CD5 deletion enhances the antitumor activity of adoptive T cell therapies.
Ruchi P PatelGuido GhilardiYunlin ZhangYi-Hao ChiangWei XiePuneeth GuruprasadKi Hyun KimInkook ChunMathew G AngelosRaymone PajarilloSeok Jae HongYong Gu LeeOlga ShestovaCarolyn ShawIvan CohenAasha GuptaTrang VuDean QianSteven YangAditya NimmagaddaAdam E SnookNicholas SicilianoAntonia RotoloArati A InamdarJaryse HarrisOsitadimma UgwuanyiMichael WangAlberto CarturanLuca ParuzzoLinhui ChenHatcher J BallardTatiana BlanchardChong XuMohamed Abdel-MohsenKhatuna GabuniaMaria WysockaGerald P LinetteBeatriz CarrenoDavid M BarrettDavid Trent TeacheyAvery D PoseyDaniel J PowellChristopher Tor SauterStefano A PileriVinodh PillaiJohn SchollerAlain H RookStephen J SchusterStefan Klaus BartaPatrizia PorazziMarco RuellaPublished in: Science immunology (2024)
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.