IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer

Abstract Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single chain variable fragment (scFv) derived from the humanized murine mAb clone, J591, as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFNy production and anti-tumor cell activity in vitro. Using two clinically-relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer. Competing Interest Statement S.J.P. is a scientific advisor to and receives royalties from Imugene Ltd, Adicet Bio, Port Therapeutics, and Celularity. L.S.L., S.J.P., and Eureka Therapeutics employees are listed as co-inventors on a patent related to the development of human constructs targeting PSMA, which is co-owned by City of Hope and Eureka Therapeutics. S.J.P. and J.P.M. are listed as co-inventors on a patent on the development of membrane-bound IL12 engineered CAR T cells for the treatment of cancer, which is owned by the City of Hope. All other authors declare that they have no competing interests. Footnotes ↵6 Lead Contact