Phase I clinical trial of a recombinant oncolytic virus injection combined with PD-1 antibody-based gene therapy for recurrent head and neck cancer in China: An open-label study

Highlights

• •VT1093 demonstrates dual anti-tumor effects through oncolytic virotherapy and anti-PD-1 immunotherapy.
• •VT1093 exhibits a favorable safety profile in treating locally advanced unresectable head and neck cancer.
• •VT1093 shows therapeutic efficacy in patients with locally advanced unresectable head and neck cancer.

Abstract

This study aims to evaluate the safety and preliminary efficacy of VT1093, an oncolytic recombinant herpes simplex virus type 1 (HSV-1) engineered to express a PD-1 monoclonal antibody, for the treatment of recurrent head and neck cancer. This open-label, single-arm, dose-escalation Phase I clinical trial was an exploratory dose-escalation study, in which the dose is progressively increased in enrolled patients until either the maximum tolerated dose (MTD) or dose-limiting toxicity (DLT) is identified. Seven patients with recurrent head and neck cancer were recruited at Beijing Tongren Hospital. Patients received either a single or multiple intratumoral injections of VT1093. For the single-dose group, patients were monitored for 28 days after treatment. For the multiple-dose group, three treatments were administered biweekly, with a 28-day follow-up after the final injection. Treatment efficacy and adverse events were monitored and recorded throughout the study. Of the seven patients enrolled, five were eligible for efficacy evaluation. Two patients did not return for follow-up evaluation after treatment and were classified as treatment ineffective. Four patients achieved stable disease (SD), while one had progressive disease (PD), resulting in a disease control rate (DCR) of 57.1 % (4/7). The most common treatment-related adverse events were mild to moderate fever and fatigue (Grade 1–2), with no Grade 3 or higher events. A promising immune profile was found in response to the oncolytic virus injection combined with PD-1 antibody. The treatment was generally well tolerated, and no DLTs were observed. VT1093 shows promising efficacy in controlling disease progression in recurrent head and neck cancer, with a favorable safety profile and low toxicity. These results support further clinical development of VT1093 as a novel therapeutic approach for this patient population.

1. Introduction

Head and neck cancers (HNC) are among the most prevalent malignancies worldwide, with their incidence steadily rising in recent decades (Tran et al., 2022). Despite advancements in clinical technologies and the introduction of multidisciplinary diagnostic and therapeutic approaches, the unique anatomical and functional characteristics of the head and neck regions pose significant treatment challenges. These limitations highlight the pressing need for innovative therapeutic strategies to improve patient outcomes.

One promising avenue is the use of oncolytic viruses (OVs), a class of replication-competent viruses that can selectively infect and kill cancer cells while stimulating an immune response. OVs replicate within tumor cells, leading to their destruction through cell lysis and simultaneously disrupting the tumor's immunosuppressive microenvironment. This action recruits immune cells to target residual tumor cells, all while sparing healthy tissues (Bell and McFadden, 2015; Gujar et al., 2019). The dual role of direct oncolysis and immune activation makes OVs particularly appealing for cancers that are difficult to treat with conventional methods, such as HNC.

An exciting development in this field is VT1093, a genetically engineered herpes simplex virus type I (HSV-1) designed by the Beijing Wellgene biotech to express a human PD-1 monoclonal antibody. This innovative therapeutic agent not only selectively replicates within tumor cells but also blocks the PD-1/PD-L1 pathway, a critical immune checkpoint that tumors exploit to evade immune detection. By expressing the PD-1 antibody during tumor lysis, VT1093 effectively enhances T cell-mediated tumor killing, modifies the tumor immune microenvironment, and promotes sustained anti-tumor immune responses (Tian et al., 2021). This dual mechanism offers a synergistic approach: the virus both directly destroys tumor cells and unleashes the immune system against the cancer.

VT1093 underwent preclinical safety and toxicology assessments at JOINN Laboratories in China and subsequently obtained clinical trial approval from the CDE (Center for Drug Evaluation). To evaluate the potential of VT1093, we conducted a Phase I clinical trial in patients with recurrent head and neck cancer. The primary objective was to assess the safety and preliminary efficacy of VT1093 administration. Early results from this trial suggest that VT1093 is well tolerated and demonstrates promising anti-tumor activity, warranting further exploration in more extensive clinical trials. By targeting both the tumor cells and the immune escape mechanisms, VT1093 represents a novel therapeutic strategy with the potential to significantly improve outcomes for HNC patients.

