Methods and compositions comprising enhanced targeted immune gene therapy for the treatment of cancer
Provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of an adenoviral vector with a genetically modified fiber incorporating a Lyp-1 peptide motif and at least one CD122/CD132 agonist and/or an immune checkpoint inhibitor.
1 . A pharmaceutical composition comprising (a) Lyp-1 chimeric adenovirus particles encoded by a chimeric adenovirus E1A 01/07 mutant vector comprising a genetically modified fiber gene encoding a fiber incorporating a LyP-1 peptide within the HI loop of the fiber, wherein the vector encodes a soluble TGFβ receptor II Fc fusion protein (sTGFβRIIFc) and Adenoviral 5/Adenoviral 48 (Ad5/48) chimeric hexon, (b) at least one CD122/CD132 agonist selected from the group consisting of an IL-2/anti-IL-2 immune complex, an IL-15/anti-IL-15 immune complex, an IL-15/IL-15 Receptor α-IgG1-Fc (IL-15/IL-15Rα-IgG1-Fc) immune complex, PEGylated IL-2, PEGylated IL-15, IL-2 mutein and/or IL-15 mutein, and (c) at least one immune checkpoint inhibitor.
2 . The composition of claim 1 , wherein the vector further comprises a heterologous gene.
3 . The composition of claim 2 , wherein the heterologous gene encodes a soluble decoy receptor, tumor suppressor, an immune stimulating sequence, anti-angiogenic sequence, prodrug activating sequence, proapoptotic sequence, chemotherapy sensitizing sequence, radiation sensitizing sequence, miRNA, siRNA, anti-sense RNA, ribozyme or clustered regularly interspaced short palindromic repeats (CRISPR) gene editing sequence.
4 . The composition of claim 3 , wherein the heterologous gene encodes melanoma differentiation associated gene-7 (MDA-7) and/or p53.
5 . The pharmaceutical composition of claim 1 , wherein the at least one checkpoint inhibitor is selected from an inhibitor of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3, KIR, or A2aR.
6 . The pharmaceutical composition of claim 1 , wherein the at least one CD122/CD132 agonist is selected from the group consisting of an IL-2/anti-IL-2 immune complex, an IL-15/anti-IL-15 immune complex, and an IL-15/IL-15 Receptor α-IgG1-Fc (IL-15/IL-15Rα-IgG1-Fc) immune complex, and the at least one immune checkpoint inhibitor is selected from an inhibitor of CTLA-4, PD-1, and PD-L1.