After a run of CTLA-4 combo failures, scientists spotlight a way to make it work — in select patients
CTLA-4/PD-(L)1 combinations have been one of the El Dorados of oncology, its promise forever behind that next hill but apparently unattainable after a series of pivotal clinical failures. But researchers at New York’s Memorial Sloan Kettering Cancer Center and the Technical University of Munich think they may know how to fix what’s wrong and boost the drive to next-gen cancer combos.
In a preclinical animal research program, researchers found that within a cell, checkpoints rely on a specific molecule — RNA-sensing molecule RIG-I — to work. If that sounds familiar, it’s because it has already been identified as a target for boosting immune responses and was subject to at least one Phase I/II trial. Pfizer in December allied itself with Kineta with $15 million upfront and $505 million in potential milestones to develop RIG-I immunotherapies, and three years ago Merck purchased German upstart Rigontec for $137 million upfront and over $400 million in potential milestones for the same purpose.
The science team’s work helps spotlight what they’re after.
Publishing in Science Immunology, the researchers found that high expression of the gene for RIG-I (gene DDX58) heralded responsiveness to CTLA-4 therapy and suggested doctors might test for RIG-I expression in tumors to predict who will respond to the therapy. They could then tailor treatments to that population. The study also suggests that combining PD-1/CTLA-4 with a RIG-I agonist might boost the effectiveness of the heretofore often disappointing therapy.
CTLA-4 and PD-1 therapies, which won their principal founders 2018’s Nobel Prize in medicine, work by targeting a receptor on T cells that stop the cell’s “checkpoint,” if you will – by blocking the receptor, it essentially releases the brakes on the immune system and allows the body’s T cells to start a full high-speed chase on the tumor(s). Several such immunotherapies have been approved in the past few years, beginning with ipilimumab for melanoma in 2011, but the ecstatic promise has turned up a lot of dry water beds of late. Trials from the major players, including Bristol-Myers Squibb, AstraZeneca, and Sanofi, attacking small cell lung cancer, head and neck carcinoma, and non-small cell lung cancer with a mix of PD-1 and CTLA-4 inhibitors have all failed.
This is not the first study looking at how to improve and tailor CTLA-4 therapies. Last year, researchers working on mice found that they could “image” the response with a radioactive tracer that latches to OX40, a molecule only found in activated T cells, and thus theoretically learn early on if a patient is responding to the therapy.
Social image: Memorial Sloan Kettering Cancer Center
