Previous studies from this group have shown that a combination of gemcitabine, a commonly used chemotherapy drug, and cytotoxic T lymphocytes (immune cells) was more effective in eliminating CCA cells compared to single-agent treatments. However, a major hurdle arose during gemcitabine treatment: CCA cells upregulated the expression of an immune checkpoint protein called programmed death-ligand 1 (PD-L1), which in turn inhibited the cytotoxicity of T lymphocytes.

To overcome this challenge and leverage the upregulation of PD-L1 caused by gemcitabine treatment, the researchers developed a novel approach. They created recombinant PD-L1xCD3 bispecific T cell engagers (BiTEs), which simultaneously block the PD-1/PD-L1 signaling pathway and recruit T lymphocytes to target and eliminate CCA cells.

Two variations of the BiTEs were generated, known as mBiTE and sBiTE. These BiTEs contained anti-PD-L1 single-chain variable fragments (scFv) derived from atezolizumab and a published sequence, respectively. Both mBiTE and sBiTE exhibited specific binding capabilities to both CD3 on T lymphocytes and PD-L1, which was overexpressed on CCA cells following gemcitabine treatment.

Excitingly, the researchers found that mBiTE and sBiTE significantly enhanced the cytotoxicity of T lymphocytes against CCA cells, particularly after gemcitabine treatment. The magnitude of the cytotoxic effect was positively correlated with the levels of PD-L1 expression. These findings pave the way for the potential use of the combination of gemcitabine and PD-L1xCD3 BiTEs as an alternative therapy for CCA.

This groundbreaking research offers new hope for patients with cholangiocarcinoma, opening doors to more effective treatment options and improved outcomes. As further studies are conducted, this innovative approach has the potential to transform the landscape of CCA treatment and bring us closer to defeating this devastating disease.