2. Materials and methods

2.1. Study design

This Phase I, single-center, open-label, single-arm, clinical trial was designed using an exploratory dose-escalation framework to assess VT1093 in patients with recurrent and unresectable head and neck cancer (HNC). Seven patients were enrolled and assigned sequentially to different dose groups. Patients received either single or multiple intratumoral injections of VT1093. In the single administration group, doses included 1 × 10⁷ pfu, 1 × 10⁸ pfu, and 5 × 10⁸ pfu. After injection, patients were monitored for 28 days, with weekly safety evaluations and treatment assessments on day 29.

For the multiple administration group, patients received 1 × 10⁸ pfu or 5 × 10⁸ pfu over three injections at two-week intervals. Safety was monitored one week after each dose, with additional evaluations two and four weeks after the final injection. Treatment outcomes were assessed on day 29 post-final injection, and patients were followed until disease progression or death.

All treatments were administered via intratumoral injection. The study was approved by the Ethics Committee of Beijing Tongren Hospital (Approval No. TREC2021–98) and registered under trial number CTR20210659. All patients or their legal representatives provided informed consent.

2.2. Inclusion criteria

The inclusion criteria for this study were as follows: (I) patients with recurrent and unresectable head and neck cancer (HNC) confirmed by histology and/or cytology; (II) patients who had failed standard treatments or were unsuitable for them, such as those with recurrence after radiotherapy, involvement of the pterygoid muscle, severe cranial neuropathy, invasion of the common/internal carotid artery, or direct extension to the skull base, mediastinal structures, or prevertebral fascia; (III) patients aged between 18 and 75 years, irrespective of gender; (IV) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (V) an expected survival time of more than three months; (VI) presence of at least one measurable lesion suitable for intratumoral injection, as defined by RECIST 1.1 criteria (Eisenhauer et al., 2009); and (VII) positive serum anti-HSV-1 antibody.

2.3. Exclusion criteria

The exclusion criteria were as follows: (I) history of severe immunotherapy-related adverse reactions to prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapies; (II) severe or uncontrolled conditions, including uncontrolled hypertension, myocardial ischemia, infarction, or arrhythmias, active or uncontrolled serious infections, history of organ or hematopoietic stem cell transplantation, severe immunodeficiency, or 24-hour urine protein >1.0 g; (III) history of type I diabetes; (IV) severe abnormalities in thyroid or adrenal function tests; (V) presence of primary or metastatic brain tumors; (VI) severe pulmonary interstitial changes or active pulmonary tuberculosis; (VII) active bleeding or significant coagulation disorders; (VIII) history of a second primary cancer within the past three years; (IX) receipt of anti-tumor treatments (endocrine therapy, chemotherapy, radiotherapy, targeted therapy, immunotherapy, or traditional Chinese medicine) within four weeks prior to the first administration; and (X) receipt of anti-HSV treatments (e.g., acyclovir, ganciclovir, valaciclovir, vidarabine) within four weeks prior to study treatment.

2.4. Study clinical assessments

2.4.1. Clinical data

Seven patients were enrolled in this study (Table 1), including five males (71.4 %) and two females (28.6 %), with ages ranging from 39 to 74 years (median age: 56). The Eastern Cooperative Oncology Group (ECOG) performance status scores ranged from 0 to 2, with a median score of 1.71. All patients were diagnosed with recurrent head and neck cancer (HNC). The tumor types included parotid gland adenoid cystic carcinoma (ACC), parotid gland mucoepidermoid carcinoma, laryngeal squamous cell carcinoma, maxillary sinus squamous cell carcinoma, nasopharyngeal carcinoma, hypopharyngeal squamous cell carcinoma, and tongue squamous cell carcinoma. Imaging (enhanced CT/MRI) confirmed disease progression, and patients were classified as stage IV (three cases), stage IVB (two cases), stage IVA (one case), and stage IVC (one case). All patients had undergone prior treatments, including surgery (5 cases, 71.4 %), chemotherapy (6 cases, 85.7 %), and radiotherapy (5 cases, 71.4 %). Four patients (57.1 %) had received more than two types of standard treatments. Tumor diameters in the injected lesions ranged from 38 mm to 105 mm, with a median diameter of 96 mm.

