Over the past few years, checkpoint blockade immunotherapies have revolutionized cancer treatment and helped many patients who were previously considered untreatable. Now, discoveries made by two Cancer Research Institute scientists could help make these and other immunotherapies even more transformative for patients.
Haidong Dong, M.D., Ph.D., currently a CRI CLIP investigator, and Svetomir Markovic, M.D., Ph.D., who was a CRI clinical investigator from 2002-2007, both at Mayo Clinic in Rochester, MN, published their latest research results in the Journal of Clinical Investigation on the significance of a biomarker called Bim. A biomarker is "any substance that can be reproducibly measured … that reflects a normal condition or a disease process in the patient," said Dr. Dong, the senior author of the study.
In this case, Dong and Markovic showed that by measuring levels of Bim—a protein made by cancer-fighting T cells—via a simple blood draw, doctors could predict which metastatic melanoma patients would benefit from anti-PD-1 checkpoint blockade.
"Patients who experienced clinical benefit … had higher levels of Bim [before treatment] compared to patients who experienced tumor growth," noted Dr. Dong.
What does that mean for patients? "If they have increased levels of Bim in their T cells, [checkpoint blockade immunotherapy] may be an optimal choice of treatment."
Furthermore, by monitoring Bim levels after treatment, doctors could determine if the immunotherapy was working. Compared to non-responders, Bim levels in responders decreased significantly after the first three months of treatment.
Crucially, Bim measurements could signal successful anti-tumor immune responses (or lack thereof) even earlier than traditional assessment tools, including radiographic imaging. Bim measurements also provided clinicians with clarity concerning the challenge of pseudoprogression, in which a tumor can appear "to get worse before it gets better."
This is important for two reasons. First, it could help ensure that patients who are experiencing pseudoprogression but are still responding aren't prematurely taken off the treatment. Second, it could help prevent patients who aren't responding from being subjected to further doses and potential side effects, and allow them to seek out other treatment options.
Bim's value as a biomarker stems from its interactions with the PD-1/PD-L1 pathway, whose activation can prevent immune responses against cancer. This has made it one of the major targets of immunotherapy. According to Dr. Dong, the high Bim levels in responders "likely reflects an abundant PD-1 interaction … with its tumor-associated ligand PD-L1."
In other words, high Bim levels mean that the tumor is protecting itself from the immune system via PD-1/PD-L1 activity, and that "during treatment, decreased levels of Bim biomarkers suggest that the immune therapy may have successfully blocked the interaction between PD-1 and PD-L1 in tumor-reactive T cell populations."
Additionally, because Bim reflects anti-cancer T cell activity in general, it also has the potential to improve other immunotherapies that involve T cells, including CAR T cell therapy.
In Dr. Dong's view, the next steps are "validation in larger groups of cancer patients with melanoma or other solid cancers (lung, kidney, bladder, etc.) … and optimization and standardization [of the testing and analysis process]."
Then, hopefully, these insights from Drs. Dong and Markovic can be put to use in the clinic, and combined with the important immunological contributions of other CRI investigators, be used to provide smarter, safer, and more effective treatment for patients with all types of cancer.