Overcoming Resistance to Immunotherapy in Head and Neck Cancer Using Radiation: A Review

Abstract

Radiation therapy remains at the center of head and neck cancer treatment. With improvements in treatment delivery, radiation therapy has become an affective ablative modality for head and neck cancers. Immune checkpoint inhibitors are now also playing a more active role both in the locally advanced and metastatic setting. With improved systemic options, local noninvasive modalities including radiation therapy are playing a critical role in overcoming resistance in head and neck cancer. The aim of this review is to describe the role of radiation therapy in modulating the tumor microenvironment and how radiation dose, fractionation and treatment field can impact the immune system and potentially effect outcomes when combined with immunotherapy. The review will encompass several common scenarios where radiation is used to improve outcomes and overcome potential resistance that may develop with immunotherapy in head and neck squamous cell carcinoma (HNSCC), including upfront locally advanced disease receiving definitive radiation and recurrent disease undergoing re-irradiation. Lastly, we will review the potential toxicities of combined therapy and future directions of their role in the management of HNSCC.

Alcohol and Head and Neck Cancer: Updates on the Role of Oxidative Stress, Genetic, Epigenetics, Oral Microbiota, Antioxidants, and Alkylating Agents

“…Treatment possibilities include tumor resection (primary and/or secondary tumor), radical neck dissection, immunotherapy, radiotherapy, checkpoint inhibitors (mainly targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and chemotherapy [ 40 , 41 , 42 , 43 , 44 , 45 ]. Recently, it has been showing how, in locally advanced HNSCC, the CTCs and the circulating tumor microemboli (CTM) have a significant prognostic impact on the potential role as predictors of induction chemotherapy benefit [ 46 ].…”

Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors

“…Therapeutic neck dissection and/or elective nodal irradiation (ENI) are utilized to minimize local and regional recurrence. Despite an aggressive treatment regimen, approximately 50% of patients with high-risk disease recur locally, regionally, or distantly by 3-years 2 . With the advent of immunotherapies, there was hope that patients with HNSCC would benefit from immune checkpoint inhibitors, but results of recent trials have dampened that hope 3 , 4 .…”

A phase I/Ib trial and biological correlate analysis of neoadjuvant SBRT with single-dose durvalumab in HPV-unrelated locally advanced HNSCC

“…Preclinical and clinical trials have shown that patients with increased T cell infiltration at the time of treatment for HPV-unrelated HNSCC have improved outcomes in response to immune checkpoint therapy 9 , 10 . Combining immunotherapies with radiation therapy to increase immune cell infiltration into the tumor microenvironment (TME) may improve response rates 11 – 13 . Hypofractionated stereotactic body radiation therapy (SBRT) may improve anti-tumor immune function instead of blunting it 13 .…”

“…Combining immunotherapies with radiation therapy to increase immune cell infiltration into the tumor microenvironment (TME) may improve response rates 11 – 13 . Hypofractionated stereotactic body radiation therapy (SBRT) may improve anti-tumor immune function instead of blunting it 13 . Dose-escalation studies have shown that hypofractionation is optimal for stimulating an anti-tumor immune response while minimizing an immune wound-healing phenotype 14 – 17 .…”