Table 1.

Clinical profile of patients receiving injections.

ID	Group	Gender	Age	Tumor type	Clinical stages	TNM stages	The long diameter of injection lesion	ECOG	Previous treatment
TR-001	1	male	74	laryngeal SCC	IVb	rT2N3bM0	103mm	2	S + R + C
TR-002	1	male	56	maxillary sinus SCC	IVc	T4bN0M1	98mm	2	S + R + C
TR-003	1	female	39	paroid mucoepidermoid carcinoma	IVb	T4bN3bM0	96mm	1	S + C
TR-006	1	male	50	nasopharyngeal carcinoma	IVa	TxN3M0	63mm	1	R + C
TR-005	M	male	62	hypopharyngeal SCC	IVb	T2N3bM0	105mm	2	S + R + C
TR-007	M	female	65	tongue SCC	IVb	T4bN2M0	38mm	2	C
TR-008	M	male	42	parotid ACC	IVb	T4bN2cM0	56mm	2	S + C

1: single dose, M: multiple dose. S: surgery, C: chemotherapy, R: radiotherapy.TR-004 was ultimately excluded due to negative HSV-1 antibody.

2.4.2. Treatment observation

All seven patients successfully completed at least one intratumoral injection of VT1093. In the single-administration group, four patients participated: two in the 1 × 10⁷ pfu dose group (TR-001, TR-002), one in the 1 × 10⁸ pfu dose group (TR-003), and one in the 5 × 10⁸ pfu dose group (TR-006). In the multiple-administration group, three patients were included: two received three injections of 1 × 10⁸ pfu (TR-005, TR-007), and one received three injections of 5 × 10⁸ pfu (TR-008). Of the seven patients, five with complete follow-up were evaluated for treatment efficacy. Two patients (TR-002, TR-005) were not evaluated for efficacy as they withdrew from the trial before the efficacy assessment could be conducted (see Fig. 1).

Fig. 1.

Treatment flowchart of 7 enrolled patients.

VT1093 is an oncolytic herpes simplex virus type I genetically engineered to express a human anti-PD-1 monoclonal antibody. Each 1.0 ml vial contains a viral titer of 1 × 10⁸ pfu/ml, with batch numbers 20,201,202 and 20,220,904.

2.4.3. Treatment effect observation

Enhanced CT/MRI scans were conducted to evaluate all lesions, both prior to treatment and on the 29th day following the last administration. Efficacy was assessed based on the RECIST 1.1 criteria, considering target lesions, non-target lesions, and the appearance of any new lesions to determine the best overall response: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), or Not Evaluable (NE). Additionally, ECOG performance status, body weight, and clinical symptoms were recorded before and after treatment to track patient conditions. Adverse events were systematically documented from the first treatment onward and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

2.5. Statistical methods

This study was limited by a small sample size and the absence of a control group, which resulted in insufficient data integrity that failed to meet the fundamental requirements for rigorous statistical analysis. Although the sample size was insufficient for comprehensive statistical analysis, the safety and efficacy of the treatments were thoroughly documented throughout the study. Therefore, in alignment with the study’s research objectives, we prioritized presenting key data in a descriptive format to ensure the comprehensiveness of information pertinent to the core exploratory aims. All patients who received treatment were included in the final analysis, regardless of whether they withdrew from the study at any point. This study presented key information clearly via tables and textual descriptions, including patient clinical characteristics, outcomes, adverse event incidence rates, and trends in lesion changes. This approach preserved data authenticity while preventing any compromise of result rigor that might arise from excessive statistical manipulation.

3. Results

All seven patients completed the treatment regimen, and no treatment-related deaths were reported. The treatment outcomes are summarized in Table 2. Among the seven enrolled patients, five were evaluable for efficacy. Four of these achieved stable disease (SD), while one had progressive disease (PD), yielding a disease control rate (DCR) of 80 % among evaluable patients. When considering all enrolled patients (intention-to-treat), the DCR was 57.1 % (4/7). Two patients (TR-002, TR-005) were not evaluated for efficacy due to early withdrawal before the first efficacy assessment, for refusing to undergo imaging evaluation.

Table 2.

