Abstract
The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.
Highlights
The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients’ survival [1].The first generation of immune checkpoint inhibitors targeted natural immune homeostasis pathways to drive anti-tumor immune responses
Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with renal cell cancers at different stages of disease
AL-B, RM, MSc, and LC: conception and design; AL-B and VH: drafting the manuscript; AB, AC, and VH: review of the literature; AL-B, LC, RM, MSc, MSa, FM, VH, and TG: critical revision of the manuscript
Summary
The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients’ survival [1]. A recent multilevel molecular analysis on the integrated TCGA RCC database showed relatively high expression of several genes representing targets for immunotherapy in ccRCC-associated molecular subtypes compared to other RCC subtypes, with additional differences within the several clear cell-enriched RCC genomic subtypes [16]. These data suggested greater levels of IC infiltrates within ccRCC relative to other RCC types [16]. The knowledge that PD-L1 expression is not binary, but instead shows a continuum with significant intratumour heterogeneity and therapy-induced changes, might
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