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Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma
Published on: May 24, 2024
Systemic antitumor responses to hypofractionated radiotherapy plus Poly(I:C) in advanced hepatocellular carcinoma: A
Liman Qiu1, Qizhen Huang2, Xinting Pan1
1The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China.
Background:
The abscopal effect, regression of unirradiated tumors after localized radiotherapy, is rare. Whether hypofractionated radiotherapy (HFRT) plus the innate immune agonist polyinosinic-polycytidylic acid [Poly(I:C)] amplifies systemic antitumor immunity in advanced hepatocellular carcinoma is unclear.
Methods:
In this single-arm, phase 2 trial (ChiCTR2100053441), 37 patients received HFRT plus subcutaneous Poly(I:C); 33 were response evaluable. Outcomes were compared with 33 propensity score-matched patients treated with HFRT alone. The primary endpoint was the objective response rate per RECIST v.1.1; secondary endpoints included progression-free survival, overall survival, and safety; and abscopal response was prespecified. Mechanisms were explored by single-cell RNA sequencing and flow cytometry in patients and by CD8 depletion and CD28 blockade in mice.
Findings:
HFRT plus Poly(I:C) was well tolerated; it was associated with a higher objective response rate (54.5% vs. 21.2%; p = 0.011) and abscopal response rate (45.0% vs. 10.5%; p = 0.042) as well as longer progression-free survival (8.4 vs. 4.6 months; adjusted hazard ratio = 0.542; p = 0.042) and overall survival (not reached vs. 13.6 months; adjusted hazard ratio = 0.386; p = 0.011) vs. HFRT alone. The progression-free survival benefit was also higher in patients concurrently receiving tyrosine kinase inhibitors (p for interaction = 0.013). Peripheral CD8+CD28+ T cell expansion correlated with abscopal tumor control; in mice, CD8+ T cells and CD28 co-stimulation were required for this effect.
Conclusions:
HFRT plus Poly(I:C) showed promising systemic antitumor activity with manageable safety in advanced hepatocellular carcinoma, with CD8+CD28+ T cells as an immune correlate of response. These exploratory findings warrant confirmation in randomized trials.
Funding:
The National Natural Science Foundation of China.
