Neoadjuvant Oncolytic Virus OrienX010 Combined with PD-1 Inhibitor Toripalimab for Resectable Acral Melanoma: Phase Ib Clinical Trial

Background

Acral melanoma (AM) is a highly aggressive subtype of melanoma with a high incidence in the Chinese population, accounting for approximately 40% of melanoma cases. Despite advances in melanoma treatment, current immunotherapies show limited efficacy in AM, with no established neoadjuvant therapeutic regimens. The unique low tumor mutational burden (TMB) and immunosuppressive microenvironment of AM contribute to its low response rate to anti-PD-1 monotherapy and poor survival outcomes.

Recently, neoadjuvant immunotherapy has been shown to elicit stronger immune responses than postoperative adjuvant therapies, improving disease-free survival (DFS) and overall survival (OS). Oncolytic virus therapy, by converting “cold” tumor microenvironments into “hot” immunogenic states, has demonstrated potential in enhancing immune checkpoint inhibitor (ICI) efficacy. However, the effectiveness of oncolytic viruses as monotherapy in AM remains limited. This study evaluates the combined use of the oncolytic virus OrienX010 (ORI) and the PD-1 inhibitor toripalimab (TORI) for resectable AM.

Methods

This study was conducted by a research team at Peking University Cancer Hospital and published in Signal Transduction and Targeted Therapy in 2024. It was a single-center, open-label, Phase Ib clinical trial (ClinicalTrials.gov NCT04197882) designed to assess the efficacy and safety of ORI and TORI as a neoadjuvant treatment. Primary endpoints included radiographic and pathological response rates, while secondary endpoints assessed 1- and 2-year recurrence-free survival (RFS), event-free survival (EFS), and safety.

Study Design

Thirty patients with stage III or IV resectable AM underwent 12 weeks of neoadjuvant therapy (ORI intratumoral injection and TORI intravenous infusion biweekly), followed by surgical resection and one year of TORI adjuvant therapy. The study included radiographic and pathological evaluations, post-treatment tissue analyses, and follow-up monitoring for RFS and EFS.

Technical Aspects

1. Oncolytic Virus OrienX010 Design: ORI, derived from herpes simplex virus type 1 (HSV-1), was engineered to delete ICP34.5, ICP47, and ICP6 genes while incorporating the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene to enhance immune cell recruitment and antigen presentation.
2. Data Analysis: Techniques included PET/CT imaging for radiographic evaluation, histological analysis of biomarkers such as tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), and serum cytokine and chemokine quantification using Olink technology.

Results

Patient Characteristics

The median patient age was 57 years (range 21–72), with 47% male participants. Disease stages included 40% stage IIIB, 47% stage IIIC, and 13% stage IVM1a.

Primary Efficacy

1. Pathological Response: Of 27 patients who underwent surgery, the overall pathological response rate was 77.8%, including 14.8% with pathological complete response (PCR), 18.5% near-PCR, and 44.5% partial pathological response (PPR).
2. Radiographic Response: Based on RECIST 1.1 criteria, the overall radiographic response rate was 36.6%.
3. Recurrence-Free Survival (RFS): One- and two-year RFS rates were 85.2% and 81.5%, significantly higher than previously reported RFS for AM adjuvant therapy (14.8–26 months).
4. Event-Free Survival (EFS): One- and two-year EFS rates were 83% and 73%, respectively.

Safety

All patients experienced treatment-related adverse events (TRAEs), most of which were mild (grade 1–2, 83.3%). Grade 3 adverse events occurred in four patients (13.3%), primarily involving soft tissue infections and neuropathy.

Biomarkers and Pathological Findings

Post-treatment tumor tissues showed significantly higher TIL and TLS infiltration in responders compared to non-responders (TIL: 95.2% vs. 50.0%, p=0.006; TLS: 70.6% vs. 16.7%, p=0.022), indicating enhanced immune activation. Serum analysis revealed increased secretion of pro-inflammatory cytokines (e.g., IFN-γ, CXCL10, IL-12) with the ORI and TORI combination.

Limitations of Imaging

While PET/CT is valuable for monitoring and staging, it showed no correlation with pathological response or survival outcomes in this study, highlighting its limitations in assessing neoadjuvant therapy efficacy.

Discussion

This study is the first to demonstrate the high pathological response rate and excellent two-year RFS for ORI and TORI combined neoadjuvant therapy in AM. Compared with traditional adjuvant approaches, this regimen exhibited significant survival benefits, offering a promising alternative therapeutic strategy.

Compared to oncolytic virus monotherapy, such as T-VEC, the ORI and TORI combination achieved superior efficacy (e.g., 2-year RFS improved from 29.5% to 81.5%). Future large-scale, multi-center randomized trials are essential to validate these findings.

Limitations

1. Small sample size and short follow-up duration.
2. Lack of direct comparison with other combination therapies (e.g., PD-1 plus CTLA-4 inhibitors).

Conclusion

This study highlights the potential of oncolytic virus and ICI synergy for AM treatment. While preliminary, the results suggest broad clinical applications with favorable efficacy and safety profiles. Future studies should explore personalized strategies to further optimize outcomes for AM patients.