Next generation predictive biomarkers for immune checkpoint inhibition

Abstract

With the advent of targeted therapies, there has been a revolution in the treatment of cancer across multiple histologies. Immune checkpoint blockade has made it possible to take advantage of receptor-ligand interactions between immune and tumor cells in a wide spectrum of malignancies. Toxicity in healthy tissue, however, can limit our use of these agents. Immune checkpoint blockade has been approved in advanced melanoma, renal cell cancer, non-small cell lung cancer, relapsed refractory Hodgkin's lymphoma, and urothelial cancer. Though FDA-approved indications for use of some of these novel agents depend on current, protein-based PD1 and PD-L1 assays, detection methods come with several caveats. Additional predictive tools must be interrogated to discern responders from non-responders. Some of these include measurement of microsatellite instability, PD-L1 amplification, CD8 infiltrate density, and tumor mutational burden. This review serves to synthesize biomarker detection at the DNA, RNA, and protein level to more accurately forecast benefit from these novel agents.

Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy

“…(22) Other factors contributing to hypermutation include dysfunction of DNA polymerase via germline mutations and molecular “smoking signatures” in NSCLC tumors that lead to differential mutational landscapes and up-regulation of PD-L1 expression. (16,20,23,24) As mentioned, other publications show a correlation between high tissue tumor mutational burden and checkpoint inhibitor response in several different tumor types. (8,10–12)…”

“…(17,18) And, at the protein level, PD-L1 expression (IHC) in tumor and/or stromal cells is associated with higher response rates to checkpoint inhibitors, though IHC variability limits the precision of this assay. (3,19,20) Specific mutational signatures, such as kataegis , a pattern of base mutations associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide) family overexpression (correlating with viral presence) are also linked to PD-L1 overexpression. (21)…”

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

“…NGS also has the ability to recognize alterations that can predict response to immunotherapy by identifying mutations in mismatch repair genes (21), microsatellite instability (MSI) (24,25,30,38,39), and PD-L1 amplification (40). …”

Tumor Lysis Syndrome Following a Single Atezolizumab Infusion for Metastatic Urothelial Carcinoma Involving Both Upper and Lower Tract

“…Since the frequency of microsatellite instability in sporadic tumors of the upper urinary tract is high, we plan to routinely screen these patients for their microsatellite-instability (MSI) status. Biomarkers such as PD-L1 expression [15], mutation load [15] and MSI status [22][23][24] may potentially help identify those at high risk for TLS, along with known clinical risk factor [3,4] for TLS. We recommend prophylaxis with allopurinol and hydration should be considered for high risk patients before PD-1 Immunotherapy.…”