Oncolytic Virotherapy for Head and Neck Cancer: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Zhan Wang.

Head and neck cancer (HNC) is a significant global health issue, and traditional treatments such as surgery, chemotherapy, and radiation therapy often have limited success, especially in advanced cases. Oncolytic virotherapy (OVT) offers a new approach.

  • head and neck cancer
  • oncolytic viruses
  • clinical trials
  • immunotherapy

1. Introduction

Head and neck cancer (HNC) refers to malignant tumors that occur within the anatomical region extending from the skull base to above the clavicles and in front of the cervical spine. It ranks as the seventh most common malignancy globally, comprising 5% of all cancers in China [1,2,3][1][2][3]. Among all head and neck malignancies, squamous cell carcinoma (SCC) accounts for approximately 90% [4], primarily originating from the oral cavity, nasal cavity, paranasal sinuses, pharynx, and larynx [3]. Due to the complex anatomical and physiological structures in the head and neck region, head and neck squamous cell carcinoma (HNSCC) exhibits high heterogeneity. More than 60% of patients are diagnosed with advanced-stage disease initially, and after comprehensive treatment, the metastasis or recurrence rate ranges from 40% to 60% [5[5][6],6], with a five-year survival rate of less than 50% [7,8,9][7][8][9].
Surgery is the primary treatment modality for HNSCC [3[3][10][11][12],10,11,12], while radiotherapy and chemotherapy are the main treatment options for inoperable cases, advanced-stage disease, or recurrent cases [13,14,15,16][13][14][15][16]. Digital techniques, navigation surgery, and artificial intelligence have been integrated into the overall management of HNCs, further enhancing the precision, safety, and effectiveness of treatment plans [17,18,19][17][18][19]. In addition to surgical, radiation, and chemotherapy approaches, targeted therapy, hyperthermia [20], and radioactive particle interstitial brachytherapy [21,22][21][22] have been utilized. Immunotherapy [23,24,25][23][24][25] has emerged as a crucial treatment option for HNCs, including immune checkpoint inhibitors (ICIs) [26], antiepidermal growth factor receptor monoclonal antibodies [27], and near-infrared photoimmunotherapy [28,29][28][29]. Immunotherapy works by harnessing the patient’s own immune system to activate antitumor immune responses, control and eliminate tumor cells, and reverse tumor immune suppression [30]. Oncolytic virus (OV) immunotherapy involves using viruses to induce tumor cell death, release tumor antigens, and activate the immune system for long-lasting antitumor responses [31,32][31][32]. Genetically modified viruses can enhance the effectiveness of oncolytic virotherapy (OVT) through various antitumor mechanisms [33].

2. Advances of OVT for HNCs

OVT for head and neck tumors is primarily administered through intratumoral or intravenous injection, and has demonstrated good safety profiles in clinical trials. Currently, viruses used in clinical trials for HNCs include DNA viruses such as AD, HSV, and vaccinia virus (VV), as well as RNA viruses such as reovirus (RV), vesicular stomatitis virus (VSV), and measles virus (MV) [37,44,55][34][35][36] (Table 1).
Table 1. Clinical trials of OVT for HNC.
Virus Type Virus Name Clinical Phase Route of

Administration		 Cotherapy Type of Cancer Status ClinicalTrials.Gov ID
Adenovirus ONYX-015 II i.t. cisplatin and fluorouracil HNSCC withdrawn NCT00006106
OBP-301 II i.t. pembrolizumab and SBRT HNSCC terminated NCT04685499
AdGV.EGR.TNF.11D I i.t. RT + 5FU + hydroxyurea HNSCC completed __
KH901 II i.t. __ HNC completed __
E10A III i.t. paclitaxel + cisplatin HNSCC unknown NCT00634595
VCN-01 I i.t. durvalumab HNC active, not recruiting NCT03799744
AdAPT-001 I i.t. ICIs solid tumor recruiting NCT04673942
NG-641 Ib i.v. pembrolizumab HNSCC recruiting NCT04830592
Herpes Simplex Virus T-VEC I/II i.t. RT + cisplatin HNSCC terminated NCT01161498
Ib/III i.t. pembrolizumab HNSCC completed NCT02626000
T-VEC II i.t. pembrolizumab sarcoma active, not recruiting NCT03069378
HF10 I i.t. __ HNSCC, breast cancer, pancreatic cancer, melanoma completed NCT01017185
OH2 I i.t. HX 008 solid tumor, gastrointestinal cancer recruiting NCT03866525
Reovirus Reolysin III i.v. carboplatin,

