Immunomodulatory and differentiating function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy

A method of cancer immunotherapy comprising administering to a subject in need thereof chimeric antigen receptor-modified immune cells (CAR-MIC) and an immunomodulatory retinoid active agent and/or rexinoid active agent (RAR/RXR active agent), and a differentiating RAR active agent, wherein the immunomodulatory RAR/RXR active agent is:

• a) a RARα antagonist, wherein the RARα antagonist is:
• i) a compound of general formula (I)
• wherein R1, R2, R3, and R6 are independently H or C1-6 alkyl;
• R4 and R5 are independently H or F;
• Ar is phenyl, pyridyl, thienyl, furyl, or naphthyl;
• X is C(CH3)2, O, S, or NR7, wherein R7 is H or C1-6 alkyl;
• X1 is H or halogen such as F, Cl or Br;
• and R8 is H or OH;
• or
• ii) a compound of general formula (II)
• wherein R1 and R2 are independently C1-6 alkyl;
• X is O, S, or CH2;
• Y is O, S, CH2, or NR3, wherein R3 is C1-6 alkyl;
• Z is Cl or Br;
• W is H or OH;
• and U is independently H or F;
• or
• iii) a compound of general formula (III):
• wherein R1 and R2 are independently H or C1-6 alkyl;
• R3 is H or F;
• Ar is phenyl, pyridyl, thienyl, furyl, or naphthyl;
• X is O, S, N, or CH2;
• W is H or OH;
• and Z is Cl or Br;
• or
• iv) BMS185411, BMS614, Ro41-5253, Ro46-5471, or AGN 194777;
• or
• b) a RAR agonist, wherein the RAR agonist is:
• i) a compound of general formula (IV):
• wherein R1 and R2 are independently H or C1-6 alkyl;
• R3 is H or F;
• and X is O, S, CH2, C(R4)2, or NRS, wherein R4 and R5 are independently H or C1-6 alkyl;
• or
• or
• iii) CD437, CD2325, CD666, or BMS961;
• or
• c) a RXR antagonist, wherein the RXR antagonist is:
• AGN195393, LGN100849,
• or
• d) a combination thereof;
• and
• wherein the differentiating RAR active agent is a RARα agonist, wherein the RARα agonist is a compound of general formula (V):
• wherein R1 is H or C1-6 alky, R2 and R3 are independently H or F, and R4 is a halogen.