Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment.

BACKGROUND: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. METHODS: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. RESULTS: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. CONCLUSIONS: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.

Rofecoxib: a possible cause of acute colitis.

Nonsteroidal antiinflammatory agents may cause relevant small bowel and colonic side effects, apart from gastroduodenal lesions. The synthesis of selective cyclooxygenase-2 (COX-2) inhibitors has been an important breakthrough in antiinflammatory therapy by decreasing the incidence of upper gastrointestinal lesions. However, there is little information available concerning their effects on gut mucosa distally to the duodenum. A case history is described of a 52-year-old woman with a temporary colostomy after resection of a sigmoid tumor and who presented with bloody diarrhea 5 days after beginning therapy with rofecoxib. The hemorrhage had its origin in the transverse colon, and the endoscopic appearance was that of actively bleeding acute hemorrhagic colitis. No other colonic lesions were detected, nor was there any evidence of related infection, bleeding diathesis, or other systemic diseases. On discontinuing rofecoxib and instituting parenteral rehydration, the bleeding and diarrhea stopped. Endoscopic follow-up revealed regenerating mucosa in the transverse colon. The time relation, the absence of other causes of hemorrhage, and the clinical evolution all strongly support the probability of a causal relation between rofecoxib and hemorrhagic colitis. This case may raise awareness concerning the possibility of colonic lesions related to the new COX-2 inhibitors, similar to what is known about nonselective antiinflammatory agents.