Neoadjuvant Stereotactic Body Radiotherapy plus Immune Therapy Favorably Remodels the Hepatocellular Carcinoma Tumor Microenvironment

PURPOSE: Although immune therapy regimens have significantly improved treatment options for patients with advanced hepatocellular carcinoma (HCC), optimal use of these regimens in earlier disease stages remains poorly defined. EXPERIMENTAL DESIGN: We conducted a single-institution, single-arm pilot study (NCT04857684) of neoadjuvant stereotactic body radiation therapy (SBRT) followed by two cycles of atezolizumab plus bevacizumab and subsequent surgical resection in patients with initially resectable HCC (n=8). The primary endpoint was safety as defined by the proportion of patients with grade 3-4 treatment-related adverse events (trAE) by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. And we dissected the detailed remodeling of the tumor immune microenvironment following treatment using single-cell-resolution spatial transcriptomics method. RESULTS: Only one patient experienced a grade 3 trAE. Seven of eight patients proceeded to surgery, and all achieved margin-negative (R0) resection; one patient did not proceed due to subsequent disagreement of resectability. One patient achieved a pathologic complete response, and all resected patients were relapse-free at data cutoff (median follow-up 16.3 months, range 2.1-19.9). Compared with unmatched treatment-naïve HCC specimens, post-treatment specimens showed significantly higher anti-cancer immune infiltration, including organized peritumoral aggregates. Immune infiltration and its proximity to tumor cells correlated with pre-operative radiographic response. CONCLUSIONS: This study provides proof-of-concept that neoadjuvant SBRT and immune therapy is safe and provides clear rationale for additional prospective clinical studies utilizing this strategy.