A theranostic drug for prostate cancer CAR T cell immunotherapy and PET imaging

Although chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic efficacy, current design of clinically approved CAR constructs renders therapies monospecific, inflexible and imperiled to severe side effects. We therefore refined the CAR approach and established a switchable platform technology termed UniCAR. Instead of directly interacting with tumor cells, UniCAR‐engrafted T cells recognize the short peptide epitope E5B9. Their on/off switch is mediated by E5B9‐comprising targeting modules (TMs), facilitating indirect cross‐linkage to antigen‐expressing cancer cells.

As all TMs described to date contain an antibody‐derived binding moiety, we aimed to develop a ligand‐based low‐molecular weight agent that enables not only UniCAR T cell retargeting, but also monitoring of the therapeutic response by non‐invasive PET imaging.

For proof of concept of this novel theranostic approach, we successfully converted the clinically approved radiotracer PSMA‐11 into a TM by fusion with E5B9 without affecting its diagnostic properties in mice and humans. Moreover, the chemically synthesized, ligand‐based compound efficiently mediated PSMA‐expressing tumor cell lysis by UniCAR T cells both in vitro and in vivo.

Taken together, the PSMA‐ligand TM represents a novel theranostic agent that is an attractive candidate for immunotherapy of prostate cancer as well as for initial diagnosis and follow‐up treatment.