Cancer-fighting virus T-VEC helps shrink tough-to-treat skin tumors

By Tarun Sai LomteReviewed by Lily Ramsey, LLMJan 30 2025

A phase II trial found that T-VEC improved tumor resectability in 50% of patients, leading to early study discontinuation, with strong immune response activation and minimal side effects.

Study: Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial). Image Credit: Kateryna Kon/Shutterstock.com

In a recent study published in Nature Cancer, researchers assessed the tolerability and effectiveness of a neoadjuvant oncolytic virus (OV) therapy in cutaneous basal cell carcinoma (BCC).

Background

The incidence of cutaneous BCC, the most common cancer globally, has doubled in the past 20 years and is projected to increase further. Treatment for most BCCs is surgical excision, which has up to 15% recurrence risk.

Based on the size and localization of BCC, plastic reconstructive surgery could be required, which may complicate the detection of early local recurrence and thus negatively impact the quality of life and well-being of patients.

In locally advanced and difficult-to-resect BCCs, neoadjuvant therapeutic approaches aim to decrease post-surgical morbidity, elevate the odds of curative resection, and alleviate recurrence risk.

Neoadjuvant therapy with hedgehog inhibitors has an overall response rate (ORR) of 71%, but adverse events (AEs) like fatigue, muscle cramps, dysgeusia, and hair loss often lead to discontinuation and low compliance.

OVs represent a class of intratumoral therapeutics that might be a safe and effective neoadjuvant therapy for difficult-to-resect BCCs.

Talimogene laherparepvec (T-VEC) is an OV, a genetically engineered herpes simplex virus 1 (HSV1), approved for treating injectable, unresectable melanoma lesions in the United States and Europe. T-VEC has a dual mode of action and can alter the tumor microenvironment (TME) by activating adaptive and innate immunity.

The study and findings

The present study presented the results of a phase II, two-stage, neoadjuvant clinical trial of T-VEC in cutaneous BCCs. The team enrolled 18 patients aged 49–92 years from January 2020 to January 2022 and assigned them to T-VEC neoadjuvant treatment.

The main endpoint was the proportion of subjects who, at the time of surgery after six T-VEC cycles, became resectable with would closure without needing plastic reconstructive surgery.

Nine patients showed a positive primary endpoint. The ORR was 55.6%; six patients achieved a complete response (CR), four had a partial response, and eight had a stable disease. Tumor size did not increase in any patient throughout treatment.

Twelve patients achieved a pathological non-CR (non-pCR), and six had a pathological CR (pCR). The average tumor area reduction was 45.4% until surgery.

Patients with the positive and negative primary endpoint had median reductions in tumor area of 62.5% and 37.7%, respectively. The relapse-free and overall survival rates were 100% at six months. However, at a median follow-up of 11 months, two patients developed new BCCs.

Four patients had T-VEC-related AEs; no serious AEs occurred. Further, spatial profiling was performed with multiplex immunofluorescence staining pre- and post-T-VEC treatment.

This analysis revealed a significant increase in cluster of differentiation 8⁺ (CD8⁺) T cells, CD68⁺ myeloid cells, and CD20⁺ B cells, and a decrease in CD4⁺ T regulatory (T_reg) cells and CD4⁺ T cells after treatment with T-VEC.

Moreover, there was a significant increase in CD8⁺ T cells, CD68⁺ myeloid cells, and CD20⁺ B cells infiltrating the interface of tumor islands post-treatment, with a substantial decrease in tumor cell density in patients with a remaining tumor post-treatment.

T-cells constituted a substantial proportion of immune cells in the TME; further analyses revealed eight clusters of T cells and one cluster of natural killer cells post-treatment.

Subjects with non-pCR showed higher T_reg cells, while those with a pCR had significantly increased cytotoxic T cell-to-T_reg cell ratio. Additional experiments revealed small, large, medium, and hyper-expanded T cell clones.

Cytotoxic T cells constituted a majority of hyper-expanded T cell clones. There was a significant increase in CD68⁺ macrophages after T-VEC treatment.

Single-cell RNA-sequencing (scRNA-seq) analysis further revealed distinct populations of myeloid cells post-treatment. Ficolin 1- and complement C1q C chain-positive macrophages constituted the majority.

Analyses of B cell subsets unveiled nine plasma and B cell clusters, with intra- and inter-patient heterogeneity. The integrated scRNA-seq and single-cell B-cell receptor (BCR) sequencing revealed that half of the BCR repertoire comprised hyper-expanded or large clones.

Only plasma cells presented hyper-expansion, while B cells showed small and medium expansion. Hyper-expanded plasma cell clones were almost exclusively immunoglobulin heavy constant γ 1 (IGHG1)-positive.

Conclusions

The findings illustrate that neoadjuvant T-VEC treatment was well-tolerated and could decrease BCC tumor size, simplify surgery, and result in complete pathological remission.

Moreover, T-VEC treatment significantly altered the intratumoral composition of immune cells and induced a robust immune response.

Furthermore, hyper-expanded IGHG1 plasma cells and cytotoxic T cells were detected. Overall, these results promote OVs as a therapeutic strategy for cutaneous BCCs.