paclitaxel		 solid tumor completed NCT01166542
Measles Virus MV-NIS I i.t. __ solid tumor completed NCT01846091
Vaccinia Virus GL-ONC1 I i.v. RT + cisplatin HNSCC completed NCT01584284
Pexa-Vec I i.t. ipilimumab solid tumor completed NCT02977156
Vesicular Stomatitis Virus VSV-IFNβ-NIS I i.t./i.v. avelumab solid tumor completed NCT02923466
VSV-IFNβ-NIS I/II i.v. pembrolizumab solid tumor recruiting NCT03647163
Newcastle Disease Virus MEDI5395 I i.v. durvalumab solid tumor recruiting NCT04830592

2.1. Adenovirus

AD contains a double-stranded DNA ranging from 26 to 45 kb, and is currently the most frequently used virus vector in cancer biotherapy. It can cause symptoms of upper respiratory tract infections [56,57][37][38]. The primary receptor for AD is the Coxsackie-adenovirus receptor (CAR), with other receptors including CD46, CD80, CD86, and desmoglein-2 (DSG2) [58][39]. Among oncolytic ADs, adenovirus type 5 (AD5) has been extensively studied, and can infect tumor cells through the CAR receptor [59][40]. In the year 2000, the National Cancer Institute in the United States initiated the phase I clinical trial of the first-generation oncolytic AD, ONYX-015, for the treatment of HNCs. This virus weakened its inhibition of the p53 gene by deleting the E1B55KD gene from its genome, thereby improving tumor targeting. In a phase II clinical trial, 37 recurrent HNSCC patients received intratumor and peritumor injections of ONYX-015. It was observed that the virus caused highly selective destruction of tumor tissue, with significant tumor regression (>50%) observed in 21% of the patients [60][41]. Unfortunately, the phase III clinical trial was terminated due to funding issues. OBP-301 (Telomelysin), based on AD5, was engineered by inserting the hTERT gene promoter upstream of the E1 gene. Studies have shown that combining OBP-301 with cisplatin enhances its effectiveness against HNSCC, and overcomes its resistance to radiotherapy [61][42]. AdGV.EGR.TNF.11D is a nonreplicating AD that expresses human TNF-α under the control of the early growth response factor 1 (EGR-1). When administered intratumorally in combination with 5-fluorouracil and hydroxyurea, it achieved an effective rate of 83.3% in recurrent HNSCC patients, with an average survival of 9.6 months [62][43]. KH901 is a recombinant oncolytic AD constructed through genetic engineering. It is primarily used for intratumoral injection in the treatment of recurrent HNC, and has entered phase II clinical trials [63][44]. In a phase I clinical trial, 23 patients received single-dose intratumoral injections of KH901 or multiple-dose injections over a period of time, and all patients showed good tolerance. The main toxicities observed were mild to moderate flu-like symptoms. No dose-limiting toxicities (DLTs) were reached in either the single-dose or multiple-dose groups, and all 23 treated patients showed an increase in AD-neutralizing antibodies. E10A is an AD that has been engineered to insert the human endostatin gene. It is primarily used for intratumoral injection in combination with paclitaxel and cisplatin for the treatment of HNSCC, and it is currently undergoing phase III clinical trials. A randomized, open-label, multicenter phase II clinical trial (NCT00634595) demonstrated that intratumoral injection of E10A in combination with paclitaxel and cisplatin could prolong progression-free survival (PFS), and improve the overall disease control rate (DCR) compared to paclitaxel and cisplatin chemotherapy alone [64][45]. Apart from fever, no other adverse events (AEs) were reported. Monoclonal antibodies that target the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) pathways have brought about a permanent transformation in the treatment of various types of tumors, some of which were previously associated with a poor prognosis, including HNSCC [65,66][46][47]. The combination of OVs and ICIs in the treatment of HNC holds great research value. Several ongoing clinical trials are dedicated to exploring the combined therapeutic effectiveness of ICIs and OVs in this context [67][48]. VCN-01 is an oncolytic AD based on AD5, with its genome engineered for selective replication in pRB-defective tumor cells. It carries a fibroblast-specific integrin-binding motif RGD sequence for tumor targeting and expresses hyaluronidase to degrade the extracellular matrix. The efficacy and safety of VCN-01 have been confirmed in various tumor models, including HNC [68][49]. Clinical trials have been initiated to investigate the combination therapy of VCN-01 with durvalumab in recurrent and metastatic HNSCC (NCT03799744). AdAPT-001 is a virus derived from human AD5 that has undergone two significant modifications [69][50]. The first modification involves a 50 base pair deletion in the E1A promoter, which makes the virus less likely to affect normal tissues, while maintaining its ability to replicate in and destroy tumor cells. The selectivity of the virus for tumors is also linked to the impaired IFN signaling in cancer cells, which renders them more susceptible to the virus’s cytolytic effects. The second modification introduces a chimeric gene consisting of TGF-β receptor II fused with the Fc portion of human IgG-1, creating a soluble TGFβR-IgG fusion protein that effectively neutralizes the activity of the pro-oncogenic cytokine, TGF-β. As demonstrated by Christopher et al. [69][50], localized oncolytic infection with AdAPT-001 is not only safe, but also overcomes resistance to systemic PD-L1 immunotherapy and provides long-lasting protection against the recurrence of tumors in experiments with syngeneic tumor rechallenge. AdAPT-001 is currently under evaluation in the phase I clinical trial known as BETA PRIME, both with and without ICIs (NCT04673942). NG-641 represents an advanced adenoviral vector for tumor-specific immuno gene therapy (T-SIGn), engineered to be blood-stable and armed with transgenes [70][51]. The mode-of-action transgene study is a phase Ib clinical trial, conducted across multiple centers and in an open-label format, focusing on dose escalation of NG-641 as a standalone treatment or in combination with pembrolizumab (NCT04830592). Eligible patients for this study include those with newly diagnosed or recurrent locally advanced HNSCC who have definitive surgery scheduled within 8 weeks of the screening.

