Neoadjuvant stereotactic body radiation therapy plus immune therapy favorably remodels the hepatocellular carcinoma tumor microenvironment.

Abstract

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. 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. 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. 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.