2585 Review Article on Synergy in Action: Novel Approaches to Combining Radiation Therapy and Immunotherapy Combinations of immunotherapy and radiation therapy in head and neck squamous cell carcinoma: a narrative review Thomas J. Hayman1, Aarti K. Bhatia2, Krishan R. Jethwa1, Melissa R. Young1, Henry S. Park1^ 1Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA; 2Section of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT, USA Contributions: (I) Conception and design: TJ Hayman, HS Park; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: TJ Hayman, HS Park; (V) Data analysis and interpretation: TJ Hayman, HS Park; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Henry S. Park, MD, MPH. Assistant Professor of Therapeutic Radiology, Yale School of Medicine, 35 Park Street, Lower Level, New Haven, CT 06520, USA. Email: [email protected]. Abstract: Radiation therapy and systemic therapy are the primary non-surgical treatment modalities for head and neck squamous cell carcinoma (HNSCC). Despite advances in our biologic understanding of this disease and the development of novel therapeutics, treatment resistance remains a significant problem. It has become increasingly evident that the innate and adaptive immune systems play a significant role in the modulation of anti-tumor responses to traditional cancer-directed therapies. By inducing DNA damage and cell death, radiation therapy appears to activate both innate and adaptive immune responses. Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) also have yielded promising results, particularly in the recurrent/metastatic setting. In this review, we will discuss the rationale for combining radiotherapy with immunotherapy to harness the immunomodulatory effects of radiation therapy on HNSCC, as well as biomarkers for immune response. We will also review recent preclinical and clinical data exploring these combinations in various contexts, including recurrent/metastatic and locally advanced disease. Among those with locally advanced HNSCC, we will discuss clinical trials employing immunotherapy either concurrently with radiation therapy or as maintenance following chemoradiation in both the definitive and postoperative settings, with or without the use of cisplatin-based or non-cisplatin-based chemotherapy. Keywords: Radiation therapy (RT); immunotherapy; synergy; head and neck cancer; squamous cell Submitted May 16, 2020. Accepted for publication Jul 23, 2020. doi: 10.21037/tcr-20-2096 View this article at: http://dx.doi.org/10.21037/tcr-20-2096 Introduction understand and exploit interactions of oncogenic signaling pathways with RT (2). Specifically, the epidermal growth Radiation therapy (RT) combined with systemic therapy factor receptor (EGFR) pathway has garnered interest both is the primary non-surgical definitive treatment option for locally advanced head and neck squamous cell carcinoma pre-clinically and clinically in HNSCC, especially after (HNSCC), which causes over 400,000 deaths annually an overall survival (OS), progression-free survival (PFS), worldwide (1). Despite treatment intensification, local and locoregional control (LRC) benefit was shown with recurrence occurs in up to 50% of patients with locally the addition of the EGFR-targeted monoclonal antibody advanced disease. This has led to a concerted effort to cetuximab to RT compared with RT alone (3). However, ^ ORCID: 0000-0002-9366-8514. © Translational Cancer Research. All rights reserved. Transl Cancer Res 2021;10(5):2571-2585 | http://dx.doi.org/10.21037/tcr-20-2096 2572 Hayman et al. Radiation and immunotherapy for head and neck cancer when cetuximab-based chemoradiotherapy was compared non-small cell lung cancer (NSCLC), melanoma, and with the combination of RT and cisplatin (a crosslinking HNSCC (nivolumab and pembrolizumab) (12). Despite cytotoxic chemotherapy), OS, PFS, and LRC were their successes, responses as monotherapy have largely significantly worse in unselected patients with HPV-positive been limited to certain subsets of patients, suggesting oropharyngeal cancer who received cetuximab rather than highlighting the importance of combination therapy and cisplatin (4,5). Furthermore, combining cetuximab and development of biomarkers to predict response. cisplatin together with RT failed to improve outcomes The rationale for the use of immunotherapy in HNSCC relative to cisplatin and RT (6). These data demonstrate stems from several observations (13). First it has been shown the need to identify novel therapies to improve patient that HNSCC has a relatively high tumor mutation burden outcomes beyond those currently achievable with the (TMB) (14), with