2.2. Herpes Simplex Virus

HSV is an enveloped virus containing approximately 150 kb of double-stranded DNA and encodes around 80 different proteins, which can be classified into type 1 and type 2 [71][52]. Due to the broad host range and the ability to carry various foreign DNA, most oncolytic HSVs entering clinical trials are modified from HSV-1 [72][53]. T-VEC is a recombinant HSV-1 that lacks the γ34.5 and ICP47 genes, but promotes US11 gene expression and encodes GM-CSF [73][54]. In preoperative lymph node injections for HNSCC, T-VEC promotes highly regressive changes in metastatic lymph nodes [74][55]. A phase Ib multicenter trial involving 36 patients investigated the safety and preliminary efficacy of T-VEC in combination with pembrolizumab for the treatment of platinum-resistant recurrent or metastatic HNCs (NCT02626000) [75][56]. The primary endpoint was DLT, and secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and safety. Most treatment-related AEs were grade 1 or 2, and treatment-related grade 2 or 3 AEs associated with T-VEC and pembrolizumab were 13.9% and 16.7%, respectively. There were no treatment-related fatal AEs. Disease control was observed in 13.9% of cases, and 10 cases (27.8%) were unable to evaluate efficacy due to early death. The median PFS and OS were 3.0 months (95% CI, 2.0–5.8 months) and 5.8 months (95% CI, 2.9–11.4 months), respectively, demonstrating the good safety profile of T-VEC. Recent research findings indicate that T-VEC has demonstrated encouraging outcomes in the management of melanoma and sarcoma in the head and neck region. As shown in the study conducted by Franke et al. [76][57], the ORR for T-VEC monotherapy in cases of head and neck melanoma at the Netherlands Cancer Institute reached 80%, with half of the patients achieving a complete response (CR). The median age at the study’s outset was 78.2 years (ranging from 35 to 97), and the median follow-up period extended to 11.6 months. The data present promising outcomes and imply that T-VEC could serve as a viable alternative to systemic therapy for this specific, predominantly elderly patient group. In a phase II clinical trial reported by Kelly et al. [77][58], the treatment combining T-VEC and pembrolizumab exhibited antitumor activity in advanced sarcoma cases, spanning various histologic subtypes of sarcoma, while maintaining a manageable safety profile (NCT03069378). This combination therapy successfully met its predetermined primary study endpoint, and further assessments of T-VEC in conjunction with pembrolizumab for patients with specific subtypes of sarcoma are in the planning stages. HF10 is a naturally occurring HSV with a UL56 gene deletion and has cell-fusion capability [78][59]. Research by Esaki et al. [79][60] showed that HF10 can replicate within HNSCC cells and kill them. HF10 induces tumor necrosis, CD8+ cell infiltration, and the release of antitumor cytokines, including IL-2, IL-12, TNF-α, and IFN-α, -β, -γ, to inhibit tumor growth and prolong survival. Mace et al. [80][61] found that HSV1716 was well-tolerated in the treatment of oral SCC, but had minimal biological activity. The main challenges include optimizing the dose, delivery, and distribution of HSV1716 into the dense heterogeneous tumor cell matrix. Increasing understanding of the interactions between HSV1716, HNSCC cells, and the immune system will help optimize antitumor efficacy. OH2, a novel oncolytic HSV-2, robustly triggers the activation of human peripheral blood mononuclear cells, resulting in heightened antitumor effectiveness in vitro and in vivo [81][62]. At present, it is in the initial phase of clinical trials (phase I) for the treatment of melanoma and various solid tumors (NCT03866525).