Clinical outcome of patients receiving injections.

ID	Group	Gender	Age	Therapeutic dose	Injection times	Therapeutic efficacy	Side effects posttreatment	Survival status (12 weeks after treatment)	Overall survival (weeks)	Other additional treatments
TR-001	1	male	74	1 × 107 pfu	1	SD	lymphopenia	death	NA	NA
TR-002	1	male	56	1 × 107 pfu	1	NA	NA	death	NA	NA
TR-003	1	female	39	1 × 108 pfu	1	SD	Fever fatigue	alive	44w	radiotherapy
TR-006	1	male	50	5 × 108 pfu	1	SD	Fever psoriasis	alive	24w	NA
TR-005	M	male	62	1 × 108 pfu	3	NA	NA	alive	40w	immunotherapy
TR-007	M	female	65	1 × 108 pfu	3	PD	Hypotension fatigue	alive	20w	NA
TR-008	M	male	42	5 × 108 pfu	3	SD	fever	death	NA	Interventional therapy

TR-004 was not enrolled for intratumoral injection of VT1093 therefore no final efficacy description was performed.

The last follow-up was in December 2023.

Notably, one patient with parotid gland mucoepidermoid carcinoma (TR-003) showed a gradual decrease in the long diameter of the treated lesion during follow-up after a single injection; the short diameter initially decreased before increasing (as measured by vernier caliper and documented with photographs, see Fig. 2A-J). Enhanced CT/MRI evaluations on day 29 post-treatment classified this patient as having SD (see Figure S1). This observation indicates that the optimal timeframe for assessing treatment efficacy following a single intratumoral injection of VT1093 may be the third week post-administration rather than the fourth.

Fig. 2.

Changes in lesion dimensions over time following VT1093 treatment. The long and short diameters of the target lesion were measured at baseline (screening period) and on days 8, 15, 22, and 29 post-treatment. A gradual reduction in lesion size was observed, with the most significant decrease recorded on day 29. Measurements were taken using enhanced imaging (CT/MRI) and verified with manual caliper assessments.

The study confirmed the safety profile of VT1093, as detailed in Table 2. Common adverse events, either possibly or definitely related to VT1093, included fever (reported in three cases) and fatigue (reported in two cases). The fever was graded as 1–2 and typically occurred within 48 h post-injection, resolving within 1–2 h after ibuprofen administration. All fatigue cases were grade 1 and did not significantly affect daily activities. One patient experienced an exacerbation of psoriasis (grade 2) post-treatment, managed with Traditional Chinese Medicine, while another reported irregular hypotension (grade 1), which resolved spontaneously without intervention. Importantly, all adverse events were classified as grade 1–2, with no serious adverse events (grade 3 or above) recorded according to CTCAE 5.0 criteria.

Five patients (TR-001, TR-003, TR-005, TR-007, TR-008) consented to participate in peripheral blood CD14/DR testing, a methodology that employs flow cytometry for the simultaneous detection of CD14 and HLA-DR, enabling the analysis of immune cell subsets. In this study, CD14/DR profiling was performed on these patients at two time points: prior to the initiation of treatment and after the completion of the treatment regimen. The key findings, summarized in Fig. 3 (A-D), revealed trends following treatment, including a decrease in suppressor T cells (Ts), an increase in the helper T cells (Th)/Ts ratio, a rise in natural killer (NK) cell count, and an overall increase in total white blood cell (WBC) count, suggesting potential immune activation. The results of the descriptive statistics are presented in Table 3.

Fig. 3.

(A) Changes in suppressor T cell (Ts) content before and after VT1093 injection, showing a trend toward reduction following treatment. (B) Changes in the helper T cell (Th)/Ts ratio before and after VT1093 injection, showing an increase post-treatment. (C) Natural killer (NK) cell content before and after VT1093 injection, illustrating a rise post-treatment. (D) Total white blood cell (WBC) count before and after VT1093 injection, showing an overall increase post-treatment.

Table 3.

Descriptive statistics of changes in peripheral blood CD14/DR assay indicators before and after injection in 5 patients.

