Next-generation CAR T cells targeting integrin αvβ6 and PD-L1 to enhance immunotherapy for cholangiocarcinoma
Year: 2025
Type: article
Abstract: Cholangiocarcinoma (CCA) is an aggressive epithelial malignancy characterized by poor prognosis, limited treatment options, and high recurrence rates even after surgery. Chimeric antigen receptor (CAR) T cell therapy has achieved notable success in hematologic malignancies, but its efficacy in solid tumors such as CCA is hindered by the immunosuppressive tumor microenvironment, particularly through PD-1/PD-L1 axis. To address these barriers, we developed a sixth-generation CAR T cell, A20 CAR6, incorporating the A20 peptide, a high-affinity ligand for integrin αvβ6—a tumor-associated antigen frequently overexpressed in CCA. Beyond antigen targeting, A20 CAR6 T cells are engineered to secrete a bispecific protein engager (BiPE) that binds PD-L1 on tumor cells and CD3 on T cells. This dual-function design aims to neutralize PD-L1–mediated immune suppression and recruit both CAR and bystander T cells to enhance tumor killing. Compared with conventional fourth-generation A20 CAR4 T cells lacking BiPE secretion, A20 CAR6 T cells exhibited superior cytotoxicity, cytokine production, and proliferation against integrin αvβ6 + /PD-L1 + CCA cells. Notably, the secreted αPD-L1/αCD3 BiPE augmented CAR T cell activity and redirected non-engineered T cells to target tumor cells, amplifying the overall anti-tumor response. These findings suggest that A20 CAR6 T cells represent a promising next-generation immunotherapy with the potential to overcome key resistance mechanisms in CCA and improve treatment outcomes. • A20 CAR6 T cells specifically target integrin αvβ6, overexpressed in cholangiocarcinoma. • Engineered CAR T cells secrete an αPD-L1/αCD3 bispecific engager (BiPE). • BiPE blocks PD-L1–mediated suppression and recruits bystander T cells. • A20 CAR6 T cells show superior cytotoxicity, cytokine release, and proliferation. • Dual-function design overcomes resistance and enhances antitumor immunity.
Source: Biomedicine & Pharmacotherapy
Institutions: Siriraj Hospital, Mahidol University
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,610
OpenAlex ID: W4416448907