Advancements in Cancer Immunotherapy: Targeting PD-L1 with Oral Small Molecules in Colon Cancer

The abstract details the development of a new generation of cancer immunotherapy agents, focusing on small molecule inhibitors of the PD-1/PD-L1 immune checkpoint axis. These inhibitors are designed to overcome limitations associated with antibody-based therapies, offering benefits such as enhanced tumor penetration, shorter half-life for better management of immune-related adverse events, and reduced cost.

The researchers embarked on a discovery and development process to identify orally available small molecules capable of targeting PD-L1. They designed and optimized a series of PD-L1 inhibitors that effectively disrupted the PD-1/PD-L1 interaction. The compounds were initially profiled using an ELISA assay and further evaluated through a functional cell-based reporter assay, mixed lymphocyte reaction (MLR) assay, and a human peripheral blood mononuclear cell (PBMC)-mediated tumor cell killing assay. Medicinal chemistry was utilized to enhance potency and oral bioavailability, with the most promising candidates being assessed in murine tumor models.

Due to the specificity of the compounds for human PD-L1, a syngeneic tumor model with murine MC-38 colon tumor cells expressing human PD-L1 was employed. The lead compounds demonstrated high potency in cell-based assays and possessed favorable oral bioavailability and safety profiles. In the MC38-hPD-L1 tumor model, the compounds significantly reduced tumor growth, comparable to the effect of an anti-human PD-L1 antibody used as a positive control. Flow cytometry analysis of the tumor microenvironment indicated that the compounds almost entirely occupied human PD-L1 on tumor cells in vivo, effectively blocking the PD-1/PD-L1 interaction and bolstering immune responses against the tumor.

In summary, the study reports the successful identification and optimization of unique small molecule inhibitors of human PD-L1. These molecules exhibited significant inhibition of the PD-1/PD-L1 interaction and signaling in vitro and potent anti-tumor effects in an animal model, marking a promising advancement in the field of cancer immunotherapy.