Combination cancer immunotherapy with pentaaza macrocyclic ring complex

1 . A method of treating a cancer in a mammalian subject afflicted with the cancer, the method comprising:

administering to the subject an immune checkpoint inhibitor, wherein the checkpoint inhibitor is at least one of an anti-CTLA4 antibody, an anti-PD-1 antibody and an anti-PDL-1 antibody;

administering to the subject a pentaaza macrocyclic ring complex corresponding to the formula (II) below, prior to, concomitantly with, or after administration of the immune checkpoint inhibitor, to increase the response of the cancer to the immune checkpoint inhibitor, and

administering a further therapy prior to, concomitantly with, or after administration of either of the immune checkpoint inhibitor and pentaaza macrocyclic ring complex, the further therapy comprising any of (i) chemotherapy and (ii) an immunotherapeutic agent other than the immune checkpoint inhibitor,

wherein the pentaaza macrocylic ring complex corresponding to formula (II) comprises the following structure:

wherein

X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; and

R A , R B , R C , and R D are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of —OR 11 , —NR 11 R 12 , —COR 11 , —CO 2 R 11 , —CONR 11 R 12 , —SR 11 , —SOR 11 , —SO 2 R 11 , —SO 2 NR 11 R 12 , —N(OR 11 )(R 12 ), —P(O)(OR 11 )(OR 12 ), —P(O)(OR 11 )(R 12 ), and —OP(O)(OR 11 )(OR 12 ), wherein Ru and R 12 are independently hydrogen or alkyl, and wherein substituted hydrocarbyl means a hydrocarbyl group that is substituted with one, two or three substitutents independently selected from alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl, or organosulfur.

2 . The method according to claim 1 , wherein the further therapy comprises any of an anti-cancer antibody, an anti-cancer cytokine and other cancer treating agent.

3 . The method according to claim 2 , wherein the anti-cancer cytokine comprises IL-2.

4 . The method according to claim 1 , wherein the pentaaza macrocyclic ring complex is represented by formula (III) or formula (IV):

wherein

X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; and

R A , R B , R C , and R D are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of —OR 11 , —NR 11 R 12 , —COR 11 , —CO 2 R 11 , —CONR 11 R 12 , —SR 11 , —SOR 11 , —SO 2 R 11 , —SO 2 NR 11 R 12 , —N(OR 11 )(R 12 ), —P(O)(OR 11 )(OR 12 ), —P(O)(OR 11 )(R 12 ), and —OP(O)(OR 11 )(OR 12 ), wherein Ru and R 12 are independently hydrogen or alkyl.

5 . The method according to claim 1 , wherein the pentaaza macrocyclic ring complex is a compound represented by a formula selected from the group consisting of formulae (V)-(XVI):

6 . The method according to claim 1 , wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions.

7 . The method according to claim 1 , wherein X and Y are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates and arylalkyl carboxylates.

8 . The method according to claim 1 , wherein X and Y are independently amino acids.

9 . The method according to claim 1 , wherein the pentaaza macrocyclic ring complex is a compound represented by a formula selected from the following group:

10 . The method according to claim 1 , wherein:

i) initial administration of the pentaaza macrocyclic ring complex in the course of therapy is no less than 3 days after initial administration of the immune checkpoint inhibitor; and/or

ii) initial administration of the pentaaza macrocyclic ring complex in the course of therapy follows two doses of the immune checkpoint inhibitor, and/or

iii) a further immune checkpoint inhibitor is administered that comprises one or more of a small molecular inhibitor, an antibody, an antigen binding fragment, and an Ig fusion protein.

11 . The method according to claim 1 :

i) comprising administering a further immune checkpoint inhibitor selected from the group consisting of areluman, IMP321, INCB024360, NLG-919, indoximod, galiximab, varlilumab, mogamulizumab, CP-870,893, MEDI-6469, IPH2101, urelumab, lirilumab, MGA271, anti-OX40, and BY55; and/or

ii) comprising administering an immune checkpoint inhibitor selected from the group consisting of ipilimumab, tremelimumab, nivolumab, pembrolizumab, pidilizumab, AMP-224, MDX-1106, AUNP 12, BMS-986016, MK-3475, CT-011, AMP224, BGB-A317, atezolizumab, MPDL3280A, MDX-1105, MEDI-4736, avelumab, BMS-936559, MSB0010718C; and/or

iii) further comprising administering one or more of an adoptive T-cell transfer and cancer vaccine to the subject, either prior to, concomitantly with, or after administration of one or more of the immune checkpoint inhibitor and pentaaza macrocyclic ring complex.

12 . The method according to claim 1 , wherein the cancer is selected from the group consisting of breast cancer, non-small-cell lung cancer, melanoma, renal cell carcinoma, urothelial carcinoma, bladder cancer, pancreatic cancer, head and neck cancers, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, and oral squamous cell carcinoma.

13 . The method according to claim 1 , wherein the pentaaza macrocyclic ring complex is administered:

i) to the subject in a dose in a range of from 0.2 mg/kg to 40 mg/kg; and/or

ii) parenterally, orally, intraperitoneally, subcutaneously, or intravenously.

14 . The method according to claim 1 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

15 . The method according to claim 1 , wherein the immune checkpoint inhibitor is an anti-CTLA4 antibody.

16 . The method according to claim 1 , wherein the immune checkpoint inhibitor is an anti-PDL-1 antibody.