Predictive biomarkers for checkpoint inhibitor-based immunotherapy

Abstract

The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Durable responses can be seen in patients with melanoma and other malignancies. Although monotherapy with PD-1 or PD-L1 agents are typically well tolerated, the risk of immune-related adverse events increases with combination regimens. The development of predictive biomarkers is needed to optimise patient benefit, minimise risk of toxicities, and guide combination approaches. The greatest focus has been on tumour-cell PD-L1 expression. Although PD-L1 positivity enriches for populations with clinical benefit, PD-L1 testing alone is insufficient for patient selection in most malignancies. In this Review, we discuss the status of PD-L1 testing and explore emerging data on new biomarker strategies with tumour-infiltrating lymphocytes, mutational burden, immune gene signatures, and multiplex immunohistochemistry. Future development of an effective predictive biomarker for checkpoint inhibitor-based immunotherapy will integrate multiple approaches for optimal characterisation of the immune tumour microenvironment.

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

“…Although the expression of PD-L1 by tumor cells potentially identifies NSCLC patients who would benefit from immune checkpoint inhibitors (ICI), it does not consistently represent a reproducible predictive biomarker of the clinical response (11)(12)(13). The attempt to correlate PD-L1 expression and patient prognosis has shown conflicting results (14)(15)(16).…”

The Use of Combination Immunotherapies as Front-Line Therapy for Non-Small-Cell Lung Cancer

“…While, PD-L1 expression is associated with a benefit from immunotherapy, it is still an imperfect biomarker that cannot fully discriminate who would benefit from therapy. Clearly, a better biomarker that can be more predictive of benefit from immunotherapy is needed, and several candidates such as mutational burden, immune gene signatures and TcR repertoire or a combination are being explored [16,17]. To manage immune-related AEs, currently steroids are the basis of treatment, while other immunomodulators such as TNF antagonist or immunosuppressive agents such as cyclosporine or mycophenolate mofetil, are used in steroid-refractory situations.…”

The Link Between Calcitriol and Anticancer Immunotherapy: Vitamin D as the Possible Balance Between Inflammation and Autoimmunity in the Immune-Checkpoint Blockade

“…Not only antigen presenting cells such as monocytes, macrophages and dendritic cells, but also activated T cells are capable to produce 1,25(OH) 2 D in sufficiently high concentrations to affect vitamin D responsive genes, by binding vitamin D responsive elements. These signals upregulate the enzyme phosphoinositide phospholipase C-γ1 (PLC-γ1), a pivotal molecule for the classical T-cell receptor (TCR) signaling pathway (Figure 1) [6,8]. In turn, antigen-specific…”

“…Despite the evidence of conditions favoring response to CKI, for instance mismatch repair deficiency [4], PD-L1 expression, high mutational burden, loss of function of genes involved in antigen presentation and IFN-γ signaling among many others [5,6], each of these represents an imperfect marker, whose negativity does not exclude a good response to immunotherapy. Several studies are still investigating potentially predictive biomarkers.…”