Many patients with advanced renal cell carcinoma have tumors that do not respond to immune checkpoint inhibitors targeted against the programmed death-1 (PD-1) pathway, despite expression of the target PD ligand 1 (PD-L1) on their tumors. Now investigators think they know why, and hope to use the information to predict which patients are likely to benefit and identify potential new therapies or combinations.
A study of renal cell carcinoma (RCC) samples from tumors with both good and poor clinical responses to treatment with the anti–PD-1 agent nivolumab (Opdivo) showed that a tumor gene–expression profile tipped more toward genes for controlling metabolic functions rather than immune functions was associated with a lack of response to anti-PD-1 therapy, reported Suzanne L. Topalian, MD, and her colleagues from Johns Hopkins University and the Sidney Kimmel Comprehensive Cancer Center, both in Baltimore.
“These findings suggest that tumor cell–intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti–PD-1,” they wrote in a study published online in Cancer Immunology Research.
The investigators obtained tumor samples from 13 patients with unresectable metastatic RCC treated in one of four clinical trials. They used radiographic staging to classify each patient as either a responder or nonresponder to anti–PD-1 therapy according to RECIST (Response Evaluation Criteria in Solid Tumors). The samples were evaluated with whole genome microarray and multiplex quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling and analysis, and the results were compared with those from eight renal cell carcinoma cell lines.
They looked for expression of nearly 30,000 gene targets in samples from responders and nonresponders and found a pattern of differential expression of genes encoding for metabolic pathways and immune functions.
Specifically, they found that the expression of genes involved in metabolic and solute transport functions (for example, UGT1A) were associated with poor response to nivolumab, whereas overexpression of genes for immune markers involved in T-cell differentiation (BACH2) and leukocyte migration (CCL3) were associated with a good response.
The investigators acknowledge that the study was retrospective and limited by the analysis of only a small number of tumor samples but suggest that their findings point the way to further investigations in larger groups of patients with RCC tumors, including those both positive and negative for PD-L1 expression.
“The general approach to identifying biomarkers of clinical response to PD-1–targeted therapies has so far focused on immunologic factors in the [tumor microenvironment]. However, a deeper level of investigation may be warranted for individual tumor types, and intersections of tumor cell–intrinsic factors with immunologic factors may be particularly revealing,” they wrote.
The study was supported by research grants from the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Bristol-Myers Squibb, the National Cancer Institute, and Stand Up To Cancer. Dr. Topalian has served as a consultant/advisory board member for Five Prime Therapeutics, MedImmune, Merck, and Pfizer, and has an ownership interest in Bristol-Myers Squibb, Five Prime Therapeutics,and Potenza Therapeutics. Other coauthors reported similar potential conflicts of interest.