Details

Autor(en) / Beteiligte

• Agarwal, Sangya
• Aznar, M. Angela
• Rech, Andrew J.
• Good, Charly R.
• Kuramitsu, Shunichiro
• Da, Tong
• Gohil, Mercy
• Chen, Linhui
• Hong, Seok-Jae Albert
• Ravikumar, Pranali
• Rennels, Austin K.
• Salas-Mckee, January
• Kong, Weimin
• Ruella, Marco
• Davis, Megan M.
• Plesa, Gabriela
• Fraietta, Joseph A.
• Porter, David L.
• Young, Regina M.
• June, Carl H.

Titel

Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells

Ist Teil von

• Immunity (Cambridge, Mass.), 2023-10, Vol.56 (10), p.2388-2407.e9

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy. [Display omitted] •CTLA4 deletion enhances CART efficacy and surface CAR expression under stress•Deletion of CTLA4 permits unopposed CD28 signaling in CAR T cells•CTLA4 deletion rescues the function of nonresponding CLL patient CAR T cells•PD-1 deficiency nullifies CD28 signaling enabled by CTLA4 deletion in CAR T cells CD19-directed CAR T cell therapy is an effective treatment for B cell malignancies, but some patients fail to respond. Agarwal et al. demonstrate that deletion of CTLA4 enhances anti-tumor efficacy and surface CAR expression in models of leukemia and lymphoma and in CLL patient CAR T cells. Interestingly, deletion of PDCD1 or of PDCD1 and CTLA4 did not promote anti-tumor efficacy of CART19 cells.