Immune checkpoint inhibitors: maximizing benefit whilst minimizing toxicity

ABSTRACT

Introduction

The advent of immunotherapy has revolutionized the treatment of cancer; anti-tumor efficacy has been observed with immune checkpoint inhibitors (ICI) in ~20 different cancer types with durable responses in some cases. However, the risk of toxicity in the form of immune-related adverse events (irAE) partially counterbalances these benefits, and there are no FDA-approved biomarkers to categorize patients by likelihood of response or risk of irAEs.

Areas covered

We conducted a thorough review of the literature of clinical studies regarding ICI and their toxicities. In this review, we synthesize the current body of literature about ICI treatment and irAE by summarizing the classes and uses of ICI, how to identify patients at risk for irAE, present the current understanding of irAE development, describe ongoing research into biomarkers of irAE, examine opportunities for irAE prevention, described management of steroid refractory irAE, and highlight future directions for development of prevention and management strategies.

Expert opinion

While ongoing biomarker studies are promising, it is unlikely that there will be a ‘one-size-fits-all’ approach to categorizing irAE risk. In contrast, improved management and irAE prophylaxis are potentially in reach, and ongoing trials will help elucidate best practices.

KEYWORDS:

• Biomarkers
• immune checkpoint inhibitors
• immunotherapy
• immune-related adverse events
• toxicity

Article highlights

• Biomarkers of ICI response include PD-L1 expression, TMB, MSI status, development of irAE, fecal microbiome composition, and TIL subtype

• Patients with autoimmune disease are able to be treated with ICI, though there is risk of disease flare with treatment

• Hypothesized mechanisms of irAE include antigen overlap between the tumor and affected organ, direct action on the affected organ, and altered cytokine signaling

• While no approved biomarkers of toxicity exist, possibilities include pre-treatment WBC counts, cytokine levels, specific auto-antibodies, and microbiome evaluation

• Ongoing work examining IL-6 blockade may support a role for prophylaxis against or treatment of irAE

• Management of steroid refractory irAE may benefit from early initiation of non-steroidal immunomodulators including infliximab and abatacept, though prospective clinical trials are needed to balance toxicity management with treatment efficacy

Declaration of interest

DB Johnson has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, has received research funding from BMS and Incyte, and has patents pending for use of MHC-II as a biomarker for immune checkpoint inhibitor response, and abatacept as treatment for immune-related adverse events.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received funding from NIH/NCI T32 CA217834-05.