Neutrophil-lymphocyte ratio as a predictive biomarker for response to high dose interleukin-2 in patients with renal cell carcinoma
This study shows that NLR could be used to help predict response to HD-IL2. HD-IL2 is a very effective treatment for a small population of patients with mRCC. Given its several acute but rare chronic toxicities, a predictive biomarker in this setting is expected to optimize selection of patients, who are most likely to derive benefit from therapy. Low NLR has been associated with a better prognosis for many different types of malignancies. This is the first report to suggest that low NLR may be “predictive” of improved survival outcomes to HD-IL2 in the setting of mRCC.
It is clear that inflammation and immune response play a pivotal role in neoplastic progression [5]. Indeed novel treatment strategies targeting the immune system, such as immune check point inhibitors, have been shown to improve outcomes and are approved for multiple malignancies. One of simplest estimations of the balance of inflammation and immune response is neutrophil/lymphocyte ratio [6, 7].
NLR has been reported to be a predictive and prognostic factor for localized renal cell carcinoma [8, 9]. In a large meta-analysis of 15 cohorts including 3357 patients, NLR predicted poorer OS (hazard ratio?=?1.82, 95% CI 1.51-2.19) [10]. Additionally, high preoperative NLR was associated with larger tumor size, higher nuclear grade, histologic tumor necrosis, and sarcomatoid differentiation [8]. Recently, on treatment neutropenia was shown to be an independent biomarker of favorable outcome in mRCC, independent of treatment type [11]. NLR was also recently shown to predict response to ipilimimab in melanoma patients. In a recent report, lower NLR ratio predicted improved overall survival in patients with metastatic melanoma [12].
Unlike recently developed immunotherapeutic agents, the mechanism of action of HD-IL2 is not fully understood. Interleukin-2 is a recombinant protein that has a wide range of effects on the immune system, including promoting proliferation and differentiation of CD4(+) T cell into specific effector T cell subsets, of CD8(+) T cells into effector T cells, and in to memory cells, but also expansion of immunosuppressive CD4(+)FOXP3 T regulatory cells in certain situations [13].
Historically, HD-IL2 therapy has generally been shown to have an objective response rate of approximately 10-20%, including complete responses in ~10% of patients. More recently, in a large cohort of patients with mRCC (n?=?391) treated with HDIL-2, a clinical benefit with HD-IL2 was seen in ~50% of patients. In addition to ~20% patients who experienced objective responses (CR in 9% and PR in 10%), an additional 32% experienced SD as the best response to treatment. The survival outcomes were similar in those experiencing PR and SD, and were significantly superior to those who did not experience objective responses or SD [14]. Although the use of HDIL-2 declined after the approval of targeted therapies starting in 2005, in the recent years with the resurgence of cancer immunotherapy in general, the use of HDIL-2 has stabilized and may have picked up [15]. Identification of predictive biomarkers in this setting is expected to further allow more patients to experience benefits of HDIL-2 while limiting toxicities and cost in others. No other therapy in the mRCC setting has been shown to be associated with durable long-term response, albeit in a small proportion of patients, in a consistently reproducible fashion. Absolute number of peripheral blood lymphocytes have been correlated with objective response in patients treated with IL-2, interferon alpha, and histamine. There was no difference in baseline levels of lymphocytes of responding versus non-responding patients [16]. This further supports that NLR probably acts as a better marker to predict response in patients with mRCC treated with HD-IL2.
One of the main limitations of this study is the retrospective nature of the study and the relatively small sample size.