Combining Radiation and Immune Checkpoint Blockade in the Treatment of Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide. Current treatment options, even though potentially curative, have many limitations including a high rate of complications. Over the past few years immune checkpoint inhibitors (ICI) targeting cytotoxic lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have changed treatment paradigms in many malignancies and are currently under investigation in HNSCC as well. Despite improvements in treatment outcomes and the implementation of combined modality approaches long-term survival rates in patients with locally advanced HNSCC remain suboptimal. Accumulating evidence suggests that under certain conditions, radiation may be delivered in conjunction with ICI to augment efficacy. In this review, we will discuss the immune modulating mechanisms of ICI and radiation, how changing the dose, fractionation, and field of radiation may alter the tumor microenvironment (TME), and how these two treatment modalities may work in concert to generate durable treatment responses against HNSCC.

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

“…3 Although effective as monotherapy, the benefits of PD1/PD-L1 blockade in NPC may be enhanced by chemoradiation. 21,22 Platinum-based chemotherapy can result in immunogenic cell death, but may also sensitize tumour cells to radiation-induced DNA damage and potentiate HMGB1/ATP release. 23 After tumour cell phagocytosis, APCs migrate to lymph nodes and prime T-cells with tumour-specific antigen.…”

Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma

“…Similar results were obtained by another small phase II trial [ 133 ], while other studies have evaluated the combination of immune checkpoint inhibition, radiotherapy and cisplatin. Taken together, there appears no major concerns of safety problems with this approach [ 134 , 135 , 136 ].…”

Emerging Concepts and Novel Strategies in Radiation Therapy for Laryngeal Cancer Management

“…The combined effects of ionizing radiation and biological agents have gained considerable interest in the recent past. Different agents, including monoclonal antibodies (cetuximab, bevacizumab) [ 91 ], proteasome inhibitors (bortezomib) [ 92 ], immunomodulatory drugs (nivolumab, pembrolizumab) [ 93 , 94 ], intra-tumoral TNFerade [ 95 ], Aurora kinase A (AURKA) and WEE1 inhibitor [ 96 ] [NC03028766], inhibitors of the enzyme poly-ADP ribose polymerase (PARP inhibitor, i.e., olaparib) [ 97 ] [NCT02229656], and peptidomimetics of the second mitochondrial-derived activator of caspases (SMAC mimetic, i.e., birinapant) [ 98 ] [NCT03803774] have or are currently being studied to evaluate their synergistic effects with RT. The current data of combining radiation and biological agents is mixed, both in clinical response and also in toxicity profiles.…”