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Nat Commun ; 14(1): 2041, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-37041154

RESUMO

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.


Assuntos
Neoplasias da Próstata , Receptores de Antígenos Quiméricos , Masculino , Camundongos , Animais , Humanos , Linfócitos T , Interleucina-12 , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Imunoterapia , Microambiente Tumoral , Antígenos de Neoplasias , Oxirredutases
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