Their breakthrough lies in the creation of anti-MUC1 chimeric antigen receptor (CAR) T cells, designed to specifically target a protein called MUC1 that is overexpressed in CCA cells. However, MUC1 overexpression also triggers the activation of PD-L1, an immune checkpoint protein that hampers the anti-tumor functions of T cells, leading to poor patient outcomes.

To overcome this hurdle, the researchers developed a novel type of T-cell called αM.CAR/SR T cells, which not only target MUC1 but also possess a PD-1-CD28 switch receptor (SR). This switch receptor activates CD28 signaling while inhibiting the PD-1/PD-L1 interaction, thereby unleashing the full potential of the T cells against the cancer cells.

In their experiments, the researchers found that αM.CAR/SR T cells exhibited a significant increase in cytotoxic activity compared to regular αM.CAR T cells. The αM.CAR/SR T cells showed enhanced production of tumor necrosis factor-α and interferon-γ, two potent anti-cancer molecules, in response to CCA cells expressing MUC1. Notably, αM.CAR/SR T cells demonstrated a remarkable ability to target CCA cells expressing PD-L1, leading to improved cancer cell destruction and increased production of granzyme B, a key molecule involved in killing cancer cells.

These findings pave the way for further testing and development of αM.CAR/SR T cells as a potential treatment option for cholangiocarcinoma. This groundbreaking research brings hope to patients and clinicians alike, offering a potential breakthrough in the battle against this devastating form of cancer.