Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy

Abstract

Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal time-window to combine immune checkpoint inhibitors with other drugs. In this review, we present the various putative markers that have been investigated as predictive tools with immune checkpoint inhibitors and could be used to help further combining treatments. Whereas none of the current biomarkers, such as the PDL1 expression of a tumor mutational burden, is suitable to identify the best way to combine treatments, monitoring circulating tumor DNA is a promising strategy, in particular to check whether the STING-cGAS pathway has been activated by cytotoxics. As such, circulating tumor DNA could help defining the best time-window to administrate immune checkpoint inhibitors after that cytotoxics have been given.

Keywords: biomarkers; combinatorial immunotherapy; cytotoxics; precision medicine.

Figure 1

Schematic representation of how immune checkpoint inhibitors work.

Figure 2

Sting/cGas Pathway.

Figure 3

Current use of biomarker prior to setting up combinatorial immunotherapy. Upfront testing helps to determine the Go/No Go by predicting the odds of success. However, no longitudinal monitoring is currently feasible and basal levels have to be considered as granted.

Figure 4

Proposed strategy for refining combinatorial immunotherapy. After that standard treatment is given, longitudinal monitoring of cell-free DNA helps to determine the best timing for further administering immune checkpoint inhibitors. Rather than pre-defined dosing, longitudinal monitoring allows customized treatment throughout time.