CD5 deletion enhances the antitumor activity of adoptive T cell therapies.

Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.

Citation

Ruchi P Patel, Guido Ghilardi, Yunlin Zhang, Yi-Hao Chiang, Wei Xie, Puneeth Guruprasad, Ki Hyun Kim, Inkook Chun, Mathew G Angelos, Raymone Pajarillo, Seok Jae Hong, Yong Gu Lee, Olga Shestova, Carolyn Shaw, Ivan Cohen, Aasha Gupta, Trang Vu, Dean Qian, Steven Yang, Aditya Nimmagadda, Adam E Snook, Nicholas Siciliano, Antonia Rotolo, Arati Inamdar, Jaryse Harris, Ositadimma Ugwuanyi, Michael Wang, Alberto Carturan, Luca Paruzzo, Linhui Chen, Hatcher J Ballard, Tatiana Blanchard, Chong Xu, Mohamed Abdel-Mohsen, Khatuna Gabunia, Maria Wysocka, Gerald P Linette, Beatriz Carreno, David M Barrett, David T Teachey, Avery D Posey, Daniel J Powell, C Tor Sauter, Stefano Pileri, Vinodh Pillai, John Scholler, Alain H Rook, Stephen J Schuster, Stefan K Barta, Patrizia Porazzi, Marco Ruella. CD5 deletion enhances the antitumor activity of adoptive T cell therapies. Science immunology. 2024 Jul 19;9(97):eadn6509

Mesh Tags

Substances

PMID: 39028827

search → result