Reshaping the tumor microenvironment of cold soft-tissue sarcomas with oncolytic viral therapy: a phase 2 trial of intratumoral JX-594 combined with avelumab and low-dose cyclophosphamide.

Most soft-tissue sarcomas (STS) exhibit an immunosuppressive tumor microenvironment (TME), leading to resistance against immune checkpoint inhibitors (ICIs) and limited therapeutic response. Preclinical data suggest that oncolytic viral therapy can remodel the TME, facilitating T cell accumulation and enhancing the immunogenicity of these tumors.We conducted the METROMAJX, a phase II clinical trial, to investigate the combination of JX-594, an oncolytic vaccinia virus engineered for selective tumor cell replication, with metronomic cyclophosphamide and the PD-L1 inhibitor avelumab in patients with advanced, 'cold' STS, characterized by an absence of tertiary lymphoid structures. The trial employed a two-stage Simon design. JX-594 was administered intratumorally at a dose of 1.109 pfu every 2 weeks for up to 4 intra-tumoral administrations. Cyclophosphamide was given orally at 50 mg twice daily in a week-on, week-off schedule, and avelumab was administered at 10 mg/kg biweekly. The primary endpoint was the 6-month non-progression rate.Fifteen patients were enrolled, with the most frequent toxicities being grade 1 fatigue and fever. Fourteen patients were assessable for efficacy analysis. At 6 months, only one patient remained progression-free, indicating that the trial did not meet the first stage endpoint of Simon's design. Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10.Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.

Deciphering the correlation between metabolic activity through 18F-FDG-PET/CT and immune landscape in soft-tissue sarcomas: an insight from the NEOSARCOMICS study.

Metabolic elevation in soft-tissue sarcomas (STS), as documented with 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET/CT) has been linked with cell proliferation, higher grade, and lower survivals. However, the recent diagnostic innovations (CINSARC gene-expression signature and tertiary lymphoid structure [TLS]) and therapeutic innovations (immune checkpoint inhibitors [ICIs]) for STS patients underscore the need to re-assess the role of 18F-FDG-PET/CT. Thus, in this correspondence, our objective was to investigate the correlations between STS metabolism as assessed by nuclear imaging, and the immune landscape as estimated by transcriptomics analysis, immunohistochemistry panels, and TLS assessment. Based on a prospective cohort of 85 adult patients with high-grade STS recruited in the NEOSARCOMICS trial (NCT02789384), we identified 3 metabolic groups according to 18F-FDG-PET/CT metrics (metabolic-low [60%], -intermediate [15.3%] and high [24.7%]). We found that T-cells CD8 pathway was significantly enriched in metabolic-high STS. Conversely, several pathways involved in antitumor immune response, cell differentiation and cell cycle, were downregulated in extreme metabolic-low STS. Next, multiplex immunofluorescence showed that densities of CD8+, CD14+, CD45+, CD68+, and c-MAF cells were significantly higher in the metabolic-high group compared to the metabolic-low group. Lastly, no association was found between metabolic group and TLS status. Overall, these results suggest that (i) rapidly proliferating and metabolically active STS can instigate a more robust immune response, thereby attracting immune cells such as T cells and macrophages, and (ii) metabolic activity and TLS could independently influence immune responses.