Current clinical and observational evidence supports the EXTREME regimen as one of the standards of care for patients with recurrent or metastatic
head and neck squamous cell carcinoma (
HNSCC) followed by the administration of
immune checkpoint inhibitors (ICIs). In addition to the inhibition of the
epidermal growth factor receptor (EGFR) pathway,
cetuximab-mediated EGFR blockade has been shown to modulate tumor microenvironment (TME) characteristics, such as antibody-dependent cellular cytotoxicity (ADCC) activity, cytotoxic T-lymphocyte (CTL) infiltration into the
tumor, anti-angiogenesis activity, and
cytokine secretion via associated natural killer (NK) cells, etc.. On the other hand, there are reports that
nivolumab affects the TME via Programmed cell death 1 (PD-1) inhibition,
Interleukin-10 upregulation via T-cells, myeloid-derived suppressor cell-mediated immune escape induction, and
tumor vessel perfusion by promoting CD8 + T-cell accumulation and
Interferon-γ production in treatment-sensitive
tumor cells. Actually,
nivolumab administration can give T cells in the TME both immune superiority and inferiority.
HNSCC treatment using
cetuximab increases the frequency of FoxP3 + intratumoral effector regulatory T cells (Tregs) expressing CTL associated
antigen (CTLA)-4, and targeting CTLA-4 + Tregs using
ipilimumab restores the cytolytic function of NK cells, which mediate ADCC activity. Treg-mediated immune suppression also contributes to clinical response to
cetuximab treatment, suggesting the possibility of the addition of
ipilimumab or the use of other Treg ablation strategies to promote antitumor immunity. Moreover, also in hyper
progression disease (HPD), intratumoral frequency of FoxP3 + effector Tregs expressing CTLA-4 is increased. Therefore, combination treatment with
cetuximab plus anti-CTLA-4 antibody
ipilimumab for
HNSCC and this combination
therapy after
nivolumab administration for HPD may be expected to result in a higher
tumor-control response. Based on the above evidence, we here suggest the efficacy of using these therapeutic strategies for patients with local-advanced, recurrent, and metastatic
HNSCC and patients who do not respond well to
nivolumab administration.