The evolving landscape of ‘next-generation’ immune checkpoint inhibitors: A review

Luca Mazzarella, Bruno Achutti Duso, Dario Trapani, Carmen Belli, Paolo D'Amico, Emanuela Ferraro, Giulia Viale, Giuseppe Curigliano

Research output: Contribution to journalReview articlepeer-review


‘First-generation’ immune checkpoint inhibitors targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed death-ligand 1 (PD(L)1) have undoubtedly revolutionised the treatment of multiple cancers in the advanced setting. Targeting signalling pathways other than core inhibitory modules may strongly impact the outcome of the antitumour immune response. Drugs targeting these pathways (‘next-generation’ immune modulators, NGIMs) constitute a major frontier in translational research and have generated unprecedented scientific and financial investment. Here, we systematically reviewed published literature, abstracts from major cancer conferences and pharma pipelines to identify NGIMs that have reached clinical development. We identified 107 molecules targeting 16 pathways, which we classified into 6 groups according to function (inhibitory vs stimulatory) and cell of predominant expression (lymphoid, non-lymphoid and natural killer). We identified all registered past and ongoing clinical trials (n = 428). We summarise the preclinical rationale for these targets, extracting translationally relevant information, and review published and preliminary clinical results. Some targets like indoleamine-2,3-dioxygenase 1, lymphocyte activation gene-3 and IL15 have experienced exceptional growth of interest, measured in terms of activated studies and expected patient enrolment over time. We conclude that in this vast and rapidly changing drug development landscape, novel trial designs and better biomarker identification are necessary to optimise resource allocation

Original languageEnglish
Pages (from-to)14-31
Number of pages18
JournalEuropean Journal of Cancer
Publication statusPublished - Aug 2019


  • 4-1BB
  • Colony stimulating factor-1 (CSF-1) pathway
  • GITR
  • IDO1
  • LAG3
  • Next generation immune-checkpoints
  • TIM3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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