Using Targeted Radiotherapy (TRT) to Drive Anti-Tumor Immune Response to Immunotherapies

A method of treating a metastatic cancer in a subject, wherein the metastatic cancer comprises a primary malignant solid tumor and one or more metastatic tumors capable of causing concomitant immune tolerance, comprising systemically administering to the subject:

• (a) an immunomodulatory dose of a targeted radiotherapy (TRT) agent that is differentially taken up by and retained within the malignant solid tumor tissue, wherein the TRT agent is a phospholipid ether metal chelate that has the formula:
• or a salt thereof, wherein:
• R1 comprises a chelating agent that is chelated to a metal atom, wherein the metal atom is a metal isotope that comprises 47Sc, 177Lu, 166Ho, 186Re, 188Re, 67Cu, 199Au, 105Rh, 223Ra, 225Ac, 212Pb, or 227Th;
• a is 0 or 1;
• Y is selected from the group consisting of —H, —OH, —COOH, —COOX, —OCOX, and —OX, wherein X is an alkyl or an arylalkyl;
• and wherein:
• (i) m is 0, b is 1, n is an integer from 12 to 30, and R2 is —N+Z3, wherein each Z is independently an alkyl or an aryl;
• or
• (ii) m is 1, b is 1, n is an integer from 12 to 30, and R2 is —N+Z3, wherein each Z is independently an alkyl or an aryl;
• or
• (iii) m is 0, b is 1, n is 18, and R2 is —N+Z3, wherein each Z is independently an alkyl or an aryl;
• or
• (iv) m is 1, b is 1, n is 18, and R2 is —N+Z3, wherein each Z is independently an alkyl or an aryl;
• and
• (b) one or more immunostimulatory agents capable of stimulating specific immune cells within the tumor microenvironment;
• whereby the concomitant immune tolerance caused by the metastatic tumors is prevented and the metastatic cancer is treated in the subject.