Methods of CD40 and toll like receptor immune activation
Provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of a TLR agonist and a chimeric CD154 polypeptide. Also provided herein are methods of enhanced immune function.
1. A method of enhancing function of an immune cell in a subject comprising: administering to the subject a combination of a chimeric CD154 polypeptide and at least one Toll Like Receptor (TLR) agonist, wherein said chimeric CD154 polypeptide comprises (a) an extracellular subdomain of human CD154 that binds to a human CD154 receptor and (b) an extracellular subdomain of non-human CD154 that has replaced a cleavage site of human CD154; and wherein said subject is not administered an antibody, antibody fragment, or antigen binding molecule targeting GITR.
2. The method of claim 1 , wherein the at least one TLR agonist is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, and TLR7/8 agonists.
3. The method of claim 1 , wherein the extracellular subdomain of non-human CD154 is an extracellular subdomain of murine CD154.
4. The method of claim 1 , wherein the chimeric CD154 polypeptide is selected from the group consisting of ISF30, ISF31, ISF32, ISF33, ISF34, ISF35, ISF36, ISF37, ISF38, ISF39, ISF40, and ISF41.
5. The method of claim 1 , wherein the chimeric CD154 polypeptide is ISF35.
6. The method of claim 1 , wherein the chimeric CD154 polypeptide is administered to a subject by providing a coding region for the chimeric CD154 polypeptide in an expression vector under control of a promoter active in a eukaryotic cell.
7. The method of claim 6 , wherein the expression vector is a viral vector.
8. The method of claim 7 , wherein the viral vector is an adenoviral vector, a retroviral vector, a pox viral vector, a herpesviral vector, an adeno-associated viral vector, or a polyoma viral vector.
9. The method of claim 8 , wherein the viral vector is an adenoviral vector.
10. A method of treating cancer in a subject comprising:
(a) removing one or more immune cells from the subject;
(b) culturing said immune cells with one or more eukaryotic cells containing a coding region for a chimeric CD154 polypeptide in an expression vector under control of a promoter active in the eukaryotic cells under conditions supporting expression of the CD154 polypeptide;
(c) administering at least a portion of said cultured immune cells back into the subject; and
(d) administering an effective amount of at least one Toll Like Receptor (TLR) agonist, wherein said subject is not administered an antibody, antibody fragment, or antigen binding molecule targeting GITR.