The Stockholm Paradigm: Climate Change and Emerging Disease

Abstract

The current excitement surrounding cancer immunotherapy stemsparticularly from clinical data involving agents mediatingimmune checkpoint receptor blockade, which have inducedunprecedented efficacy against a range of tumours comparedwith previous immunotherapeutic approaches. However, animportant consideration in targeting checkpoint receptors hasbeen the emergence of associated toxicities termedimmune-related adverse events (irAEs). In light of theclinical benefits observed after co-blockade of checkpointreceptors and data from preclinical mouse models, there is nowa strong rationale to combine different checkpoint receptorstogether, with other immunotherapies or more conventionaltherapies to assess if clinical benefits to cancer patientscan be further improved. However, one may predict thefrequency and severity of irAEs will increase withcombinations, which may result in premature therapy cessation,thus limiting the realization of such an approach. Inaddition, there is a limit to how many different combinationtherapies that can be tested in a timely manner given thelegal, regulatory and budgetary issues associated withconducting clinical trials. Thus, there is a need to developpreclinical mouse models that more accurately inform us as towhich immunotherapies might combine best to provide theoptimal therapeutic index (maximal anti-tumour efficacy andlow level irAEs) in different cancer settings. In this reviewwe will discuss the irAEs observed in patients aftercheckpoint blockade and discuss which mouse models of cancercan be appropriate to assess the development of tumourimmunity and irAEs following combination cancerimmunotherapies.