Descriptive Statistics	Ts(CD3+CD8+)	Th/Ts	NK(CD3-CD16+CD56+)	WBC_CD59+
Median	−3.54	0.14	0.31	1.68
95 %CI	(−7.13, −0.57)	(0.00, 0.25)	(−1.89, 4.00)	(−0.43, 2.79)

Two patients presented with pre-existing conditions that violated the inclusion criteria. TR-001 had a hemoglobin level of 76 g/L (below the threshold of 85 g/L) but voluntarily chose to participate due to perceived potential benefits. Following treatment, TR-001 reported relief from cancer-related pain at the lesion site, with no increase in adverse reactions. TR-005, who had a negative serum anti-HSV-1 antibody at enrollment but lacked other viable treatment options, also chose to participate but subsequently exited the study due to tumor progression, with no adverse reactions observed during the trial. This case provides valuable insights for future studies regarding the exclusion of patients with negative anti-HSV-1 antibodies.

4. Discussion

The etiology and presentation of head and neck cancer (HNC), which includes nasopharyngeal, sinonasal, lip, oral cavity, oropharyngeal, laryngeal cancers, and salivary gland tumors, are notably diverse and complex. According to the International Agency for Research on Cancer (IARC), approximately 142,000 new cases of HNC were diagnosed in China in 2020, resulting in around 75,000 deaths. Standard treatment protocols for advanced stage head and neck squamous cell carcinoma (HNSCC) typically involve a combination of surgery, radiation, and chemotherapy (J.J. Caudell et al., 2022). However, the unique anatomical location of head and neck tumors introduces significant treatment-related risks, such as impacts on organ function, aesthetic deformities, and potential cranial nerve damage, leading to recurrence and metastasis rates as high as 40–60 %. Tumor heterogeneity is a primary factor limiting the efficacy of monotherapies. Consequently, the use of multi-targeted drug combinations that leverage various anticancer mechanisms has emerged as a promising strategy to address these challenges, becoming a focal point of recent research (Hanahan and Weinberg, 2011). Among numerous cancer treatment drug combinations, the combination of immune checkpoint inhibitors and oncolytic viruses has shown significant potential (Harrington et al., 2019).

A meta-analysis by Chen et al. in 2023 reviewed current clinical trials on neoadjuvant immunotherapy, indicating that HNC patients may benefit from such approaches, particularly when combined with chemotherapy (Chen et al., 2023). However, more clinical data are required to establish conclusive evidence. For recurrent or metastatic unresectable HNC, objective response rates remain a significant concern, despite advancements in adjuvant immunotherapy. The emergence of intratumoral injections of oncolytic viruses offers a new treatment modality with low side effects and promising efficacy (Huang et al., 2023), enhancing the feasibility of treating recurrent or unresectable HNC.

Oncolytic virus therapy targets tumor cells, leading to tumor destruction through cytopathic effects. In a 2017 Phase I clinical study, Ribas et al. explored the combination of the oncolytic virus T-VEC and the anti-PD-1 monoclonal antibody pembrolizumab in malignant melanoma, reporting an objective response rate (ORR) of 61.9 % and a complete response rate of 33.3 % (Ribas et al., 2017). Previous studies indicated that both agents alone yielded ORRs of 20–30 %, underscoring the enhanced efficacy of combination therapy (Andtbacka et al., 2015; Robert et al., 2015). Harrington et al. published findings in 2020 on T-VEC combined with pembrolizumab for recurrent or metastatic HNSCC, where 55.6 % of patients experienced adverse events related to T-VEC and 58.3 % related to pembrolizumab, indicating tolerable safety profiles (Harrington et al., 2020). Furthermore, a Phase I/II study in 2021 by Zhang et al. assessed the oncolytic virus BS-001 (OH2) combined with HX008 in advanced solid tumors, demonstrating no serious adverse events. OH2 is a gene-carrying GM-CSF HSV-2 oncolytic virus. The study included 54 subjects, with 40 receiving single-drug OH2 therapy and 14 receiving the OH2 and HX008 combination therapy. Two subjects from each group achieved immune partial response (iPR), with no serious treatment-related adverse events observed (Zhang et al., 2021). Studies have shown that OH2 can modify the tumor microenvironment, significantly increasing the density of CD3+ and CD8+ cells and the expression of PD-L1 compared to baseline. Although changes in the tumor microenvironment were observed, clinical trials utilizing a single oncolytic virus combined with a PD-1 inhibitor for HNC have yet to be conducted. VT1093, an oncolytic recombinant herpes simplex virus type 1 (HSV-1), retained the intrinsic advantages of oncolytic viruses while specifically abrogating tumor cell immune evasion mediated by the PD-1/PD-L1 pathway. This mechanism conferred superior therapeutic efficacy. In contrast to prior combination regimens in which oncolytic viruses and PD-1 antibodies were administered separately, VT1093 achieved functional integration via genetic engineering, which substantially enhanced both the agent’s efficacy and its targeting precision, making our study a pioneering effort in this domain.

