulation.
16. A method for inducing an antibody immune response and/or a cell-mediated immune response to a neoantigen, said method comprising administering the composition of claim 1 to a subject in need thereof.
17. The method of claim 16 which comprises only a single administration of the composition to the subject.
18. The method of claim 16 , wherein the composition comprises a low dose amount of the neoantigen.
19. The method according to claim 16 , which is a method for the treatment and/or prevention of cancer.
20. The method according to claim 16 , which further comprises administering to the subject an agent that interferes with DNA replication and/or an immune response checkpoint inhibitor.
21. The method according to claim 20 , wherein the agent that interferes with DNA replication is cyclophosphamide and the immune response checkpoint inhibitor is an inhibitor of Programmed Death-Ligand 1 (PD-L1), Programmed Death 1 (PD-1), CTLA-4, PD-L2, LAG3, TIM3, 41BB, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD160, CD226, CD276, DR3, GAL9, GITR, HVEM, IDO1, IDO2, inducible T cell costimulatory (ICOS), KIR, LAIR1, LIGHT, macrophage receptor with collageneous structure (MARCO), phosphatidylserine (PS), OX-40, SLAM, TIGIT, VISTA, VTCN1, or any combination thereof.
22. A kit comprising:
a first container comprising a lipid molecule mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol, a T-helper epitope, a polyI:C polynucleotide adjuvant, and a neoantigen; and
a second container comprising mannide oleate in mineral oil solution.