Targeting the immune milieu in gastrointestinal cancers

Fiona Turkes,Justin Mencel,Naureen Starling

doi:10.1007/s00535-020-01710-x

Fiona Turkes, Justin Mencel + Show 1 more

Open Access

https://doi.org/10.1007/s00535-020-01710-x

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Abstract

Gastrointestinal (GI) cancers are among the most common and lethal solid tumors worldwide. Unlike in malignancies such as lung, renal and skin cancers, the activity of immunotherapeutic agents in GI cancers has, on the whole, been much less remarkable and do not apply to the majority. Furthermore, while incremental progress has been made and approvals for use of immune checkpoint inhibitors (ICIs) in specific subsets of patients with GI cancers are coming through, in a population of ‘all-comers’, it is frequently unclear as to who may benefit most due to the relative lack of reliable predictive biomarkers. For most patients with newly diagnosed advanced or metastatic GI cancer, the mainstay of treatment still involves chemotherapy and/or a targeted agent however, beyond the second-line this paradigm confers minimal patient benefit. Thus, current research efforts are concentrating on broadening the applicability of ICIs in GI cancers by combining them with agents designed to beneficially remodel the tumor microenvironment (TME) for more effective anti-cancer immunity with intention of improving patient outcomes. This review will discuss the currently approved ICIs available for the treatment of GI cancers, the strategies underway focusing on combining ICIs with agents that target the TME and touch on recent progress toward identification of predictors of sensitivity to immune checkpoint blockade in GI cancers.

Highlights

Gastrointestinal cancers are a huge global health problem
Human papilloma virus (HPV) infection has been associated with higher numbers of tumor infiltrating lymphocytes and up-regulation of PD-1 checkpoints and is attributable to over 80% of case of squamous cell carcinoma of the anal canal (SCCA) [43]
In KEYNOTE 012, where patients were subjected to repeated ontreatment biopsies, there was substantial disparity in PD-L1 expression between samples [29]. These findings suggest that PD-L1 status alone may not be the most useful predictor of successful immune checkpoint inhibitors (ICIs) therapy in esophagogastric cancer

Summary

Introduction

Gastrointestinal cancers are a huge global health problem. In 2018 almost 5 million new cases were diagnosed [1], the vast majority of which would have been at an advanced stage. CD cluster of differentiation, CSF-1 colony stimulating factor-1, CSFR-1 colony stimulating factor-1 receptor, DKK Dickkopf related protein, DNMT DNA methyltransferase, FAK focal adhesion kinase, GI gastrointestinal, HCC hepatocellular carcinoma, HDAC histone deacetylase, ICI Immune checkpoint inhibitor, IDO indoleamine 2,3 dioxygenase, mCRC metastatic colorectal cancer, MSI microsatellite instability, MSS Microsatellite stable, NSCLC Non-small cell lung cancer, OGA oesophagogastric cancer, PDAC pancreatic ductal adenocarcinoma, PD-L1 programmed death-ligand, pMMR proficient MisMatch Repair, SCC squamous cell carcinoma, TKI tyrosine kinase inhibitor, TS thymidylate synthase, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, WT wild-type is data to support the use of ramucirumab, a monoclonal antibody to VEGFR-2, in combination with paclitaxel in advanced OGA in the later line setting [79] Sorafenib and lenvatinib, both with anti-VEGF activity, are effective for treatment of advanced HCC [80]. More promising strategies in the pipeline may include partnering CD40 agonists which favorably alter the immune component of the PDAC stroma [143]. with chemotherapy and PD-1 blockade (Table 4) and use of the bispecific antibody, M7824, which blocks both immune-inhibitory TGFb and PD-L1 pathways and has demonstrated some efficacy signals in patients with PDAC and BTC [144, 145]

Conclusion

Findings

Compliance with ethical standards