Immunostimulatory agents in combination with angiogenesis inhibitors
The invention provides compositions and methods of treating cancer in a patient with a combination therapy comprising administering to the patient a fusion protein of SEQ ID NO: 1, in combination with an angiogenesis inhibitor (e.g., an anti-VEGF antibody or lenvatinib).
1. A method of treating cancer in a patient in need thereof, the method comprising:
i) Administering to the patient a therapeutically effective amount of a fusion protein of SEQ ID NO: 1 and
ii) Administering to the patient a therapeutically effective amount of lenvatinib;
wherein step (i) is carried out simultaneously with step (ii).
2. The method of claim 1 , wherein an effective amount of the fusion protein of SEQ ID NO: 1 is an amount effective to activate the IL-2 intermediate receptor, IL-2Rβγ.
3. The method of claim 1 , wherein the fusion protein of SEQ ID NO: 1 is administered by intravenous or subcutaneous injection.
4. The method of claim 1 , wherein the lenvatinib inhibits more than one receptor tyrosine kinase.
5. The method of claim 4 , wherein the lenvatinib inhibits one or more of the following receptor tyrosine kinases: vascular endothelial growth factor receptors types 1, 2, and 3; platelet derived growth factor receptors, types alpha and beta platelet derived growth factor receptors, and fibroblast growth factor receptors, types 1, 2, and 3.
6. The method of claim 1 , wherein lenvatinib is administered orally.
7. The method of claim 1 , wherein the combination of steps (i) and (ii) results in an increase in CD8+ T cells in the tumors and spleen of the patient as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
8. The method of claim 7 , wherein the increase in CD8+ T cells is at least 2-fold greater as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
9. The method of claim 7 , wherein there is no increase in CD4+ T regulatory (T regs ) cells or conventional CD4 + T cells in the patient.
10. The method of claim 1 , wherein the combination of steps (i) and (ii) results in an increase in CD8+ T cells and dendritic cells in the tumors and spleen of the patient and a decrease in tumor associated macrophages in the patient as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
11. The method of claim 10 , wherein there is no increase in CD4+ T regulatory (T regs ) cells in the patient.
12. The method of claim 11 , wherein the combination of steps (i) and (ii) results in an increase in CD8+ T cells and dendritic cells in the tumors and spleen of the patient and a decrease in tumor-associated macrophages in the patient as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
13. The method of claim 1 , wherein the progression free survival of the patient is increased by at least about 10% as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
14. The method of claim 1 , wherein the combination of steps (i) and (ii) results in greater expression of genes associated with cytotoxic immune cell function, T cell activation, and antigen presentation as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
15. The method of claim 1 wherein the combination of steps (i) and (ii) results in a decrease in Esm1 expression, and increased expression of Type I interferon and Type II interferon-associated genes as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.
16. The method of claim 1 , wherein the combination of steps (i) and (ii) results in changes in expression of a greater total number of genes as compared to administration of a therapeutically effective amount of the fusion protein of SEQ ID NO: 1 as a monotherapy or administration of a therapeutically effective amount of the lenvatinib as a monotherapy.