Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

Abstract

The emergence of immunotherapy in oncology requires the discovery, validation and subsequent adoption of robust, sensitive and specific predictive and prognostic biomarkers for daily practice. Until now, anti-PD-L1 immunohistochemistry (IHC) on tissue sections has been the only validated companion diagnostic test for first-line immunotherapy for advanced and metastatic cancer, notably non-small-cell lung cancer (NSCLC). However, detection of this biomarker presents limitations that have stimulated the development of other biomarkers and other approaches. Within this context, the use of a liquid biopsy (LB) could provide an important complementary or alternative added value to PD-L1 IHC. In this review, we discuss how LBs have been used in the field of immuno-oncology (I-O) to predict response, relapse or adverse advents for patients undergoing immune-checkpoint inhibitor (ICI) therapy (anti-PD-1/PD-L1 and CTLA-4) and we highlight recent developments. Circulating tumor cells (CTCs), cell-free DNA (cfDNA), proteins and cytokines detected in plasma as well as circulating T-lymphocytes are discussed as potential sources for developing new I-O biomarkers. The quantification of cfDNA as a predictive biomarker, as well as its sequencing for the determination of tumor mutational burden, is already well advanced. Additionally, the quantification of PD-L1 from CTCs, bound on exosomes or free in plasma, as well as the determination of cytokines, are also being actively investigated with promising results having recently been published. Lastly, analysis of T-lymphocytes, especially by analyzing the T-cell receptor, has recently emerged as a valuable biomarker that might become relevant for the prediction of response to ICIs. While LBs have not yet been implemented in routine I-O clinical practice, recent promising data and rapidly advancing technologies indicate that this approach has the potential to soon personalize the clinical management of cancer patients receiving ICIs.

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study

“…b Changes in target lesions from baseline to best response or the initial radiographic assessment, as well as treatment information (regimen, line, and response) and PD-L1 expression levels of 10 patients who received ICIs. Abbreviations: PFS -progression-free survival, ICIimmune checkpoint inhibitor, MKI -multi-kinase inhibitor, PD -progression disease, SD -stable disease, PR -partial response of their functions [24], TCR repertoire analysis can be utilized to stratify patients with long survival or screen ICI candidates in the future.…”

“…The T cell receptor (TCR) repertoire has recently emerged as a novel biomarker [23,24]. Previous pilot studies showed that tumor-infiltrated TCR clonality [25] and peripheral blood T cell receptor repertoire diversity [26][27][28] could have a potential role as predictors of the response to ICI therapy.…”

Progress Toward Identifying Exact Proxies for Predicting Response to Immunotherapies

“…It can be detected using standard ELISA assays in patient blood, with high PDL-1 levels associating to adverse prognosis in multiple tumor types. In NSCLC for example, high soluble PDL-1 is associated with adverse prognosis, and studies in melanoma suggest it could even be utilized as a dynamic predictor of durable efficacy to checkpoint inhibitors (Hofman et al, 2019). Mechanistically, it is plausible that elevated soluble PDL-1 levels reflect an immunocompromised/suppressed state, and as such interfere with CPI efficacy (Zhou et al, 2017).…”

“…It relies on capturing epithelial cell adhesion molecule (EpCAM) positive tumor cells from whole blood, however, its broad clinical value remains elusive. Determining PDL-1 expression on CTCs, in addition to all preceding challenges of this technology (namely false positive or negative assay results) and ability to ensure specificity, heightens the risk for co-isolating cellular populations like myeloid cells, and misidentifying them as CTCs expressing PDL-1 (Hofman et al, 2019).…”

“Circulating Tumor Cells: Finding Rare Events for a Huge Knowledge of Cancer Dissemination”

“…A second example is PD-L1 as one immune checkpoint regulator; it has become an exciting new therapeutic target leading to long lasting remissions in patients with advanced malignancies [14,15]. Kloten et al highlighted the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients [16].…”