“This study demonstrates the power of a novel technology developed by Dr. Ring when he was at Yale. His REAP platform allows us to study levels of thousands of autoantibodies in a single experiment. When applied to large collections of carefully collected human samples, we stand to learn a lot about the biology of responses and how to improve our clinical outcomes,” Kluger says.
As used in this study, REAP—rapid extracellular antigen profiling—analyzed antibody and autoantibody interaction with proteins on the surface of human cells in patient blood samples.
Typically, autoantibodies are antibodies that have lost their way. Instead of attacking threats to the body, including infectious pathogens such as cancer or viruses, they mistakenly target healthy tissue. However, the findings of this study revealed that some autoantibodies in the treated cancer patients were associated with “dramatically altered odds ratios” that in some cases helped, and in others hindered, the anti-tumor effectiveness of immunotherapy.
"Our analysis shows that certain naturally occurring autoantibodies can tilt the odds dramatically toward shrinking tumors," says Ring, senior author of the study. "We saw some cases where autoantibodies boosted a patient's likelihood of responding to checkpoint blockade by as much as 5- to 10-fold. For years, autoantibodies were viewed mainly as bad actors in autoimmune disease, but we're discovering they can also act as potent, built-in therapeutics."
Notably, the team found that autoantibodies blocking proteins called interferons were linked to better anti-tumor responses to checkpoint inhibitors.
"In some patients, their immune system essentially brewed its own companion drug," Ring says. "Their autoantibodies neutralized interferon and that amplified the effect of checkpoint blockade [the immunotherapy]. This finding gives us a clear blueprint for combination therapies that intentionally modulate the interferon pathway for everyone else."
Not all autoantibodies were beneficial. In some cases, autoantibodies were associated with patients experiencing dramatically reduced benefits from the immunotherapy. Those autoantibodies highlighted the importance of their targets, suggesting that reversing the effects of those antibodies could restore immunotherapy effectiveness in those patients.
Overall, the study summarized that the relationships between the individual autoantibodies and the impact on immunity effectiveness “underscores a more profound interplay” than previously recognized and recommended further research including clinical studies.
Ring characterized the study findings as “only the beginning. We're now extending the search to other cancers and treatments so we can harness—or bypass—autoantibodies to make immunotherapy work for far more patients."
The research reported in this news article was supported by the National Institutes of Health (grants P50 CA121974 and R01CA227473); Yale Cancer Center; Yale Gruber Fellowship; Yale Medical Scientist Training Program; Mark Foundation for Cancer Research; Pew Charitable Trusts; gifts to Fred Hutch; and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.