CD5 deletion enhances the antitumor activity of adoptive T cell therapies

• DOI: 10.1126/sciimmunol.adn6509
• Publication Date: 2024-07-19T17:58:35Z
• Authors: 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
• Keywords: Mice; 0303 health sciences; 03 medical and health sciences; Receptors, Chimeric Antigen; T-Lymphocytes; Cell Line, Tumor; Animals; Humans; Female; CRISPR-Cas Systems; CD5 Antigens; Immunotherapy, Adoptive

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.