The enrolled patients had recurrent HNC, with having received one or more standard treatments (including surgery and radiotherapy). In this study, we utilized the recombinant herpes simplex virus type 1, VT1093 injection, which expresses the PD-1 monoclonal antibody and is approved by the National Medicinal Products Agency for clinical trials. After intratumoral administration, VT1093 selectively replicates in actively dividing tumor cells, leading to tumor lysis. T cells are recruited to the tumor lesion, decreasing tumor cell proliferation and partially increasing PD-1 and Tregs as a negative feedback mechanism. The PD-1 monoclonal antibody expressed by VT1093 enhances the immune response through the immune checkpoint inhibitor mechanism, further bolstering T cell recruitment and immune cell activation. Oncolytic virus infection upregulates the expression of γ-interferon, enhancing PD-L1 expression, which may render tumors more sensitive to immune checkpoint inhibitors (Lichty et al., 2014). This mechanism could be particularly beneficial for tumors that are ineffective or resistant to conventional immune checkpoint inhibitors.

This study aimed to investigate the safety and preliminary efficacy of VT1093 injection in treating recurrent HNC. Patients received single or multiple intratumoral injections to target lesions, which employed the exploratory dose-escalation method. Efficacy was evaluated through imaging examinations with regular follow-ups, and post-treatment adverse effects were systematically observed and recorded. The results indicated that four out of five patients evaluated for efficacy achieved stable disease (SD), suggesting that VT1093 injection has some inhibitory effects on HNC, consistent with the disease control rate observed in a 2018 multicenter, open-label Phase Ib clinical study focused on herpes simplex virus-1 (HSV-1) (Eissa et al., 2018).

In this study, patients receiving the VT1093 injection tolerated the treatment well. The most common adverse reactions (either related or possibly related) associated with the study drug were fever and fatigue, with incidence rates of 42.9 % and 28.6 %, respectively. This is similar to clinical trial results for similar products (Hu et al., 2006). While similar products often cause pain at the injection site (Xu et al., 2003), the observation of injection site pain may be influenced by the fact that most enrolled patients had tumor-related pain. One patient developed tachycardia (grade 2) within 48 h after administration but reported no discomfort. Cardiac enzymes and echocardiography showed no abnormalities, and the patient recovered after drug treatment. Previous patients did not experience similar symptoms, suggesting they were likely not related to the study drug. During the study period, no common adverse events associated with similar products—such as stiffness, anorexia, nausea, vomiting, leukopenia, influenza-like symptoms, liver function abnormalities, or alopecia—were reported (Hu et al., 2006; Kaufman and Bines, 2010; Senzer et al., 2007; Xu et al., 2003). For patients with recurrent head and neck tumors who have received multiple prior treatments and exhibited poor general health status, VT1093 treatment was associated with lower treatment-related risks compared with alternative therapeutic modalities, resulting in higher treatment tolerance. Lin et al. reported a Phase I clinical trial conducted at Brigham and Women’s Hospital involving 41 recurrent glioblastoma patients injected with CAN-3110, another herpes simplex virus type 1 derivative. No dose-limiting toxicity (DLT) or maximum tolerated dose (MTD) was observed, indicating that VT1093 injection has a relatively wide therapeutic window (Ling et al., 2023).

In this study, peripheral blood CD14/DR profiling conducted before and after treatment in five patients revealed a detectable increase in the Th/Ts ratio and a concomitant rise in NK cell count following VT1093 injection. The observed increase in leukocyte count could potentially be attributed to a systemic inflammatory response, which may be induced by fever. These observations suggest a highly promising enhancement of immune activation, which may reflect a strengthened immune response against the tumor (Kyrysyuk and Wucherpfennig, 2023). Such findings imply that VT1093 injection has the potential to modulate and improve the overall systemic immune status of the patients. However, to substantiate these preliminary results and better understand the therapeutic implications, larger-scale clinical trials with higher dosing regimens, increased administration frequency, and a more extensive patient cohort are essential for further validation.

