Reducing tumor burden by administering CCR1 antagonists in combination with PD-1 inhibitors or PD-L1 inhibitors
The present invention provides methods for reducing tumor burden, tumor growth, tumor progression, and/or metastasis in a subject suffering from a solid tumor cancer such as triple negative breast cancer. The methods include administering to a subject in need thereof a therapeutically effective amount of a PD-L1 inhibitor or a PD-1 inhibitor in combination with a small molecule chemokine receptor antagonist that blocks CCR1.
1. A method for treating a subject having a solid tumor expressing PD-L1, said method comprising administering to the subject in need thereof a therapeutically effective amount of a CCR1 chemokine receptor antagonist, and a therapeutically effective amount of a PD-L1 inhibitor
wherein the CCR1 chemokine receptor antagonist has the formula (IIIb1a):
wherein each A is N or CH and at least one A is N; R 1 is halogen; R 3 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl and C 2-8 alkenyl; and R 8 is C 1-8 alkyl; or a pharmaceutically acceptable salt thereof, and
wherein the solid tumor is triple negative breast cancer.
2. The method of claim 1 , wherein the CCR1 chemokine receptor antagonist is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 or claim 2 , 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.
4. The method of claim 1 or claim 2 , wherein the CCR1 chemokine receptor antagonist and the PD-L1 inhibitor are administered concomitantly.
5. The method of claim 4 , wherein the CCR1 chemokine receptor antagonist, and the PD-L1 inhibitor are administered in a combination formulation.
6. The method of claim 1 or claim 2 , wherein the CCR1 chemokine receptor antagonist, and the PD-L1 inhibitor are administered sequentially.
7. The method of claim 6 , wherein the CCR1 chemokine receptor antagonist is administered prior to administration of the PD-L1 inhibitor.
8. The method of claim 6 , wherein the CCR1 chemokine receptor antagonist is administered after the administration of the PD-L1 inhibitor.
9. The method of claim 1 or claim 2 , wherein the CCR1 chemokine receptor antagonist is administered orally and the PD-L1 inhibitor is administered intravenously.
10. The method of claim 1 or claim 2 , wherein the subject is a human subject.