Immune Checkpoint Inhibitor Toxicity in Head and Neck Cancer: From Identification to Management

Abstract

Benefiting from the continuously clarifying underlying biology of immune checkpoints and ligand–receptor interactions, the emergence of new anticancer treatment strategy, immunotherapy has shown substantial benefits on several liquid and solid tumors. Immune checkpoint inhibitors (ICIs) can block the negative regulatory components and enhance the T cell function, thus leading to prominent anticancer activity. On account of their promising effect on various malignancies shown in clinical trials, ICIs have been considered to be the most potent anticancer agents in the near future. Head and neck cancer is the seventh most common neoplasm worldwide, and the gross 5-year survival rate was only 60%. Managing locoregionally advanced, recurrent, or metastatic head and neck tumors is still a challenging problem for both oncologists and surgeons. Recent clinical trials employing the immune-modulating antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) herald a new era of anticancer therapy. However, like all other anticancer drugs, ICIs also have side effects while upregulating the immune system to enhance antitumor response, which were known as immune-related adverse events (irAEs). Generally, most irAEs were transient, but sometimes they can cause serious organ dysfunction, even fatal. In addition, due to the distinct anatomical feature, advanced head and neck tumors often affect the upper aerodigestive tract and cause serious dyspnea or dysphagia. Toxicities of ICIs may be more lethal for such patients. Thus, with the increasing application of anti-checkpoint agents in head and neck cancer, there is urgent need to ascertain the safety of this novel treatment strategy. Here, we compile this review of existing clinical trials on the toxicity of ICIs during cancer treatment. The particular clinical manifestation, characteristics of complication development in fatal cases, and the management strategies were discussed. This may provide vital information for future oncology trials and clinical practice.

Head and neck squamous cell carcinoma

“…The non-redundant functions of PD1 and CTLA4 in regulating the adaptive immune system serve as the basis for combining PD1 and CTLA4 inhibitors for cancer therapy, including HNSCC, in ongoing clinical trials. Whereas PD1 and PDL1 inhibitors are generally well tolerated, CTLA4 inhibitors are associated with more toxicity 247 , and it will be important to balance efficacy and toxicity when combining these agents. In addition, although adaptive immune cell therapies (for example, chimeric antigen receptor (CAR) T cells) and therapeutic vaccines are not FDA-approved, they are under active investigation in head and neck cancer and represent a promising new avenue for therapy.…”

Nivolumab‐related tracheobronchial chondritis: Extremely rare manifestation of an immune‐related adverse effect

“…Nivolumab, as an antibody that binds to the programmed cell death‐1 receptor, is an ICI that has been recognized as a promising agent against RMSCCHN refractory to chemotherapy; however, its mechanism of action may result in irAEs. Most irAEs are transient and mild, such as skin disorders and gastrointestinal symptoms, but serious fatal complications, such as interstitial pneumonia (IP), myocarditis, pituitary insufficiency, and ischemic colitis may occur in exceedingly rare cases 4 . Because irAEs may affect any organ system, with various clinical presentations, other unprecedented irAEs may also occur.…”

Immunosuppressive microenvironment in oral cancer: implications for cancer immunotherapy

“…CPI PD-1 and PD-L1 were the first to be approved as second-line treatments for HNSCC [157]. The CPIs that have been tested on HNSCC incorporate PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab, durvalumab, and avelumab), and CTLA4 (ipilimumab and tremelimumab) [158][159][160][161]. Besides these, lymphocyte activated gene (LAG)-3, Tim-3, and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) are also checkpoint molecules associated with the tumor immune evasion but their role in HNSCC is not well understood.…”