New Therapies in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent.

Keywords: cancer; head; immunotherapy; neck; squamous cell.

Figure 1. Stimulation of the EGFR Pathway Drives Survival and Proliferation of Tumor Cells

The epidermal growth factor receptor (EGFR) transduces extracellular signals by activating phosphoinositide 3-kinase (PI3K), which in turn facilitates the conversion of phosphatidylinositol 4,5-bisphosphate (PIP₂) to phosphatidylinositol 3,4,5-trisphosphate (PIP₃). Presence of PIP₃ ultimately results in cell survival and proliferation via several downstream mediators, notably the mechanistic target of rapamycin (mTOR). EGFR can also activate the signal transducer and activator of transcription 3 (STAT3), which is a transcription factor for genes involved in cell survival and proliferation. Monoclonal antibody-based therapeutics include cetuximab, panitumumab, nimotuzumab, zalutumumab, Sym004, ABBV-221, and imgatuzumab, which all target the EGFR extracellular domain. Erlotinib, gefitinib, dacomitinib, and afatinib are small molecule tyrosine kinase inhibitors that are directed toward the EGFR intracellular domain. PI3K is targeted by small molecules that include buparlisib, SF1126, alpelisib, INCB050465, copanlisib, and IPI-549. Sirolimus, everolimus, and temsirolimus are related compounds that inhibit mTOR. In addition to small molecule inhibition, therapeutic oligonucleotide decoys can bind to STAT3, and antisense oligonucleotides like AZD9150 can silence STAT3 mRNA.

Figure 2. Immunotherapy Landscape in Head and Neck Cancer

Binding of programmed cell death protein 1 (PD-1) to its ligand, PD-L, causes T cell suppression. Pembrolizumab and nivolumab are mAbs that bind to PD-1 and antagonize its immunosuppressive effects. Activation of cytotoxic T-lymphocyte-associated protein (CTLA-4) also causes T cell suppression. Moreover, binding of CTLA-4 to B7 causes B7 downregulation, which is also immunosuppressive. Ipilimumab prevents ligand binding to CTLA-4, thereby antagonizing this immunosuppression. Activation of co-stimulatory receptors, such as CD40, glucocorticoid-induced tumor necrosis factor receptor (GITR), and toll-like receptors (TLRs), causes immune system stimulation. Binding of mAb SEA-CD40 to CD40 causes antigen presenting cell (APC) maturation and can also induce antibody-dependent cell-mediated cytotoxicity (ADCC) by binding the FcγRIIIα receptor. The mAb INCAGN01876 binds GITR and ultimately leads to T cell proliferation. The small molecule motolimod, and oligonucleotide SD-101 bind TLRs on APCs, thereby stimulating host defense. Indoleamine 2,3-dioxygenase (IDO) and arginase 1 (Arg1) deplete tryptophan and L-arginine, respectively. Both amino acids are essential for T cell proliferation. Epacadostat inhibits IDO while INCB001158 inhibits Arg1. Inducible nitric oxide synthase (NOS2) produces nitric oxide (NO), which causes T cell suppression. L-NMMA is a NOS2 inhibitor.