This study constituted a phase I clinical trial with a small sample size. While it provided preliminary data to inform the clinical application of VT1093, numerous limitations remained that warranted attention and refinement in subsequent investigations. Due to early patient withdrawals, the sample size was compressed, and as a consequence, the planned research design was not executed perfectly. As a result, the small sample size significantly restricts the precision of the data analysis, thereby limiting the ability to conduct more robust statistical evaluations that could yield more reliable and generalizable results. Ultimately, safety and preliminary efficacy could only be documented via descriptive statistics, without robust statistical substantiation. Furthermore, the relatively short follow-up period for the enrolled patients impedes a comprehensive assessment of the long-term effects of treatment, and an extension of the follow-up duration—such as 6 months or 1 year—would have been beneficial in evaluating the sustained impact of the intervention. In addition to the assessment of overall survival (OS) and progression-free survival (PFS), it is essential to incorporate more extensive and detailed evaluations, including peripheral blood laboratory tests, as well as focused and whole-body imaging assessments, to more thoroughly investigate the long-term effects of VT1093 on survival, disease progression, and the tumor microenvironment in patients with recurrent head and neck cancer. Furthermore, given the typically short survival period of patients with recurrent head and neck tumors, the use of disease control rate as a short-term endpoint in this study had limited relevance to the long-term patient benefits under investigation. Whether VT1093 conferred sustained disease control efficacy remains inconclusive. While the results of this study suggest that VT1093 exhibits a favorable safety profile and demonstrates some therapeutic efficacy, the need for larger, more rigorously designed Phase II/III clinical trials is evident in order to confirm these preliminary findings and further validate its clinical significance and potential for broader therapeutic application.

5. Conclusion

In conclusion, the results of this study demonstrate that single or multiple intratumoral administrations of VT1093 injection are feasible for treating recurrent HNC, with a favorable safety profile and minimal side effects. Ongoing patient follow-ups indicate potential for improved overall survival with increased dosage and frequency of administration. The innovation of VT1093 lies not only in its breakthrough "integrated oncolytic-immune blockade" mechanism but also in its design that addresses the clinical challenges associated with recurrent head and neck cancer, which offered promising clinical translational value. The preliminary findings of this study establish a solid foundation for the subsequent Phase II clinical trial of VT1093. If its long-term efficacy and safety can be further validated, VT1093 holds promise as a novel therapeutic option for patients with recurrent head and neck tumors.

Funding

This work was funded by Capital Health Research and Development of Special (2022–1–2051)

Ethical approval

The study was approved by the ethical committee of the Beijing Tongren Hospital, Capital Medical University (Reference number: TREC2021–98). The patients provided their written informed consent to participate in this study.

Author statement

We declare that this manuscript is original, has not been published before, and is not currently being considered for publication elsewhere.

We confirm that the manuscript has been read and approved by all named authors, and there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We understand that the co-corresponding authors are the primary contacts for the editorial process. They are responsible for communicating with the other authors about progress, submissions of revisions, and find approval of proofs.

CRediT authorship contribution statement

Siyu Zhu: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Data curation. Qi Zhong: Formal analysis. Yang Zhang: Formal analysis. Lizhen Hou: Data curation. Hongzhi Ma: Data curation. Ling Feng: Data curation. Xixi Shen: Formal analysis. Jiaming Chen: Formal analysis. Yurong He: Formal analysis. Jingwen Lyu: Data curation. Tiantian Wang: Data curation. Rui Zhao: Data curation. Jingfeng Li: Data curation. Jugao Fang: Writing – review & editing, Conceptualization. Shizhi He: Writing – review & editing, Funding acquisition, Data curation, Conceptualization.

Declaration of competing interest

The authors declare no potential conflicts of interest.

Appendix. Supplementary materials

Fig. S1. Imaging assessments before and after VT1093 treatment. Comparative enhanced CT/MRI scans of the target lesion before treatment and on day 29 post-treatment. The images depict the reduction in lesion size and changes in tumor morphology, reflecting the therapeutic effect of VT1093.

Data availability

Data will be made available on request.