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Gene expression profile may predict response to nivolumab in renal cell carcinoma
Patients with PD-L1–positive renal cell carcinoma who failed to respond to nivolumab often had higher expressions of metabolic genes than responders, according to the results of a retrospective analysis.
“Given that nivolumab [Opdivo, Bristol-Myers Squibb] 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,” Suzanne L. Topalian, MD, professor of surgery and oncology at Johns Hopkins School of Medicine, director of the melanoma program at Sidney Kimmel Comprehensive Cancer Center, and associate director of the Bloomberg–Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, said in a press release. “Our data suggest that resistance can also be caused by tumor-specific mechanisms.”
Suzanne L. Topalian
Approximately 15% to 30% of patients with renal cell carcinoma respond to immunotherapies that target the PD-1/PD-L1 pathway, such as nivolumab.
Because immunotherapies can be associated with serious adverse events, researchers have sought to identify patients unlikely to respond from these treatments.
Topalian and colleagues had access to 13 formalin-fixed, paraffin-embedded pretreatment tumor biopsies from patients involved in clinical trials of nivolumab.
All samples came from patients with metastatic, PD-L1–positive disease. Four patients responded to treatment; the other nine did not.
The researchers isolated RNA from PD-L1–positive tumor regions and performed whole-genome expression profiling, which covered 29,377 genes, as well as multiplex quantitative gene expression analysis.
A prior study of archival melanoma specimens showed that immune-related genes overexpressed in PD-L1–positive melanomas — including CD8A, IFNG, PRF1, CCL5, CD163, TLR3, CXCL1, LYZ, CD274, LAG3 and IL10 — also were overexpressed in renal cell carcinoma specimens.
However, these genes did not appear to be significantly differentially expressed in relation to clinical therapeutic outcomes.
Whole-genome profiling identified 113 genes overexpressed in tumors from responding patients, as well as 110 genes overexpressed in tumors from nonresponding patients.
Upregulated genes found in nonresponders appeared functionally associated with metabolic pathways.
In particular, UGT1A family members — which are found in kidney cancer cell lines — correlated with treatment failure in PD-L1–positive patients. The UDP-glucuronosyltransferase UGT146 was upregulated 300-fold in nonresponding patients (P = .007); UGT1A1 and UGT1A3 also were upregulated.
Conversely, immune-related genes — such as CCL3, PLEC, NFATC1, BACH2 and WHSC1 — appeared upregulated in patients who responded to nivolumab.
In order to determine whether the upregulation of UGT1A6 corresponded with adverse outcomes in nonresponding patients, Topalian and colleagues accessed The Cancer Genome Atlas and collected RNA data from 444 patients with renal cell carcinoma.
The researchers did not observe a significant connection between UGT1A6 upregulation and OS, suggesting that the gene expression was not associated with poorer outcomes in this patient population.
Topalian and colleagues acknowledged the retrospective study design and the small sample population as study limitations, and they cautioned that the findings still must be validated in a larger dataset.
“If these data are reproduced in larger groups of patients, we could potentially use the information to guide treatment decisions for patients with renal cell carcinoma,” Topalian said. “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.” – by Cameron Kelsall
Disclosure: Bristol-Myers Squibb provided funding for this research. Topalian reports ownership interests in Bristol-Myers Squibb, Five Prime Therapeutics and Potenza Therapeutics, as well as consultant roles with Five Prime Therapeutics, MedImmune, Merck and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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Matthew R. Zibelman
Suzanne L. Topalian, MD, and colleagues studied pretreatment tumor specimens from patients with renal cell carcinoma treated on a clinical trial with the PD-1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb). Selected specimens were taken from both responders and nonresponders, and various advanced sequencing platforms were used to identify differences that may help prospectively identify those most likely to respond to treatment. Most notably, their findings suggest that certain intrinsic tumor metabolic pathways may be overexpressed disproportionately in nonresponders and could predict resistance to PD-1 inhibition, as well as help uncover a source-resistant mechanism that could be therapeutically targeted.
Nivolumab has changed the therapeutic landscape for treatment of metastatic renal cell carcinoma, but because the majority of patients do not respond to treatment, techniques to identify likely responders or nonresponders prior to treatment initiation are coveted. This study implicates several genes associated with tumor cell metabolism and toxin transport as being overexpressed more commonly in nonresponders. Although these data need to be confirmed in larger cohorts of patients, this information is important in that it could help better understand tumor cell–specific mechanisms of resistance to checkpoint blockade, and it is hypothesis-generating in an effort to uncover novel pathways that may be targeted to overcome resistance.
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