Immune Checkpoint Inhibitor Exposure in Pregnancy: A Scoping Review

Abstract

Since their approval, immune checkpoint inhibitors (ICIs) have become the standard of care for multiple malignancies. ICIs enhance tumor destruction by blocking important immunomodulatory pathways that regulate T-cell activation. These pathways include programmed cell death protein-1 and its ligands (programmed cell death protein-1 and programmed death ligand-1, respectively) and cytotoxic T-lymphocyte-associated protein 4. While blocking these pathways can enhance tumor destruction, these pathways are critical for the development of maternal tolerance towards the fetus. Therefore, if ICIs disrupt these immunomodulatory pathways, there could be a maternal immune response against the fetus, as was found in animal studies. With few reported cases of human pregnancy exposure to ICIs, the effects of ICIs on human pregnancy remain largely unknown. Here, we review and summarize the 6 cases of maternal exposure to immunotherapy that have been published before the present study. To add to the evidence, we present a case series of 2 patients who have been exposed to immunotherapy in pregnancy.

FIGURE 1

A, An illustration of the PD-1/PD-L1 pathway at baseline, before immune checkpoint inhibitor exposure. If PD-1 is bound to PD-L1, there is no T-cell activation and an immunotolerant effect toward the fetus is observed. B, An illustration of the PD-1/PD-L1 pathway after exposure to immune checkpoint inhibitors. The introduction of an anti-PD-1/PD-L1 monoclonal antibody promotes T-cell activation (enhancing tumor destruction) and possible fetal rejection. PD-1 indicates programmed cell death-1; PD-L1, programmed cell death ligand-1.

FIGURE 2

A, An illustration of the CTLA-4 pathway at baseline, before immune checkpoint inhibitor exposure. If CTLA-4 is bound to the B7 ligands, there is no T-cell activation and an immunotolerant effect toward the fetus is observed. B, An illustration of the CTLA-4 pathway after exposure to immune checkpoint inhibitors. The introduction of an anti-CTLA-4 monoclonal antibody promotes T-cell activation (enhancing tumor destruction) and possible fetal rejection. CTLA-4 indicates cytotoxic T-lymphocyte–associated protein 4.