This study is the first to evaluate the neoadjuvant immunotherapy strategy of combining T-VEC with atezolizumab in HER2-negative breast cancer, demonstrating favorable safety and a promising pathological complete response rate, particularly standing out in the hormone receptor-positive subtype.
Literature Overview
The article titled 'Talimogene laherparepvec and atezolizumab in HER2-negative breast cancer following neoadjuvant chemotherapy: a window-of-opportunity phase II trial (SOLTI-1503 PROMETEO)', published in Nature Communications, reviews and summarizes the safety and efficacy of the oncolytic virus T-VEC combined with the PD-L1 inhibitor atezolizumab as preoperative window therapy in patients with HER2-negative breast cancer who have residual disease after neoadjuvant chemotherapy. The study found that this combination was well tolerated and achieved residual cancer burden (RCB) class 0/I in over one-quarter of patients, while inducing significant activation of the immune microenvironment, suggesting its potential value in managing residual disease. The study further revealed dynamic changes in the tumor immune microenvironment before and after treatment, providing new insights into the application of immunotherapy in non-pCR patients.Background Knowledge
HER2-negative breast cancer is one of the major subtypes of breast cancer, including triple-negative breast cancer (TNBC) and hormone receptor-positive (HR+) subtypes, which have relatively low pathological complete response (pCR) rates to neoadjuvant chemotherapy, especially the HR+ subtype. Patients who do not achieve pCR are at high risk of recurrence and urgently need effective adjuvant or perioperative intervention strategies. In recent years, immune checkpoint inhibitors (such as anti-PD-1/PD-L1 antibodies) have shown certain efficacy in TNBC, but response rates are lower in the HR+ subtype, partly due to their immunologically 'cold' tumor microenvironment. Oncolytic viruses such as talimogene laherparepvec (T-VEC) can lyse tumor cells to release tumor antigens, promote dendritic cell activation and T-cell infiltration, thereby converting 'cold' tumors into 'hot' tumors. T-VEC encodes GM-CSF, which enhances antigen presentation and theoretically synergizes with PD-L1 inhibitors to boost antitumor immunity. However, clinical exploration of this combination strategy in HER2-negative breast cancer, especially in the HR+ subtype, remains limited. This study adopts a 'window-of-opportunity' design, administering short-term treatment before surgery, allowing rapid assessment of the drug's biological activity and analysis of immune microenvironment changes through paired samples, providing mechanistic support for subsequent large-scale studies. This research fills the evidence gap for oncolytic virus combined with immunotherapy in managing residual disease in breast cancer and has significant translational medical implications.
Research Methods and Experiments
This was a single-arm, phase II, preoperative window-of-opportunity clinical trial (SOLTI-1503 PROMETEO, NCT03802604), enrolling 28 patients with HER2-negative breast cancer confirmed by imaging and pathology to have residual disease (≥10 mm) after neoadjuvant chemotherapy, including HR+/HER2- (n=20) and TNBC (n=8) subtypes. The treatment regimen consisted of an initial intratumoral injection of T-VEC (10^6 PFU/mL), followed by T-VEC (10^8 PFU/mL) administered every two weeks combined with intravenous atezolizumab (840 mg), for a total of four cycles. The primary endpoint was the proportion of patients achieving residual cancer burden (RCB) class 0/I at surgery. Secondary endpoints included safety, pCR rate, and imaging response. Exploratory endpoints covered dynamic changes in biomarkers such as tumor-infiltrating lymphocytes (TILs), PD-L1 expression, and immune-related gene expression signatures (iGES). All patients underwent central pathology review and multisite biospecimen collection (baseline, screening, C2D1, C3D1, surgery) for immunohistochemistry, TILs scoring, and RNA sequencing analysis.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to demonstrate the feasibility and immune-activating potential of combining T-VEC with atezolizumab as preoperative immunotherapy in HER2-negative breast cancer. Notably, a 30% pCR rate was achieved in the HR+/HER2- subtype—far exceeding historical controls—challenging the traditional notion that this subtype is insensitive to immunotherapy and suggesting that oncolytic viruses may effectively remodel its immune microenvironment. The window-of-opportunity design, with multisite biospecimen analysis, provides direct evidence of the drug’s mechanism of action and strong biomarker support for future studies.
However, the study was single-arm and lacked a control group, making it impossible to exclude the influence of the natural disease course after neoadjuvant chemotherapy. Additionally, none of the patients received immunotherapy during NAC, differing from current standard care for TNBC, which limits the direct generalizability of the results. Future studies should conduct randomized controlled trials comparing T-VEC plus atezolizumab versus standard therapy in patients with residual disease, and explore more effective treatment sequences, such as using T-VEC to initiate immune response before introducing PD-L1 inhibitors. Furthermore, the predictive value of baseline immune features should be further validated to enable precise patient selection.
Conclusion
This study systematically evaluated the safety and biological activity of T-VEC combined with atezolizumab in patients with HER2-negative breast cancer who had residual disease after neoadjuvant chemotherapy. The results show that the combination is well tolerated, significantly activates the tumor immune microenvironment, and induces a high pCR rate, demonstrating encouraging efficacy particularly in the HR+/HER2- subtype, which traditionally responds poorly to immunotherapy. The study not only validates the feasibility of combining oncolytic viruses with immune checkpoint inhibitors but also reveals their substantial potential in reshaping 'cold' tumor microenvironments. Although larger randomized trials are needed for further validation, this study provides new perioperative immunotherapy strategies for high-risk HER2-negative breast cancer patients, especially those with HR+ subtypes. Future research should focus on optimizing treatment sequences, identifying predictive biomarkers, and evaluating the incremental value of this strategy in contemporary treatment settings (e.g., after neoadjuvant chemotherapy combined with immunotherapy) to advance personalized immunotherapy development.
