Details

Autor(en) / Beteiligte

• Goodman, Daniel B
• Azimi, Camillia S
• Kearns, Kendall
• Talbot, Alexis
• Garakani, Kiavash
• Garcia, Julie
• Patel, Nisarg
• Hwang, Byungjin
• Lee, David
• Park, Emily
• Vykunta, Vivasvan S
• Shy, Brian R
• Ye, Chun Jimmie
• Eyquem, Justin
• Marson, Alexander
• Bluestone, Jeffrey A
• Roybal, Kole T

Titel

Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies

Ist Teil von

• Science translational medicine, 2022-11, Vol.14 (670), p.eabm1463

Ort / Verlag

United States

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers but have shown limited efficacy in persistent, recurrent malignancies. Here, we introduce "CAR Pooling," a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with signaling domains derived from a range of immune cell lineages were evaluated in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several domains were identified from the tumor necrosis factor (TNF) receptor family that have been primarily associated with B cells. CD40 enhanced proliferation, whereas B cell-activating factor receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) promoted cytotoxicity. These functions were enhanced relative to clinical benchmarks after prolonged antigen stimulation, and CAR T cell signaling through these domains fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic transcriptional signature previously associated with positive clinical outcomes. We also observed that replacing the 4-1BB intracellular signaling domain with the BAFF-R signaling domain in a clinically validated B cell maturation antigen (BCMA)-specific CAR resulted in enhanced activity in a xenotransplant model of multiple myeloma. Together, these results show that CAR Pooling is a general approach for rapid exploration of CAR architecture and activity to improve the efficacy of CAR T cell therapies.