Heather Lin

Purpose: Postoperative stereotactic radiation (SRT) is the standard-of-care for resected brain metastases. Implantation of cesium-131 collagen tiles (tile-based radiation therapy [TBRT]) initiates focal radiation immediately after resection, potentially offering therapeutic and logistical advantages. Radiation One and Done Study, a randomized, open-label, noninferiority, phase III trial (ClinicalTrials.gov identifier: NCT04365374 ), compared the safety and efficacy of resection with TBRT (R + TBRT) with resection with SRT (R + SRT) for patients with a newly diagnosed brain metastasis indicated for surgical resection. Methods: Across 32 US centers, patients were preoperatively randomly assigned 1:1 to R + TBRT or R + SRT. Any nonresected brain metastases received SRT postoperatively. Co-primary outcomes were time-to-surgical bed recurrence (SBR) and surgical bed recurrence-free survival (SB-RFS). Outcomes were analyzed using Cox proportional hazards models with stratification factors as covariates. Multiplicity was controlled by hierarchical testing. Analyses used the prespecified modified intention-to-treat (mITT) population (patients who underwent surgery, had pathologic confirmation of brain metastasis, and had follow-up information). Results: From April 2021 to August 2025, 230 patients were randomly assigned (115 per arm), 204 of whom (103 R + TBRT, 101 R + SRT) comprised the mITT population. The median follow-up was 12.9 months. The median time-to-SBR was not reached in R + TBRT versus 17.4 months in R + SRT (hazard ratio [HR]: 0.06 [95% CI, 0.01 to 0.46]; P = .0070). SB-RFS was improved with R + TBRT, with a median of not reached versus 10.9 months in R + SRT (HR, 0.48 [95% CI, 0.30 to 0.76]; P = .0021). Overall adverse events did not appear to differ: 83 patients (79.0% [95% CI, 70.0 to 86.4]) in R + TBRT versus 67 patients (80.7% [95% CI, 70.6 to 88.6]) in R + SRT. Conclusion: For patients with newly diagnosed brain metastases requiring resection, R + TBRT significantly improved SBR and SB-RFS, demonstrating both noninferiority and superiority.

The Supplementary File contains figures S1 to S15 and Table S1, which contain supporting data for the experiments reported in the main manuscript.

Purpose:The anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab (IPI), has shown clinical benefit across multiple tumor types, both as monotherapy and in combination with nivolumab or chemotherapy. However, not all tumors respond, and peripheral effects can lead to immune-related adverse events. We characterized three novel anti–CTLA-4 antibodies: peptide-masked [PROBODY conditionally activatable therapeutic (PB)], non-fucosylated (NF), and combined NF-PB (BMS-986288). Experimental Design:We evaluated the preclinical characteristics, including pharmacodynamics, tolerability, antitumor activity and efficacy, and peripheral immune responses, of these novel anti–CTLA-4 antibodies using in vitro systems, animal models, and human data. This includes data from preclinical mouse models of colorectal cancer as well as non–small cell lung cancer. Results:NF demonstrated greater T-cell priming and antitumor activity than both IPI and the unmasked PB antibody in cell-based assays and mouse models. Whereas the intact PB antibody showed minimal CTLA-4 binding and peripheral immune activation, unmasking restored its functional activity to levels comparable with those of IPI. Unmasked anti–CTLA-4 NF-PB retained the effectiveness of anti–CTLA-4 NF, and both molecules demonstrated more profound antitumor activity, increased effector memory T-cell response, and prolonged survival in mouse models compared with IPI. Anti–CTLA-4 NF-PB demonstrated reduced peripheral immune responses compared with anti–CTLA-4 NF or IPI in non-human primates and patients with solid tumors. Conclusions:Anti–CTLA-4 NF-PB has enhanced antitumor activity, efficacy, and reduced peripheral activity in preclinical models, and has the potential to provide therapeutic benefit in solid tumors.See related commentary by Galvez-Cancino et al., p. 3112

Supplementary figure S1. Effects of fecal microbiota transfer from Lcn2-deficient mice in various mouse models.

Differentially expressed genes in the myeloid cluster of the colonic lamina propria.

Differentially expressed genes in the tumor microenvironment.

Supplementary figure S2. scRNA-seq of the colonic lamina propria in the syngeneic mice following FMT.

Table S1 from Inflammation Mediated by Gut Microbiome Alterations Promotes Lung Cancer Development and an Immunosuppressed Tumor Microenvironment

Comparative analysis of microbial abundance in murine fecal samples across FMT groups.

Supplementary Figure S4. Immune changes within the TME induced by inflammation related to gut microbiome alterations.