Abstract:
The advent of novel, innovative, and effective anti-cancer immunotherapies has
engendered an era of renewed optimism among cancer specialists and their patients.
Foremost among these successful immunotherapies are monoclonal antibodies (MAbs)
which target immune checkpoint inhibitor (ICI) molecules, most prominently cytotoxic
T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein-1 (PD-1)
and its major ligand, PD-L1. These immunotherapeutic agents are, however, often
associated with the occurrence of immune-mediated toxicities known as immune-related
adverse events (IRAEs). The incidence of severe toxicities increases substantially when
these agents are used together, particularly with CTLA-4 in combination with PD-1 or
PD-L1 antagonists. Accordingly, dissociating the beneficial anti-tumor therapeutic activity
of these agents from the emergence of IRAEs represents a significant challenge to
attaining the optimum efficacy of ICI-targeted immunotherapy of cancer. This situation is
compounded by an increasing awareness, possibly unsurprising, that both the beneficial
and harmful effects of ICI-targeted therapies appear to result from an over-reactive
immune system. Nevertheless, this challenge may not be insurmountable. This
contention is based on acquisition of recent insights into the role of the gut microbiome
and its products as determinants of the efficacy of ICI-targeted immunotherapy, as well
as an increasing realization of the enigmatic involvement of Th17 cells in both anti-tumor
activity and the pathogenesis of some types of IRAEs. Evidence linking the beneficial and
harmful activities of ICI-targeted immunotherapy, recent mechanistic insights focusing on
the gut microbiome and Th17 cells, as well as strategies to attenuate IRAEs in the setting
of retention of therapeutic activity, therefore represent the major thrusts of this review.
