Deletion of the inhibitory co-receptor CTLA4 enhances and invigorates chimeric antigen receptor T cells

• Published in: Immunity (Cambridge, Mass.) Vol. 56; no. 10; pp. 2388 - 2407.e9
• Main Authors: Agarwal, Sangya, Aznar, M. Angela, Rech, Andrew J., Good, Charly R., Kuramitsu, Shunichiro, Da, Tong, Gohil, Mercy, Chen, Linhui, Albert Hong, Seok-Jae, 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.
• Format: Journal Article
• Language: English
• Published: 29-09-2023
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.09.001

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 CTLA-4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of
CTLA4
in preclinical models of leukemia and myeloma improved CART cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to
CTLA4
, and not seen upon deletion of
CTLA4
and/or
PDCD1
in CART cells. Mechanistically, CTLA-4 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 leukemia patients that previously failed CART cell treatment. Thus, selective deletion of
CTLA4
reinvigorates dysfunctional CLL patient T cells, providing a strategy for increasing patient responses to CART cell therapy.
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 CART cells. Interestingly, deletion of
PDCD1
or of
PDCD1
and
CTLA4
did not promote antitumor efficacy of CART19 cells.