Vaccine compositions comprising an amphipathic compound, a neoantigen and a hydrophobic carrier, and methods of use thereof

Abstract

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 - 41 . (canceled) 
     
     
         42 . A vaccine composition comprising:
 (a) an amphipathic compound selected from a phospholipid or a mixture of phospholipids;   (b) a neoantigen;   (c) a hydrophobic carrier selected from an oil, a mixture of oils, or a mannide oleate in mineral oil solution;   (d) a T-helper epitope; and   (e) a polyI:C polynucleotide adjuvant.   
     
     
         43 . The composition of  claim 42 , wherein the composition is water-free or substantially free of water, wherein a composition that is substantially free of water comprises less than about 10%, 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. 
     
     
         44 . The composition of  claim 42 , wherein the neoantigen is a neoantigenic peptide or a polynucleotide encoding a neoantigenic peptide. 
     
     
         45 . The composition of  claim 44 , wherein the neoantigenic peptide is 5 to 50 amino acids in length. 
     
     
         46 . The composition of  claim 44 , wherein the neoantigenic peptide comprises one or more neoepitopes. 
     
     
         47 . The composition of  claim 46 , 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. 
     
     
         48 . The composition of  claim 42 , wherein the neoantigen comprises the amino acid sequence PSKPSFQEFVDWENVSPELNSTDQPFL (SEQ ID NO: 2). 
     
     
         49 . The composition of  claim 42 , wherein the neoantigen is a weakly immunogenic antigen. 
     
     
         50 . The composition of  claim 42 , wherein the composition comprises a low dose amount of the neoantigen. 
     
     
         51 . The composition of  claim 42 , wherein the neoantigen is sufficiently hydrophobic, or is made sufficiently hydrophobic, such that the neoantigen is miscible in the hydrophobic carrier. 
     
     
         52 . The composition of  claim 51 , 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.   
     
     
         53 . The composition of  claim 42 , wherein the composition further comprises cholesterol. 
     
     
         54 . The composition of  claim 42 , wherein the polyI:C polynucleotide adjuvant is a DNA and/or RNA polyI:C polynucleotide adjuvant. 
     
     
         55 . The composition of  claim 42 , 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 FNNFTVSFWRVPKVSASHLE (SEQ ID NO: 7); or modified Tetanus toxin peptide A16L comprising the amino acid sequence AQYIKANSKFIGITEL (SEQ ID NO: 1). 
     
     
         56 . The composition of  claim 42 , which comprises:
 (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 universal T-helper epitope from tetanus toxoid comprising the amino acid sequence AQYIKANSKFIGITEL (SEQ ID NO: 1); and   (e) a polyI:C polynucleotide adjuvant.   
     
     
         57 . The composition of  claim 42 , which generates an enhanced cell-mediated immune response that is at least 2-fold, 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. 
     
     
         58 . The composition of  claim 57 , wherein the enhanced cell-mediated immune response is provided by only a single immunization with the composition. 
     
     
         59 . The composition of  claim 57 , 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. 
     
     
         60 . 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 42  to a subject in need thereof. 
     
     
         61 . The method of  claim 60  which comprises only a single administration of the composition to the subject. 
     
     
         62 . The method of  claim 60 , wherein the composition comprises a low dose amount of the neoantigen. 
     
     
         63 . The method according to  claim 60 , which is a method for the treatment and/or prevention of cancer. 
     
     
         64 . The method according to  claim 60 , which further comprises administering to the subject an agent that interferes with DNA replication and/or an immune response checkpoint inhibitor. 
     
     
         65 . The method according to  claim 64 , 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, 41BB, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD160, CD226, CD276, DR3, GALS, 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. 
     
     
         66 . A kit comprising:
 a first container comprising an amphipathic compound selected from a phospholipid or a mixture of phospholipids, a T-helper epitope, a polyI:C polynucleotide adjuvant, and a neoantigen; and   a second container comprising a hydrophobic carrier selected from an oil, a mixture of oils, or a mannide oleate in mineral oil solution.