Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

Abstract

Immunotherapy, especially the immune checkpoint inhibitors (ICIs) such as the pembrolizumab and nivolumab have contributed to significant improvements in treatment outcomes and survival of head and neck cancer (HNC) patients. Still, only a subset of patients benefits from ICIs and hence the race is on to identify combination therapies that could improve response rates. Increasingly, genetic alterations that occur within cancer cells have been shown to modulate the tumor microenvironment resulting in immune evasion, and these have led to the emergence of trials that rationalize a combination of targeted therapy with immunotherapy. In this review, we aim to provide an overview of the biological rationale and current strategies of combining targeted therapy with the approved ICIs in HNC. We summarize the ongoing combinatorial clinical trials and discuss emerging immunomodulatory targets. We also discuss the challenges and gaps that have yet to be addressed, as well as future perspectives in combining these different drug classes.

Keywords: cancer genetics; drug combinations; head and neck cancer; immune checkpoint inhibitor (ICI); immunotherapy; targeted therapy.

Figure 1

Summary of the immunomodulatory effects of inhibiting oncogenic signaling pathways in HNC. These targeted agents not only result in tumor-intrinsic killing, but also modulate the tumor microenvironment, such as increasing immune cell infiltration, activation and differentiation, increasing MHC class I and II antigen presentation, increasing PD-L1 expression, and inhibiting regulatory T cells proliferation. *For illustration purpose only, icons are not drawn in actual scale ratio. ** Some icons are taken from Servier Medical Art (smart.servier.com).