Published online Aug 15, 2015. doi: 10.4251/wjgo.v7.i8.95
Peer-review started: February 22, 2015
First decision: March 20, 2015
Revised: May 12, 2015
Accepted: May 27, 2015
Article in press: May 28, 2015
Published online: August 15, 2015
Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program
death-1 (PD-1) and program death-ligand 1 (PD-L1) will
lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 mAbs (MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase II will start soon. In metastatic colorectal cancer (CRC), a phase III trial of MPDL3280A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration (i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection of patients likely to benefit from ICIs.
Core tip: Anti-program death-1 and anti-program death-ligand 1 (PD-L1) monoclonal antibodies have been designed to restore T cell activity, since human tumors tend to activate this immune regulatory checkpoint as a means of escaping immunosurveillance. A PD-L1 expression is present in 30% to 50% of digestive cancers and accumulating data are in favor of an association between this PD-L1 expression and response to treatment, which make digestive cancers promising candidates for those breakthrough immunotherapies. We review the ongoing clinical trials and the major challenges ahead of us in order to learn how, when and for which patients we should use these therapeutics.