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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.
Highlights
Doom and GloomPrecision medicine is a broad generic term, generally used to describe all of the resources used to decipher the molecular and genomic profiles of tumors, primarily for selecting the drugs which are the most likely to be clinically effective in cancer patients.For decades, improving either response rates or survival in cancer patients has been achieved in a stepwise manner
The role of tumor immunity has been known for decades [2], the introduction of immune checkpoint inhibitors as new anticancer agents quickly led to spectacular improvements in clinical outcomes, including 5 year-survival rates above
These results suggest that stimulator of interferon genes (STING)-cyclic GMP-AMP synthase (cGAS) signaling plays a pivotal role in the intrinsic antitumor immunity and that this pathway should be activated to harness tumor immunity in patients
Summary
Precision medicine is a broad generic term, generally used to describe all of the resources used to decipher the molecular and genomic profiles of tumors, primarily for selecting the drugs which are the most likely to be clinically effective in cancer patients. The role of tumor immunity has been known for decades [2], the introduction of immune checkpoint inhibitors (e.g., anti-CTLA4, or PD1/PDL1 axis antagonists) as new anticancer agents quickly led to spectacular improvements in clinical outcomes, including 5 year-survival rates above. Today a rising amount of evidence suggests that to achieve a maximum efficacy while controlling toxicities, there is probably an optimal way immune checkpoint inhibitors should be combined with other anticancer drugs or with radiation therapy [3]. Molecular target expression (e.g., PD-L1), inflammation state (e.g., Myeloid-Derived Suppressive Cells, tertiary lymphoid structures, tumor-infiltrating lymphocytes), and tumor antigen expression (e.g., tumor mutational burden, microsatellite instability) are the most frequently tested markers All these markers are still characterized by inconsistencies in predictive cut-off values depending on the studies, lowering their implementation in routine oncology as robust decision-making tools
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