Immuno-oncology, Pre-clinical

Blocking PD-L1 production in mice, UCSF team spotlights preclinical promise of a Pfizer-backed I/O drug

The checkpoint frenzy in the immuno-oncology sphere has largely focused on blocking the ligand-receptor duo of PD-L1 and PD-1, which cancer cells use to shield themselves from the immune system. Dissatisfied by the ability of PD-L1 agents to go after aggressive, metastatic cancers, a group of UCSF researchers are charting a new path: What if the production of checkpoint proteins could be stopped from the outset?

Davide Ruggero

In a mice trial, the researchers found that they could pull back the “robust PD-L1 invisibility cloak” used by cancer cells, increasing survival rates by disrupting the translation of RNA into proteins — using a molecule developed by eFFECTOR Therapeutics, a biotech co-founded by the study’s senior author, Davide Ruggero.

The approach stems from Ruggero’s observation that aggressive types of liver cancer are driven by oncogenes that can hijack protein translation — in which ribosomes assemble proteins at the direction of RNA — to boost production of proteins that help the tumor skirt an immune attack.

“If aggressive liver cancer depends on this increased translation, it may die if you hit it with a translation inhibitor,” said Ruggero in a statement. “This is the basis of an emerging movement in cancer therapy.”

Yichen Xu

Ruggero and his team took into a preclinical trial a compound known as eFT508 — now in Phase II as both a monotherapy and an add-on to checkpoints — which inhibits eIF4E, a cellular “translation factor” they say is responsible for pairing RNA with ribosomes. The drug did what it was supposed to do, halving PD-L1 protein levels and increasing survival rates in mice with tumors driven by both the MYC and KRAS genes, but not so much among mice carrying KRAS tumors.

That’s in line with the scientists’ theory that a higher level of PD-L1 translation and production explains why MYC/KRAS tumors grow more aggressively, metastasize more often and are generally deadlier than KRAS tumors.

It’s not just PD-L1, either. MYC/KRAS is also responsible for elevated levels of other proteins that cancer cells rely on to reproduce, evade the immune system and spread between organs, suggested Yichen Xu, a postdoc in Ruggero’s lab who served as a lead author of the study.

Published in Nature Medicine, the paper offers validation for eFFECTOR’s stated aim to “translationally regulate gene expression” — an approach that has convinced Pfizer and Merck KGaA to bankroll a collaboration testing a combo in hopes of boosting the effectiveness of its PD-L1 therapy Bavencio, having had to contend with multiple flops. Merck is also in for a Keytruda/eFT508 combo slated to begin Phase II in the coming months.


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