A significant increase in expression of metabolism-associated genes has been identified in patients with PD-L1- positive renal cell carcinomas that did not respond to nivolumab. This significant difference was found when the expression profiles of nonresponders were compared with those of patients who did respond to the therapy.
The results of this study, carried out by Suzanne L Topalian (Johns Hopkins University School of Medicine; MD, USA) and colleagues, appeared recently in the journal Cancer Immunology Research.
“Between 15–30% of patients with renal cell carcinoma, the most common type of kidney cancer, have substantial and durable responses to immunotherapeutics that target the PD-1/PD-L1 pathway, such as nivolumab,” commented Topalian. “Researchers are now trying to identify markers that can predict whether or not a patient is likely to respond to these treatments, so that those who are unlikely to respond are saved the time and can avoid the potential adverse effects of a treatment unlikely to benefit them.”
Discussing the premise of this study, Topalian continued: “Evidence from some studies suggests that renal cell carcinomas positive for PD-L1 are more likely to respond to PD-1 pathway blockers compared to those negative for PD-L1, but not all PD-L1–positive renal cell carcinomas respond to these immunotherapies.”
To further investigate nivolumab response in this setting, Topalian and team analyzed archived pretreatment tumor samples from 13 patients with metastatic renal cell carcinoma positive for PD-L1 who had gone on to receive nivolumab through clinical trials.
Of the thirteen individuals, it was known that four had demonstrated a clinical response to nivolumab and the remaining nine had not. The team carried out whole-genome expression profiling on these samples, investigating the expression of 29,377 genes. The results of these analyses indicated significantly elevated levels of 110 genes in tumors from nonresponding patients, the majority of which were related to metabolism.
As Topalian highlighted, these data suggest that resistance to nivolumab could be caused by tumor-specific mechanisms, as well as immune system-related mechanisms.
While limited by the small number of samples analyzed, the team hope these notable results are the catalyst for further exploration in larger cohorts of renal cell carcinoma patients. If these data are reproduced in a larger group, expression of metabolism-associated genes could in future be used to guide treatment decisions for patients with renal cell carcinoma.
Additionally, similar analyses may be carried out in other tumor types. Topalian continued: “Given the success of our unbiased whole-genome expression profiling approach, we are looking to extend these studies to analyze other types of cancer, as well as to confirm our current results in additional renal cell carcinomas from patients receiving anti–PD-1 therapies. Such studies may also reveal new drug targets for combination therapies with anti–PD-1.”