Therapeutic RNA

A method for treating, or reducing the likelihood of, a solid tumor comprising administering to a subject in need thereof a composition comprising RNA encoding an IL-12sc protein, RNA encoding an IL-15 sushi protein, RNA encoding an IFNα protein, and RNA encoding a GM-CSF protein, wherein each RNA comprises a modified nucleoside in place of each uridine, wherein the modified nucleoside is pseudouridine (ψ), N1-methyl-pseudouridine (m1ψ), 5-methyl-uridine (m5U), or a combination thereof, and wherein

• the IL-12sc protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:
• 14;
• the IL-15 sushi protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:
• 24
• the IFNα protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:
• 19;
• and
• the GM-CSF protein comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO:
• 27.

A method for treating, or reducing the likelihood of, a solid tumor comprising administering to a subject in need thereof a composition comprising RNA encoding an IL-12sc protein, RNA encoding an IL-15 sushi protein, RNA encoding an IFNα protein, and RNA encoding a GM-CSF protein, wherein the coding sequence of the RNA encoding an IL-12sc protein consists of the sequence of SEQ ID NO:

• 18 with an N1-methyl-pseudouridine (m1ψ) in place of each uridine, the coding sequence of the RNA encoding an IL-15 sushi protein consists of the sequence of SEQ ID NO:
• 26 with an N1-methyl-pseudouridine (m1ψ) in place of each uridine, the coding sequence of the RNA encoding an IFNα protein consists of the sequence of SEQ ID NO:
• 23 with an N1-methyl-pseudouridine (m1ψ) in place of each uridine, and the coding sequence of the RNA encoding a GM-CSF protein consists of the sequence of SEQ ID NO:
• 29 with an N1-methyl-pseudouridine (m1ψ) in place of each uridine,
• wherein each of the RNAs comprises:
• a 5′ cap comprising m27,3′-OGppp(m12′-O)ApG or 3′-O-Me-m7G(5′)ppp(5′)G;
• a 5′ UTR comprising the nucleotide sequence of SEQ ID NO:
• 2, 4, or 6;
• a 3′ UTR comprising the nucleotide sequence of SEQ ID NO:
• 8;
• and
• a poly-A tail comprising the nucleotide sequence of SEQ ID NO:
• 78;
• and
• wherein the molar ratio or weight ratio of the RNAs in the composition is 1:1:1:1.