MRNA COMBINATION THERAPY FOR THE TREATMENT OF CANCER
The present disclosure relates to the use of nucleic acid (e.g., mRNA) combination therapies for the treatment of cancer. The disclosure provides compositions, and methods for their preparation, manufacture, and therapeutic use, wherein those compositions comprise at least two polynucleotides (e.g., mRNAs) in combination wherein the at least two polynucleotides are selected from the group consisting of (i) a polynucleotide encoding an immune response primer (e.g., IL23), (ii) a polynucleotide encoding an immune response co-stimulatory signal (e.g., OX40L), (iii) a polynucleotide encoding a checkpoint inhibitor (e.g., an anti CTLA-4 antibody), and, (iv) a combination thereof. The therapeutic methods disclosed herein comprise, e.g., the administration of a combination therapy disclosed herein for the treatment of cancer, e.g., by reducing the size of a tumor or inhibiting the growth of a tumor, in a subject in need thereof. In some aspects, the combination therapies disclosed herein disclosed are administered intratumorally.
1 - 183 . (canceled)
184 . A method for increasing immune cell activation in a subject, comprising administering to the subject a lipid nanoparticle (LNP) comprising a messenger RNA (mRNA), wherein the mRNA comprises an open reading frame (ORF) encoding a fusion protein comprising a human IL-15 polypeptide and a human IL-15Rα extracellular domain or portion thereof, and wherein the LNP comprises an ionizable amino lipid, a phospholipid, a sterol, and a PEG-modified lipid, thereby increasing immune cell activation in the subject.
185 . The method of claim 184 , wherein the IL-15Rα extracellular domain or portion thereof comprises a sushi domain.
186 . The method of claim 184 , wherein the IL-15 polypeptide and the IL-15Rα extracellular domain or portion thereof are fused directly or by a linker.
187 . The method of claim 184 , wherein the mRNA comprises uridine nucleosides and the uridine nucleosides are chemically-modified.
188 . The method of claim 187 , wherein the chemically-modified nucleosides are N1-methylpseudouridines (m1ψ).
189 . The method of claim 184 , wherein the mRNA comprises a microRNA (miR) binding site.
190 . The method of claim 184 , wherein the LNP comprises a molar ratio of 40-60% ionizable amino lipid, 8-16% phospholipid, 30-45% sterol, and 1-5% PEG-modified lipid.
191 . The method of claim 190 , wherein the ionizable amino lipid comprises
192 . The method of claim 184 , wherein the LNP comprises a molar ratio of 45-65% ionizable amino lipid, 5-10% phospholipid, 25-40% sterol, and 0.5-5% PEG-modified lipid.
193 . The method of claim 192 , wherein the ionizable amino lipid comprises Compound 25.
194 . A method for increasing immune cell activation in a subject, comprising administering to the subject an LNP comprising an mRNA, wherein the mRNA comprises an ORF encoding a fusion protein comprising a human IL-15 polypeptide and a human IL-15Rα sushi domain, wherein the human IL-15Rα sushi domain comprises amino acids 37 to 107 of SEQ ID NO: 808, and wherein the LNP comprises an ionizable amino lipid, a phospholipid, a sterol, and a PEG-modified lipid, thereby increasing immune cell activation in the subject.
195 . The method of claim 194 , wherein the IL-15 polypeptide comprises amino acids 30 to 162 of SEQ ID NO: 810.
196 . The method of claim 194 , wherein the IL-15 polypeptide and the IL-15Rα sushi domain are fused directly or by a linker.
197 . The method of claim 194 , wherein the mRNA comprises uridine nucleosides and the uridine nucleosides are chemically-modified.
198 . The method of claim 197 , wherein the chemically-modified nucleosides are N1-methylpseudouridines (m1ψ).
199 . The method of claim 194 , wherein the mRNA comprises a miR binding site.
200 . The method of claim 194 , wherein the LNP comprises a molar ratio of 40-60% ionizable amino lipid, 8-16% phospholipid, 30-45% sterol, and 1-5% PEG-modified lipid.
201 . The method of claim 200 , wherein the ionizable amino lipid comprises Compound 25.
202 . The method of claim 194 , wherein the LNP comprises a molar ratio of 45-65% ionizable amino lipid, 5-10% phospholipid, 25-40% sterol, and 0.5-5% PEG-modified lipid.
203 . The method of claim 202 , wherein the ionizable amino lipid comprises Compound 25.
204 . An LNP comprising an mRNA, wherein the mRNA comprises an ORF encoding a fusion protein comprising a human IL-15 polypeptide and a human IL-15Rα extracellular domain or portion thereof, and wherein the LNP comprises an ionizable amino lipid, a phospholipid, a sterol, and a PEG-modified lipid.