Concatemeric peptide epitope rnas

Abstract

The invention relates to concatemeric peptide epitope RNAs, as well as methods and compositions thereof. mRNA vaccines are also provided according to the invention, including cancer vaccines.

1 - 77 . (canceled) 
     
     
         78 . A method of treating cancer in a subject, the method comprising:
 administering to a subject having cancer (i) a lipid delivery vehicle comprising a personalized cancer vaccine and (ii) an immune checkpoint inhibitor,   wherein the personalized cancer vaccine comprises an mRNA comprising an open reading frame encoding a concatemeric cancer antigen comprising 2-100 peptide epitopes arranged to minimize pseudo-epitopes.   
     
     
         79 . The method of  claim 78 , wherein at least 30% of the peptide epitopes in the mRNA are MHC class I epitopes. 
     
     
         80 . The method of  claim 78 , wherein each peptide epitope encoded by the mRNA comprises 31 amino acids and includes a centrally located mutation encoded by a SNP with 15 flanking amino acids on each side of the SNP-encoded mutation. 
     
     
         81 . The method of  claim 78 , wherein the peptide epitopes encoded by the mRNA are T cell epitopes and/or B cell epitopes. 
     
     
         82 . The method of  claim 81 , wherein the T cell epitope comprises between 8-11 amino acids. 
     
     
         83 . The method of  claim 81 , wherein the B cell epitope comprises between 13-17 amino acids. 
     
     
         84 . The method of  claim 78 , wherein the lipid delivery vehicle is a lipid nanoparticle comprising an ionizable cationic lipid, a non-cationic lipid, a sterol, and a PEG-modified lipid. 
     
     
         85 . The method of  claim 84 , wherein the lipid nanoparticle carrier comprises a molar ratio of about 20-60% ionizable cationic lipid; 5-25% non-cationic lipid; 25-55% sterol; and 0.5-15% PEG-modified lipid. 
     
     
         86 . The method of  claim 78 , wherein the lipid delivery vehicle is a liposome. 
     
     
         87 . The method of  claim 78 , wherein the lipid delivery vehicle is a lipoplex. 
     
     
         88 . The method of  claim 78 , wherein the lipid delivery vehicle comprising the personalized cancer vaccine and the immune checkpoint inhibitor are administered in separate compositions. 
     
     
         89 . The method of  claim 78 , wherein the immune checkpoint inhibitor binds to PD-1, TIM-3, VISTA, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, or LAG3. 
     
     
         90 . The method of  claim 89 , wherein the immune checkpoint inhibitor is an antibody. 
     
     
         91 . The method of  claim 90 , wherein the immune checkpoint inhibitor binds to PD-1. 
     
     
         92 . The method of  claim 78 , wherein the immune checkpoint inhibitor is Pembrolizumab. 
     
     
         93 . The method of  claim 78 , wherein at least 30% of the epitopes encoded by the mRNA are MHC class II epitopes. 
     
     
         94 . The method of  claim 78 , wherein one or more of the 2-100 peptide epitopes are interspersed by a linker. 
     
     
         95 . The method of  claim 94 , wherein the linker is a single amino acid linker. 
     
     
         96 . The method of  claim 78 , wherein the 2-100 peptide epitopes comprising the concatemeric cancer antigen are directly linked to each other. 
     
     
         97 . The method of  claim 78 , wherein each peptide epitope encoded by the mRNA comprises 25-35 amino acids and includes a centrally located mutation encoded by a single nucleotide polymorphism (SNP). 
     
     
         98 . The method of  claim 78 , wherein at least 50% of the peptide epitopes encoded by the mRNA have a predicted binding affinity of IC >500 nM for HLA-A, HLA-B and/or DRB1.