Therapeutic T cells with 3-in-1 strategy for the treatment of biliary tract cancer.

T cell therapy for tumors faces barriers like heterogeneous antigen expression, an unfriendly tumor microenvironment, and limited T cell expansion. We adopt a 3-in-1 strategy to produce super circulating TIL-like (tumor-infiltrating lymphocyte-like) cells (ScTILs): modifying PD-1-positive peripheral blood T cells with an enhance receptor (ER), a PD-1 and CD28 fusion protein to reverse inhibitory signal, and an anti-CD19 chimeric antigen receptor (CAR) for expansion (CFE). ScTILs kill tumor cells effectively in vitro and in vivo. Clinically, ten advanced biliary tract cancer (BTC) patients receive ScTILs treatment; post hoc analysis shows that ScTILs monotherapy yields a median overall survival (OS) of 18.3 months in appropriate dose or normal B cell groups (5/10), outperforming first-line BTC treatment (OS ∼12 months). It skips chemo-pre-treatment and interleukin-2 (IL-2), with better safety, no reliance on surgical materials, and a shorter production cycle. Overall, ScTILs are a promising therapy for future BTC treatment. This study is registered with ChiCTR (ChiCTR2000029738).