Scientists at the Sidney Kimmel Comprehensive Cancer Center have discovered that certain genes involved in metabolic processes are upregulated in patients with renal cell carcinoma (RCC) who are resistant to nivolumab.
The main difference between the 2 FDA approved programmed death 1 or PD-1 inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda), is the biomarker-directed treatment. While pembrolizumab has been developed for treating patients who overexpress the programmed death-ligand 1 (PD-L1), there are no such restrictions when choosing patients for nivolumab treatment. However, a new study from the Johns Hopkins University could soon changes that.
Scientists at the Sidney Kimmel Comprehensive Cancer Center have discovered that certain genes involved in metabolic processes are upregulated in patients with renal cell carcinoma (RCC) who are resistant to nivolumab. This could prove a significant lead in selecting positive responders for nivolumab, at least in RCC.
“Between 15 and 30 percent 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,” said Suzanne L. Topalian, MD, professor of surgery and oncology at Hopkins, and director of the Melanoma Program at the cancer center. With the current study, Topalian’s group tried to identify the mechanism of resistance in the nonresponders.
Consenting participants, with PD-L1—positive RCC, who enrolled in the trial were classified as responders and nonresponders to anti–PD-1 therapy. PD-L1 expression was quantified in the pretreatment tumor specimens using immunohistochemistry. The pretreatment specimens were also subjected to a global gene expression profiling that covered nearly 30,000 genes. The study identified an elevated expression of 110 genes in the tumors of nonresponders, a majority of which are associated with metabolic processes in cells.
The authors propose that RCCs resistant to anti—PD-1 therapy might display a metabolic shift that is associated with the overexpression of proteins associated with metabolic processes such as glucuronidation and nutrient transport. The most highly expressed gene was UGT1A6, which is primarily known to promote cellular clearance of toxins and exogenous lipophilic chemicals. The authors propose that increased clearance of toxins could render the tumor cells more capable of overriding the immune system.
“Given that nivolumab works by releasing the brakes on the immune system, most studies of treatment resistance so far have focused on looking for immune system—related mechanisms,” said Topalian. “Our data suggest that resistance can also be caused by tumor-specific mechanisms.”
Although a retrospective study in a small number of participants, the results can provide a lead for prospective trial design for RCC in the future.
Cancer Immunol Res
Ascierto M, McMiller TL, Berger AE, et al. The intratumoral balance between metabolic and immunologic gene expression is associated with anti—PD-1 response in patients with renal cell carcinoma [published online August 4, 2016]. . doi: 10.1158/2326-6066.CIR-16-0072.