Immune checkpoint inhibitors for the treatment of sepsis:insights from preclinical and clinical development

ABSTRACT

Introduction

It is now well established that sepsis induces a state of acquired immunosuppression, with an increased risk of secondary infections that contributes to patients’ worsening. Thus, tackling sepsis-induced immunosuppression represents a promising perspective.

Areas covered

Of mechanisms responsible for sepsis-induced immunosuppression, the increased expression of co-inhibitory receptors such as PD-1, CTLA4, TIM-3, LAG-3, or BTLA and their ligands recently received considerable interest since their inhibition, thanks to the so-called checkpoint inhibitors (CPI), provided astonishing results in cancer by rebooting immune functions. This review reports on the first landmarks of these molecules in sepsis.

Expert opinion

Preclinical results are positive and the first human early phase clinical trials showed a beneficial effect on immunological functions and/or markers and suggested that tolerance of CPIs side effects, mainly auto-immune disorders, is acceptable in sepsis. Elsewhere, in some specific severe ICU infections such as fungal infections, preliminary convincing case reports have been published. Overall, the first results regarding CPIs in sepsis appear encouraging. However, further efforts are warranted, especially in defining the right patients to be treated (i.e. in an individualized approach) and establishing the optimal time to start an immune restoration. Larger trials are now mandatory to confirm CPIs’ potential in sepsis.

KEYWORDS:

• Sepsis
• fungal infection
• check point inhibitors
• critically ill
• septic shock
• immunomodulation

Article highlights

• Sepsis induces acquired immunosuppression.

• Co-inhibitory receptors (aka immune checkpoint) play a role in decreasing immune functions in sepsis, especially those of T cells (decreased proliferation and cytokine production, increased exhaustion).

• In cancer, the blockade of co-inhibitory receptors (mainly PD-1 and CTLA-4) by CPI improves the prognosis of various solid tumors by stimulating immune responses.

• Cancer immunotherapy paved the way for immunostimulation approaches in sepsis.

• Nivolumab (anti-PD-1) and BMS-936559 compound (an anti-PDL-1 humanized monoclonal IgG4 antibody) have been tested in early-stage study in human sepsis and provided adequate PK data.

• Adverse impact of immune restoration in human sepsis requires further evaluation; however, Immune-related adverse events were infrequent in available phase I trials.

• A better characterization of septic patients that may benefit from immune restoration remains to be clarified (i.e. criteria for patients’ stratification)

• Encouraging results limited to case reports have been obtained in the treatment of life-threatening fungal infections.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.