Metastatic clear cell renal cell carcinoma (mccRCC), an aggressive type of kidney cancer, historically has presented limited treatment options. Immune checkpoint inhibitors, a form of immunotherapy, can lead to exceptional, durable responses (when the tumor substantially shrinks for a very long period of time) for some patients with mccRRC, allowing them to live longer with a better quality of life. However, the molecular reasons behind these exceptional responses have not been well defined.
In a new study, researchers uncovered factors behind why some patients may respond better to certain immunotherapy treatments. The study’s results were published in Nature Cancer on January 9. Yale scientists worked in close collaboration with lead researchers from Dana Farber Cancer Institute and The University of Texas MD Anderson Cancer Center.
“What we know is that for metastatic kidney cancer, there isn’t just one reason for what specific treatment you should use,” said co-senior author, David Braun, MD, PhD, a medical oncologist and member of the Center of Molecular and Cellular Oncology at Yale Cancer Center. “It’s very complex and there are many factors that contribute to a strong response to treatment. We hope by uncovering these factors, it can improve patient response and treatment options.”
Researchers analyzed data from more than 1,000 patients from around the world with mccRCC who received standard-of-care immunotherapies. Two immunotherapy treatment combinations were studied: PD-1/PD-L1 inhibitor and CTLA-4 inhibitor (IO/IO), and a combination of PD-1/PD-L1 inhibitor with a VEGF-receptor inhibitor (IO/VEGF). In the IO/IO cohort, patients with exceptional responses had a significantly higher total of clonal neoantigens, which are unique DNA changes present on all of the cancer cells, which lead to “antigens” that the immune system can target. In the IO/VEGF cohort, patients who had exceptional responses showed a strong presence of B-cell receptor signaling pathways and tertiary lymphoid structures (where immune cells gather before attacking the cancer) as well as heightened metabolic activity.
“Based on this research, there are multiple paths for exceptional response,” said Braun, who is also the Louis Goodman and Alfred Gilman Yale Scholar. “One is through the presence of these clonal neoantigens, another is through tertiary structures, and the last is a favorable metabolic activity. Using these pathways, we hope we can get a tumor to a point where it might respond in a very phenomenal way to immunotherapy treatment.”
Yale’s Renee Maria Saliby joined Braun in this study as a co-first author.