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.
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 the fusion protein of SEQ ID NO: 1; and
ii) administering to the patient a therapeutically effective amount of an angiogenesis inhibitor;
wherein step (i) is carried out before, after or 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 angiogenesis inhibitor inhibits more than one receptor tyrosine kinase.
5 . The method of claim 4 , wherein the angiogenesis inhibitor 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 the angiogenesis inhibitor is a compound of Formula I
7 . The method of claim 6 , wherein Formula I is administered orally.
8 . 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 variant of the fusion protein of SEQ ID NO: 1 wherein the variant is at least 80% identical to SEQ ID NO: 1; and
ii) administering to the patient a therapeutically effective amount of an angiogenesis inhibitor;
wherein step (i) carried out before, after or simultaneously with step (ii).
9 . The method of claim 1 , wherein an effective amount of the variant fusion protein is an amount effective to activate the IL-2 intermediate receptor, IL-2Rβγ.
10 . The method of claim 8 , wherein the variant fusion protein is administered by intravenous or subcutaneous injection.
11 . The method of claim 8 , wherein the angiogenesis inhibitor inhibits more than one receptor tyrosine kinase.
12 . The method of claim 11 , wherein the angiogenesis inhibitor 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.
13 . The method of claim 8 , wherein the angiogenesis inhibitor is a compound of Formula I
14 . The method of claim 13 , wherein Formula I is administered orally.
15 . The method of claim 8 , wherein the variant fusion protein is at least 90% identical to the fusion protein of SEQ ID NO: 1.
16 . The method of claim 8 , wherein the variant fusion protein is at least 98% identical to the fusion protein of SEQ ID NO: 1.
17 . 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 an angiogenesis inhibitor as a monotherapy.
18 . The method of claim 17 , 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 an angiogenesis inhibitor as a monotherapy.
19 . The method of claim 17 , wherein there is no increase in CD4+ T regulatory (T regs ) cells or conventional CD4 + T cells in the patient.
20 . The method of claim 17 , 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 an angiogenesis inhibitor as a monotherapy.
21 . The method of claim 1 , wherein the combination of steps (i) and (ii) results in an increase 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 an angiogenesis inhibitor as a monotherapy.
22 . The method of claim 21 , 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 an angiogenesis inhibitor as a monotherapy.
23 . The method of claim 21 , wherein there is no increase in CD4+ T regulatory (T regs ) cells in the patient.
24 . The method of claim 21 , 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 an angiogenesis inhibitor as a monotherapy.
25 . 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 an angiogenesis inhibitor as a monotherapy.
26 . 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 an angiogenesis inhibitor as a monotherapy.
27 . 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 an angiogenesis inhibitor as a monotherapy.
28 . 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 an angiogenesis inhibitor as a monotherapy.
29 . A method of treating cancer in a patient in need thereof, the method comprising:
i) administering to the patient a therapeutically effective amount of the fusion protein of SEQ ID NO: 1; and
ii) administering to the patient a therapeutically effective amount of lucitanib;
wherein step (i) is carried out before, after or simultaneously with step (ii).
30 . The method of claim 28 , wherein lucitanib is represented by a compound of Formula I