Compositions and methods for enhancing car-t cell performance and for cancer immunotherapy

6:

• A method for:
• metabolically enhancing chimeric antigen receptor (CAR)-T cell function and persistence in vitro or in vivo, or
• enhancing CAR-T cell efficacy in cancer immunotherapy,
• the method comprising:
• (a) administering to an individual in need thereof a CAR-T cell or a genetically engineered T cell with an inhibitor of a squalene synthase or Fdft1;
• (b) administering to an individual in need thereof a CAR-T cell or a genetically engineered T cell that has been ex vivo exposed to an inhibitor of a squalene synthase or an Fdft1 inhibitor;
• or
• (c) administering to an individual in need thereof a CAR-T cell or a genetically engineered T cell that has been genetically modified to have a phenotype comprising:
• no expression of, or substantially no expression or activity of, or less than wild type levels of expression or activity of, a squalene synthase or Fdft1 enzyme or gene.

7:

• The method of claim 6, wherein the small molecule Fdft1 inhibitor comprises:
• (a) mevastatin, or a compound having the formula:
• (b) zaragozic acid A (ZAA), or a compound having the formula:
• (c) a compound having the formula:
• (d) bavachinin, or a compound having the formula:
• or
• (e) a salt, an isomer, deuterated isoform, optical isomer or stereoisomer, a racemate or racemic mixture, an enantiomer, an individual diastereomer or a diastereomeric mixture, an analog, a crystalline product or a crystalline intermediate, a pharmaceutically acceptable salt thereof, or a prodrug or a bioisostere of any of (a) to (d).

8:

• The method of claim 7, wherein the inhibitor of the squalene synthase or Fdft1 inhibitor is formulated:
• (a) in a liquid, a gel, a hydrogel, a vesicle, a liposome, a nanoparticle, a nanolipid particle, a powder or an aqueous or a saline formulation, or for administration in vitro or in vivo;
• (b) for enteral or parenteral administration;
• (c) in or as a liposome, a nanoparticle, or a nanoliposome;
• (d) in or as a dendrimer, a tablet, a pill, a capsule, a gel, a hydrogel, a geltab, a liquid, a powder, an emulsion, a lotion, an aerosol, a spray, a lozenge, an aqueous or a sterile or an injectable solution, an eye drop, or an implant;
• or
• (e) for intravenous injection, subcutaneous injection, intramuscular injection, inhalation, or intravitreal injection.

11:

• A method for treating or ameliorating a cancer in an individual in need thereof comprising administering to the individual in need thereof an inhibitor of a squalene synthase or an Fdft1 inhibitor,
• wherein optionally the inhibitor of a squalene synthase or Fdft1 is a small molecule, a peptide or a polypeptide, or a nucleic acid inhibitor of squalene synthase or Fdft1 expression or activity,
• and optionally the nucleic acid inhibitor of squalene synthase or Fdft1 inhibitor expression or activity comprises an antisense or miRNA molecule, or a CRISPR cassette or nucleic acid module,
• and optionally the polypeptide inhibitor of squalene synthase or Fdft1 inhibitor expression or activity comprises an anti-squalene synthase or Fdft1 antibody.

13:

• The method of claim 11, wherein the small molecule Fdft1 inhibitor comprises:
• (a) mevastatin, or a compound having the formula:
• (b) zaragozic acid A (ZAA), or a compound having the formula:
• (c) a compound having the formula:
• (d) bavachinin, or a compound having the formula:
• or
• (e) a salt, an isomer, deuterated isoform, optical isomer or stereoisomer, a racemate or racemic mixture, an enantiomer, an individual diastereomer or a diastereomeric mixture, an analog, a crystalline product or a crystalline intermediate, a pharmaceutically acceptable salt thereof, a prodrug or a bioisostere of any of (a) to (d).

14:

• The method of claim 11, wherein the inhibitor of a squalene synthase or Fdft1 inhibitor is formulated:
• (a) in a liquid, a gel, a hydrogel, a vesicle, a liposome, a nanoparticle, a nanolipid particle, a powder or an aqueous or a saline formulation, or for administration in vitro or in vivo;
• (b) for enteral or parenteral administration;
• (c) in or as a liposome, a nanoparticle, or a nanoliposome;
• (d) in or as a dendrimer, a tablet, a pill, a capsule, a gel, a hydrogel, a geltab, a liquid, a powder, an emulsion, a lotion, an aerosol, a spray, a lozenge, an aqueous or a sterile or an injectable solution, an eye drop, or an implant;
• or
• (e) for intravenous injection, subcutaneous injection, intramuscular injection, inhalation, or intravitreal injection.

15:

• An inhibitor of a squalene synthase or an Fdft1 inhibitor for use in treating cancer,
• wherein optionally the inhibitor of a squalene synthase or Fdft1 is a small molecule, a peptide or a polypeptide, or a nucleic acid inhibitor of squalene synthase or Fdft1 expression or activity,
• and optionally the nucleic acid inhibitor of squalene synthase or Fdft1 inhibitor expression or activity comprises an antisense or miRNA molecule, or a CRISPR cassette or nucleic acid module,
• and optionally the polypeptide inhibitor of squalene synthase or Fdft1 inhibitor expression or activity comprises an anti-squalene synthase or Fdft1 antibody,
• and optionally the inhibitor of a squalene synthase or the Fdft1 inhibitor is administered with, or formulated with, a programmed cell death protein 1 (PD-1) inhibitor.