2.3. Other OVs

In addition to AD and HSV, various OVs have been used in clinical trials for the treatment of HNC. RV is a naturally occurring OV [82][63]. Oncolytics Biotech reported the data from a randomized, two-arm, double-blind, multicenter phase III clinical trial of RV in combination with standard chemotherapy for advanced stage HNC. Compared to chemotherapy alone, the combination therapy improved the median PFS of patients (94 days vs. 50 days). However, it was associated with increased side effects such as fever, chills, nausea, and diarrhea, although most patients tolerated it well [83][64]. Reolysin (Pelareorep) is derived from Reovirus type 3 Dearing, a naturally occurring OV that activates the RAS pathway and has cytotoxic effects on tumor cells [84,85][65][66]. The phase III clinical trial of combination therapy involving intravenous Reolysin with paclitaxel and carboplatin in HNC patients has been completed (NCT01166542). In phase I and II clinical trials [86][67], involving 24 patients with HNSCC and other HNCs, 1 patient achieved CR, 6 patients achieved partial response (PR), 2 patients had a major clinical response (mCR) after initial radiotherapy, 6 patients had stable disease (SD), and 5 patients experienced disease progression (DP). MV is a negative-sense single-stranded RNA virus [87][68]. MV-NIS is an OV in which the sodium iodine symporter (NIS) gene is inserted into the MV genome, allowing infected cells to be imaged using single-photon emission computed tomography (SPECT) [88][69]. A phase I trial of intratumoral administration of MV-NIS for the treatment of HNSCC has been completed at the Mayo Clinic (NCT01846091). VV is a double-stranded DNA virus, and most adults lack corresponding antibodies. It can infect primary and distant metastatic lesions through intravenous injection [89][70]. GL-ONC1 (GLV-1H68) is a VV-based oncolytic virus in which the viral thymidine kinase (TK), hemagglutinin (HA), and F14.5L genes are replaced by β-galactosidase, β-glucuronidase, and renilla luciferase/green fluorescence (RLuc-GFP), respectively [90,91][71][72]. In a phase I clinical trial, Mell et al. [91][72] found that intravenous injection of GL-ONC1 in combination with cisplatin chemotherapy and radiotherapy improved overall survival in late-stage HNC patients. The one-year and two-year PFS rates were 74.4% and 64.1%, and the one-year and two-year OS rates were 84.6% and 69.2%, respectively. Pexa-Vec is an oncolytic VV engineered with a deletion in the thymidine kinase gene and carries transgenes for GM-CSF and β-galactosidase [92][73]. A phase I clinical trial has been completed to evaluate the intratumoral administration of Pexa-Vec in combination with the CTLA-4 inhibitor ipilimumab for patients with metastatic or advanced tumors (NCT02977156). VSV-hIFNβ-NIS is an oncolytic VSV that expresses human IFN-β and NIS, known to induce rapid and potent tumor regression with systemic treatment [93][74]. VSV-hIFNβ-NIS is involved in two phase I combination trials: one combines it with the anti-PD-L1 antibody avelumab for patients with refractory metastatic solid tumors (NCT02923466), and the other combines it with the anti-PD1 antibody pembrolizumab for patients with select solid tumors (NCT03647163). MEDI5395 is a recombinant Newcastle disease virus (NDV) carrying a GM-CSF transgene [94][75]. Recently, MEDI5395 has entered a phase I trial in combination with the PD-L1 inhibitor durvalumab (NCT03889275).

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