Therapeutic compositions and methods for treating tumors

A method of halting or reversing progressive cancer in a subject, the method comprising:

• administering a compound of Formula (I),
• or a pharmaceutically acceptable salt thereof, wherein:
• R1, R4, and R6, are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1,-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, —CO—O—R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CH2CO—R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups;
• R1′ and R1″ are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, —CO—O—R7, cyano, alkylthio, halogenated alkyl including polyhalogenated alkyl, halogenated carbonyl, and carbonyl —CH2CO—R7, wherein R7 is selected from a hydrogen atom, a halogen atom, and saturated C1-C24 alkyl, unsaturated C1-C24 alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups;
• R, R1′ and R1″ are either covalently bound to one another or are not covalently bound to one another;
• R2, R3, and R5 are each separately selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen atom, and saturated C1-C12 alkyl, unsaturated C1-C12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl and substituted sulfonyl groups;
• m is an integer equal to zero, one or two;
• X1 and X2 are separately selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and
• Y is selected from the group consisting NR5, an oxygen atom, a sulfur atom, a oxidized sulfur atom, a methylene group and a substituted methylene group;
• Z, for each separate n, if non-zero, and Z1, Z2, Z3 and Z4 are each separately selected from a carbon atom, a sulfur atom, a nitrogen atom or an oxygen atom;
• the dashed bonds may be either single or double bonds,
• wherein the subject was resistant to prior treatment with one or more immune checkpoint inhibitors.

A method of treating cancer in a subject who exhibited resistance to checkpoint inhibitor therapy, the method comprising:

• identifying a subject with a cancer that has shown resistance to one or more immune checkpoint inhibitors;
• and
• co-administering to the subject plinabulin and one or more immune checkpoint inhibitors,
• wherein the one or more immune checkpoint inhibitors is an inhibitor of PD-1, PD-L1 or CTLA-4.