Methods of treating solid tumors with CCR2 antagonists
The present disclosure provides, inter alia, methods of treating a solid-tumor by administering an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. Also provided herein are methods of reducing the number of macrophages in a solid tumor microenvironment, said method comprising administering effective amount of a Chemokine Receptor 2 (CCR2) antagonist. In an additional aspect, the current disclosure further provides methods of increasing the number CD8+ T cells in a solid tumor microenvironment, said method comprising administering effective amount of a Chemokine Receptor 2 (CCR2) antagonist. In some embodiments, the CCR2 antagonist has the formula I:
1. A method of treating cutaneous T cell lymphoma (CTCL), said method comprising administering to a subject in need thereof an effective amount of a Chemokine Receptor 2 (CCR2) antagonist, wherein said CCR2 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 g 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 subject in need thereof has Stage IA CTCL.
3. The method of claim 1 , wherein the subject in need thereof has Stage IB CTCL.
4. The method of claim 1 , wherein the subject in need thereof has Stage IIA CTCL.
5. The method of claim 1 , wherein the subject in need thereof has Stage IIB CTCL.
6. The method of claim 1 , wherein the subject in need thereof has Stage III CTCL.
7. The method of claim 1 , wherein the subject in need thereof has Stage IV CTCL.
8. The method of claim 1 , wherein said CCR2 antagonist is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein said CCR2 antagonist has the formula of Compound 1
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein said CCR2 antagonist has the formula of Compound 2
or a pharmaceutically acceptable salt thereof.
11. The method of claim 1 , further comprising administering one or more additional therapeutic agents.
12. The method of claim 11 , wherein the one or more additional therapeutic agents is an immune-checkpoint inhibitor.
13. The method of claim 12 , wherein the immune-checkpoint inhibitor is a PD-1 and/or PD-L1 inhibitor.
14. The method of claim 13 , wherein the PD-1 and/or PD-L1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, and STI-1110.
15. The method of claim 13 , wherein the PD-1 and/or PD-L1 inhibitor is selected from the group consisting of Nivolumab, Pembrolizumab, and Pidilizumab.
16. The method of claim 13 , wherein the PD-1 and/or 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.