Abstract
Background: In the recent years, immunotherapeutics and specifically immunecheckpoints inhibitors have marked a significant shift in the diagnostic and therapeutic algorithm of Non-Small Cell Lung Cancer (NSCLC), allowing us to use immunotherapeutics alone or combined with chemotherapy for a great subset of patients. However, new interesting approaches are being presently investigated, markedly immunotherapy combinations, that is, the use of two or more immunotherapeutics combined.
Methods: In particular, the combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has already provided groundbreaking positive results in the advanced NSCLC and other combinations are currently under investigation.
Results: Therefore, this paper aims to provide a comprehensive state-of-the-art review about immunotherapy combination, along with suggestions about future directions. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov.
Conclusion: Nivolumab plus ipilimumab represent the most promising immunotherapy combination for the treatment of advanced NSCLC patients; safety, tolerability and efficacy of new immunotherapeutics (in monotherapy and in immunotherapy combinations) must be further assessed in future studies.
Keywords: NSCLC, immunotherapy, combination therapy, immune modulators, TMB, LAG-3, OX40, IDO1.
Graphical Abstract
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[http://dx.doi.org/10.21037/tcr.2018.10.10]
[http://dx.doi.org/10.3389/fphar.2017.00561] [PMID: 28878676]
[http://dx.doi.org/10.3389/fimmu.2017.01597] [PMID: 29255458]
[http://dx.doi.org/10.1007/s00262-004-0593-x] [PMID: 15599732]
[http://dx.doi.org/10.1016/j.jtho.2016.04.014]
[http://dx.doi.org/10.3747/co.25.3976] [PMID: 30111979]
[http://dx.doi.org/10.1084/jem.20160801] [PMID: 28302645]
[http://dx.doi.org/10.1177/1753465817750075] [PMID: 29385894]
[http://dx.doi.org/10.1002/cncr.31105] [PMID: 29211297]
[http://dx.doi.org/10.7150/jca.17144] [PMID: 28261342]
[http://dx.doi.org/10.1358/dot.2015.51.1.2250387] [PMID: 25685857]
[http://dx.doi.org/10.1038/s41598-017-06002-8] [PMID: 28717238]
[http://dx.doi.org/10.1097/COC.0000000000000239]
[http://dx.doi.org/10.1186/s40425-018-0349-3] [PMID: 29769148]
[http://dx.doi.org/10.4049/jimmunol.177.2.1052] [PMID: 16818761]
[http://dx.doi.org/10.1007/s00262-017-2039-2] [PMID: 28707078]
[http://dx.doi.org/10.1136/esmoopen-2017-000213] [PMID: 28761757]
[PMID: 23390376]
[http://dx.doi.org/10.1016/j.jtho.2017.01.019] [PMID: 28132868]
[http://dx.doi.org/10.1016/j.cllc.2017.12.001] [PMID: 29396238]
[http://dx.doi.org/10.1007/82_2010_114] [PMID: 21086108]
[http://dx.doi.org/10.1111/imr.12520] [PMID: 28258697]
[http://dx.doi.org/10.3390/ijms18030645] [PMID: 28300768]
[http://dx.doi.org/10.1002/eji.200839028] [PMID: 19544488]
[PMID: 28695059]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-3107] [PMID: 28539467]
[http://dx.doi.org/10.1038/cr.2017.90] [PMID: 28685773]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2428] [PMID: 27208063]
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0072] [PMID: 24894088]
[http://dx.doi.org/10.1158/1078-0432.CCR-17-2542] [PMID: 29203588]
[http://dx.doi.org/10.1016/j.ejca.2017.01.001] [PMID: 28335888]
[http://dx.doi.org/10.1111/j.1365-2567.2010.03398.x] [PMID: 21214544]
[http://dx.doi.org/10.1111/j.1365-2567.2011.03415.x] [PMID: 21342183]
[http://dx.doi.org/10.1158/2326-6066.CIR-13-0219] [PMID: 24592397]
[http://dx.doi.org/10.2147/DDDT.S163304] [PMID: 29731605]
[http://dx.doi.org/10.5483/BMBRep.2014.47.3.283] [PMID: 24499671]
[http://dx.doi.org/10.1111/j.1600-065X.2009.00765.x] [PMID: 19426223]
[http://dx.doi.org/10.1182/blood-2017-06-741041] [PMID: 29118009]
[http://dx.doi.org/10.1007/s00262-016-1829-2] [PMID: 27034234]
[http://dx.doi.org/10.1111/j.1600-065X.2009.00766.x] [PMID: 19426222]
[http://dx.doi.org/10.1053/j.seminoncol.2010.09.013] [PMID: 21074068]
[PMID: 26629424]
[http://dx.doi.org/10.1002/eji.200636933] [PMID: 17407102]
[http://dx.doi.org/10.4161/onci.21425] [PMID: 23264908]
[http://dx.doi.org/10.1016/j.ejca.2016.06.028] [PMID: 27591414]
[http://dx.doi.org/10.2217/imt.15.32] [PMID: 26098609]
[http://dx.doi.org/10.3389/fimmu.2018.00151] [PMID: 29445380]
[http://dx.doi.org/10.1038/cmi.2017.143] [PMID: 29375124]
[http://dx.doi.org/10.1097/PAS.0000000000001099] [PMID: 29901571]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0150] [PMID: 27440266]
[http://dx.doi.org/10.1016/j.intimp.2017.03.024] [PMID: 28365507]
[http://dx.doi.org/10.1186/s13045-018-0644-y] [PMID: 30068361]
[http://dx.doi.org/10.1016/j.ejca.2017.01.011] [PMID: 28324751]
[http://dx.doi.org/10.1007/978-3-540-89615-9_14] [PMID: 19639290]
[http://dx.doi.org/10.1186/s40425-018-0360-8] [PMID: 29914571]
[http://dx.doi.org/10.1016/j.cell.2008.07.001] [PMID: 18662538]
[http://dx.doi.org/10.1007/s10555-006-9006-2] [PMID: 16951986]
[http://dx.doi.org/10.1016/j.trecan.2016.11.008] [PMID: 28718426]
[http://dx.doi.org/10.1080/2162402X.2016.1257453] [PMID: 28197376]
[http://dx.doi.org/10.1517/14728222.2013.782287] [PMID: 23651053]
[http://dx.doi.org/10.1016/j.cell.2017.01.017] [PMID: 28187290]
[http://dx.doi.org/10.3390/ijms19051340] [PMID: 29724044]
[PMID: 26712084]
[http://dx.doi.org/10.1056/NEJMoa1507643] [PMID: 26412456]
[http://dx.doi.org/10.1056/NEJMoa1504627] [PMID: 26028407]
[PMID: 27979383]
[http://dx.doi.org/10.1038/d41586-017-08702-7] [PMID: 29293245]
[http://dx.doi.org/10.20892/j.issn.2095-3941.2016.0015] [PMID: 27458526]
[http://dx.doi.org/10.1186/s40425-017-0218-5] [PMID: 28239469]
[http://dx.doi.org/10.1016/S1470-2045(15)00544-6] [PMID: 26858122]
[http://dx.doi.org/10.1016/S1556-0864(16)30301-X]
[http://dx.doi.org/10.1186/2051-1426-3-S2-P171]
[http://dx.doi.org/10.1016/j.cllc.2016.03.003] [PMID: 27265743]
[http://dx.doi.org/10.1177/1758835918804151] [PMID: 30344651]
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.9027]
[http://dx.doi.org/10.1016/S1470-2045(16)30624-6] [PMID: 27932067]
[http://dx.doi.org/10.1158/1538-7445.AM2018-CT078]