COMBINATION THERAPY USING A CHEMOKINE RECEPTOR 2 (CCR2) ANTAGONIST AND A PD-1 AND/OR PD-L1 INHIBITOR
The present disclosure is drawn to the combination therapy of a Chemokine Receptor 2 (CCR2) antagonist and a PD-1 and/or PD-L1 inhibitor in the treatment of a central nervous system cancer.
1 . A method of treating a glioma in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a compound of formula (Ic):
or a pharmaceutically acceptable salt thereof, and a PD-1 and/or PD-L1 inhibitor selected from nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab, wherein:
X 3 and X 4 are each independently selected from the group consisting of hydrogen, halogen, unsubstituted C 1-8 alkyl, and C 1-8 haloalkyl;
Y 9 is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-8 alkyl; and
Y 11 is CH—, —N—, or −N + (O) − —.
2 . The method of claim 1 , wherein the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
3 . The method of claim 1 , wherein the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
4 . The method of claim 1 , wherein the compound of Formula (Ic) or a pharmaceutically acceptable salt thereof is
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 1 , wherein the glioma is a glioblastoma.
6 . The method of claim 1 , wherein the glioma is characterized as being CCR2 + .
7 . The method of claim 1 , wherein the administering promotes a decrease in CD45 hi /CD11b + /Ly6C hi cells in a tumor microenvironment and promotes an increase in CD45 hi /CD11b + /Ly6C hi cells in bone marrow.
8 . The method of claim 1 , wherein the administering promotes an infiltration of a population of T-cells into a tumor microenvironment in the subject.
9 . The method of claim 8 , wherein the population of T-cells comprises a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD4 + .
10 . The method of claim 8 , wherein the population of T-cells comprises a subpopulation of T-cells characterized as being CD45 + /CD3 + /CD8 + .
11 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is provided as a pharmaceutical composition for oral administration.
12 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is from 50 mg to 300 mg.
13 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, and the PD-1 and/or PD-L1 inhibitor are administered concomitantly.
14 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, and the PD-1 and/or PD-L1 inhibitor are administered in a combination formulation.
15 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, and the PD-1 and/or PD-L1 inhibitor are administered sequentially.
16 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is administered prior to the administration of the PD-1 and/or PD-L1 inhibitor.
17 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is administered after the administration of the PD-1 and/or PD-L1 inhibitor.
18 . The method of claim 1 , wherein the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, is administered orally and the PD-1 and/or PD-L1 inhibitor is administered intravenously.
19 . The method of claim 1 , wherein the subject is a human subject.
20 . The method of claim 1 , wherein the compound of formula (Ic), or a pharmaceutically acceptable salt thereof, is administered at a dosage of about 0.001 to about 100 mg/kg.
21 . The method of claim 1 , wherein:
X 3 is C 1-8 haloalkyl; and
X 4 is halogen or unsubstituted C 1-8 alkyl.
Y 9 is halogen or unsubstituted C 1-8 alkyl; and
Y 11 is —CH— or —N—.
22 . The method of claim 1 , wherein:
X 3 is CF 3 ;
X 4 is Cl or CH 3 ; and
Y 9 is Cl or CH 3 .
23 . The method of claim 1 , wherein the glioma is an immune checkpoint inhibitor resistant glioma.
24 . The method of claim 1 , wherein the administering increases the durability of overall response to treatment.
25 . The method of claim 1 , wherein the administering reduces exhaustion in intratumoral T-cells.