high TMB shown to be predictive for combination of RT with standard cytotoxic and/or EGFR- increased efficacy of ICIs (7,15). In human papillomavirus targeted systemic therapy. (HPV)-negative HNSCC, the carcinogen and tobacco Over the past decade there has been increasing mutagenesis signatures are thought be associated with recognition of the immune system’s importance in the enhanced ICI response (13). Conversely, HPV-positive regulation of oncogenesis and response to therapy. HNSCC are postulated to be rendered sensitive to ICIs Numerous preclinical and clinical studies have shown that secondary to APOBEC (apolipoprotein B mRNA editing tumors are able to evade immune recognition via a variety catalytic polypeptide-like) proteins and their associated of mechanisms leading to tumor progression and ultimately gene-editing function (16,17). Several APOBEC proteins death (7,8). Specifically, two immune checkpoint pathways, have increased expression in HPV-positive HNSCC relative cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and to HPV-negative disease, as they are viral response genes. programmed cell death protein 1/programmed cell death APOBEC proteins lead to mutagenesis with these neo- ligand 1 (PD-1/PD-L1) have been the most well-studied peptides predicted to exhibit greater hydrophobicity and targets for immunotherapy (9). CTLA-4 regulates the hence enhanced immunogenicity and correlation with amplitude of early activation of naïve and memory T-cells increased ICI response (18). Additionally, HNSCC has via its binding to B7-1 or B7-2 molecules on the antigen been shown to be immunosuppressive with many patients presenting cells (APCs) (9). It inhibits or dampens T-cell with HNSCC showing impaired TILs, natural killer (NK) function primarily by diminishing signaling through the co- cells, and decreased antigen-presenting capacity (13). stimulatory CD28 receptor by competing with CD28 for Furthermore, upregulation of PD-L1 in HNSCC and other binding to B7-1 or B7-2. This prevents the necessary second tumor types lead to impaired T-cell function (8). Therefore, signal that supports T-cell activation and stops a T-cell immunomodulatory therapies that can simultaneously mediated sustained immune response (10). Whereas CTLA- reverse the immunosuppressive phenotype of HNSCC 4 is involved in the early immune response, PD-1/PD-L1 and take advantage of increased mutagenesis may have function primarily to constrain the activity of T-cells in the therapeutic significance for patients with HNSCC. periphery to limit autoimmunity. The interaction of PD-L1 RT remains a critical modality for both definitive and with PD-1 [present on most tumor-infiltrating lymphocytes palliative treatments in HNSCC. The immunomodulatory (TILs)] lowers the threshold for lymphocyte apoptosis, leads effects of RT have been recognized for decades, given that to anergy by blunting T-cell receptor (TCR) signaling, and the toxicities of RT are often immunologically-mediated (e.g., ultimately causes T-cell depletion and exhaustion (10,11). fibrosis, necrosis, and acute inflammation) (19). Furthermore, Ipilimumab, an inhibitory monoclonal anti-CTLA-4 preclinical and clinical data have characterized the antibody, was the first immune checkpoint inhibitor (ICI) immunomodulatory effects of radiation, leading to significant to be tested and approved for use in cancer therapy with interest in combining ICIs and other immunotherapies with large clinical trials showing improvements in OS, PFS, RT. In this review, we highlight the relevant studies that have and response rates in melanoma and other malignancies; examined combinations of ICIs and RT for HNSCC, as however, there is no clear evidence that CTLA-4-directed well as future possible combinations with immunotherapies therapy is active in HNSCC (10). Drugs targeting PD-1 beyond ICIs. (e.g., nivolumab and pembrolizumab) and PD-L1 (e.g., We present the following article in accordance with the atezolizumab and durvalumab) have been developed NARRATIVE REVIEW Reporting Checklist (available at and approved for use in several malignancies, including http://dx.doi.org/10.21037/tcr-20-2096). © Translational Cancer Research. All rights reserved. Transl Cancer Res 2021;10(5):2571-2585 | http://dx.doi.org/10.21037/tcr-20-2096 Translational Cancer Research, 2020 2573 Effects of HPV status on immune true in HPV-positive HNSCC as well, and suggests that microenvironment in HNSCC having higher-risk HPV-positive disease (e.g., >10 pack year smoking history) may inform response to ICIs, but this HPV status of HNSCC is strongly prognostic and deserves further evaluation. predictive with regards