NEW YORK (Reuters Health) - Greater expression of genes associated with tumor metabolism may predict resistance to therapy in patients with PD-L1-positive renal cell carcinoma, Maryland-based researchers report.
Approximately 15% to 30% of patients with advanced renal cell carcinoma have "durable objective tumor regressions" to immunotherapies such as nivolumab that target the PD-1/PD-L1 pathway, according to Dr. Suzanne L. Topalian and colleagues at The Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center in Baltimore.
"As therapy with drugs blocking the tumor immune-suppressive PD-1/PD-L1 pathway is now showing long-term benefit in patients with several types of cancers, including kidney cancer, it is becoming increasingly important to find biomarkers to identify those patients whose tumors are most likely, or unlikely, to respond to treatment," Dr. Topalian told Reuters Health by email.
"This follows the example of drugs inhibiting molecular driver pathways in cancer - so-called 'targeted' therapies - where a particular mutation in the tumor is required in order for the drug to be effective," she explained.
"However, immunotherapy biomarkers are different because their expression may vary according to the activation state of the immune system as it fights cancer, or the time or location in the body where this interaction occurs," she said.
To assess factors that might influence treatment response, Dr. Topalian and colleagues analyzed archived pretreatment tumor samples from 13 patients with metastatic renal cell carcinoma whose cancer was PD-L1-positive and who went on to receive nivolumab in clinical trials.
Four patients had responded to treatment and nine had not, according to their report online August 4 in Cancer Immunology Research.
Analyses of immune-related genes did not reveal significant differences between responders and nonresponders, so the researchers turned to whole-genome profiling. They analyzed 11 samples from the original cohort (four responders and seven nonresponders), covering 29,377 gene targets.
Genes expressed at elevated levels in tumors from nonresponders were mainly associated with metabolism - specifically, UGT1A family members. These genes were also found in kidney cancer cell lines.
By contrast, tumors from responders overexpressed immune markers such as BACH2, a regulator of CD4+ T cell differentiation, and CCL3, a protein involved in leukocyte migration.
The authors conclude, "These findings suggest that tumor cell-intrinsic metabolic factors may contribute to treatment resistance in (renal cell carcinoma), thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti-PD-1."
Dr. Topalian added, "Further research is needed to know if targeting tumor metabolic genes in combination with anti-PD-1 therapy in kidney cancer may provide increased efficacy."
Dr. Brian Rini of the Cleveland Clinic Taussig Cancer Institute in Ohio commented by email, "This important study is a step in the right direction of further understanding the biology of response and resistance to checkpoint inhibitors in kidney cancer patients. There are clear biologic differences in responding and non-responding patients, as demonstrated with gene expression studies. Additional insight is needed to translate these findings into the clinic to allow for the optimal application of new immunotherapies."
The study was funded in part by a Bristol-Myers Squibb grant to Dr. Topalian.
SOURCE: http://bit.ly/2b8wnZg
Cancer Immunol Res 2016.
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