Trends in Immunology
Feature ReviewPredicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines
Section snippets
Immunotoxicity: An Impediment for Immune Checkpoint Inhibitors
The clinical success of immune checkpoint inhibitors (CPIs, see Glossary) – monoclonal antibodies (mAbs) targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1)/PD-ligand-1 (PD-L1) – has led to their clinical FDA approval to treat multiple cancers. However, given the increasing number of patients receiving CPIs, cases of immune-related adverse events (irAEs) are growing, with reports demonstrating their development in a wide range of organs (Table 1) [1,2]
Cytokines as Indicators of irAE Susceptibility
Circulating cytokines may serve as potential biomarkers for identifying individuals at risk of developing irAEs (Table 2). For example, cytokine profiles were assessed longitudinally in metastatic melanoma patients receiving CPI treatment to determine their correlation with severe irAEs, agnostic of affected tissue [11]. A consistent subset of cytokines [granulocyte colony stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), fractalkine, fibroblast growth factor-2,
Clinical Utility of Cytokine Inhibitors in the Treatment of irAEs
Cytokine inhibitors targeting TNF-α, (infliximab, adalimumab, etanercept), IL-6 (tocilizumab), and IL-17A (secukinumab) have been increasingly used to treat CPI-induced irAEs in some cancer patients (Figure 2). These therapies are predominantly administered as a secondary immunosuppressive agent to corticosteroids in complex or severe irAEs, with case reports and retrospective studies reporting clinical results (Table 3). Both infliximab (anti-TNF-α Ab) and tocilizumab (anti-IL-6 receptor Ab)
Inhibiting Cytokines to Limit irAEs and the Consequences for Infective Immunity
The inclusion of cytokine inhibitors in the treatment of irAEs has both advantages and disadvantages, given their potential to impact multiple aspects of the immune system, including infection and antitumor immunity (Table 4). Melanoma patients receiving infliximab to quell irAEs exhibited a higher risk of infection than patients who did not receive infliximab [31]. Reactivation of cytomegalovirus has been reported in metastatic melanoma patients developing anti-TNF-α Ab-refractory CPI-induced
Uncoupling Toxicity and Antitumor Efficacy by Targeting Cytokines
The connectivity between the therapeutic outcome for cancer and the development of irAEs in response to CPI treatment emphasizes the need for precision targeting to uncouple irAEs without sacrificing antitumor immunity [48,49]. Preclinical mouse models that integrate the assessment of antitumor immunity alongside an immune response primed to develop immunotoxicity may help to predict clinically viable treatment options in cancer patients [50]. In addition, evidence from case studies may also
Next-Generation Cytokine Targets To Modulate Cancer Immunotherapy-Induced irAEs
With an increasing number of studies highlighting the ability of next-generation immunotherapies to engage individual cytokines in the control of antitumor immune responses, additional studies to determine their impact on irAE development are needed. For some cytokines, their ability to initiate pleiotropic immune responses that both increase antitumor immunity and reduce autoimmunity could advance their potential for clinical utility alongside CPI treatment, in particular in mitigating irAEs.
Concluding Remarks
Predictive strategies that define the risk of irAEs versus tumor benefit will be essential for optimizing CPI treatment use, or alternatively for redirecting patients towards safer therapeutic modalities. We posit that cytokine responses harbor the potential to delineate these effects. Treatment discontinuation because of the development of irAEs poses a significant impact on the survival benefit gained from CPI treatment [100]. Not only is rapid resolution of irAEs required, but prevention of
Acknowledgments
A.Y. was supported by a National Health and Medical Research Council C.J. Martin Fellowship (GNT1143981). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award K99CA246061 (A.Y.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was also supported by the Parker Institute for Cancer Immunotherapy. We also
Declaration of Interests
J.A.B. is the founder of Sonoma Biotherapeutics and Celsius Therapeutics; a member of the Board of Directors of Gilead, Provention Bio, Sonoma Biotherapeutics, and the Parker Institute for Cancer Immunotherapy; and is a member of the scientific advisory boards of Arcus Biosciences, Solid Biosciences, and Vir Biotechnology. A.Y. and J.H.K. declare no conflicts of interest.
Glossary
- Biomarker
- a measurable indicator that correlates with the presence of a disease or treatment outcome.
- CD4+ type 1 T helper (Th1) cells
- interact with antigen presenting cells to identify cellular and pathogenic abnormalities; polarization to Th1 cells requires IL-12, IFN-γ, and expression of the transcription factor T-bet. Th1 cells are commonly associated with an immune reaction towards viral pathogens, intracellular bacteria, and activation of the immune response to provide antitumor immunity.
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