Combination therapy using a chemokine receptor 2 (CCR2) antagonist and a PD-1/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 cancer.
1. A method of treating colorectal cancer in a mammal, said method comprising administering a therapeutically effective amount of a CCR2 chemokine receptor antagonist and a therapeutically effective amount of a PD-1 and/or PD-L1 inhibitor, wherein said CCR2 chemokine receptor antagonist is a compound of Formula (Ia4)
or a pharmaceutically acceptable salt thereof; wherein
the subscripts m and n are each independently 1;
R 3 is selected from the group consisting of C 1-8 alkyl and C 3-8 cycloalkyl;
R 4 is selected from the group consisting of H and C 1-8 alkyl;
the subscript p is 1 or 2;
each R x is independently selected from the group consisting of halogen, —R c , —OR a , —O—X 1 —OR a , and —X 1 —OR a , wherein each X 1 is a C 1-4 alkylene; each R a is selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R c is independently selected from the group consisting of C 1-8 alkyl and C 1-8 haloalkyl;
the subscript q is 1 or 2;
each R z is independently selected from the group consisting of halogen, —R i , —CO 2 R g , and tetrazole; wherein each R 9 is selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; each R i is independently selected from the group consisting of C 1-8 alkyl, and C 1-8 haloalkyl.
2. The method of claim 1 , wherein the said CCR2 inhibitor has the formula
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein said CCR2 inhibitor has the formula
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein said CCR2 inhibitor has the formula
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein said PD-1 and/or PD-L1 inhibitor is a PD-1 inhibitor.
6. The method of claim 5 wherein the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MED-0680, SHR-1210, PF-06801591, PDR-001, GB-226, and STI-1110.
7. The method of claim 5 , wherein the PD-1 inhibitor is selected from the group consisting of Nivolumab, Pembrolizumab, and Pidilizumab.
8. The method of claim 1 , wherein said PD-1 and/or PD-L1 inhibitor is a PD-L1 inhibitor.
9. The method of claim 8 , wherein the PD-L1 inhibitor is selected from the group consisting of durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, CA-327, STI-1014, and KY-1003.
10. The method of claim 1 , wherein the CCR2 chemokine receptor antagonist and the PD-1 inhibitor and/or the PD-L1 inhibitor are administered concomitantly.
11. The method of claim 10 , wherein the CCR2 chemokine receptor antagonist, and the PD-1 inhibitor and/or the PD-L1 inhibitor are administered in a combination formulation.
12. The method of claim 1 , wherein the CCR2 chemokine receptor antagonist, and the PD-1 inhibitor and/or the PD-L1 inhibitor are administered sequentially.
13. The method of claim 12 , wherein the CCR2 chemokine receptor antagonist is administered prior to administration of the PD-1 inhibitor and/or the PD-L1 inhibitor.
14. The method of claim 12 , wherein the CCR2 chemokine receptor antagonist is administered after the administration of the PD-1 inhibitor and/or the PD-L1 inhibitor.
15. The method of claim 1 , wherein the CCR2 chemokine receptor antagonist is administered orally and the PD-1 inhibitor and/or the PD-L1 inhibitor is administered intravenously.
16. The method of claim 1 , wherein the mammal is a human subject.