Systemic antitumor responses to hypofractionated radiotherapy plus Poly(I:C) in advanced hepatocellular carcinoma: A phase 2 trial
(1) Qiu L (2) Huang Q (3) Pan X (4) Chen G (5) Liu W (6) Wang K (7) Zhou Y (8) Xie R (9) Dong X (10) Wu Q (11) Li Z (12) Zeng Y (13) Ji H (14) Cai Z (15) Liu X
In a phase 2 clinical trial in 37 patients with advanced HCC, Qiu et al. observed that adding s.c. Poly(I:C) to hypofractionated radiotherapy (HFRT) was well tolerated, and evaluable patients had better overall responses (54.5% vs. 21.2% with HRFT alone), abscopal responses, 6-month disease control, PFS, and OS, with even more pronounced benefits in subset of patients treated with a TKI (mostly lenvatinib, but also soratenib). Systemic responses were associated with increases in circulating CD28+CD8+ T cells. In mice, CD8+ T cells and CD28 co-stimulation were required for abscopal effects, and lenvatinib enhanced T cell infiltration by normalizing the tumor vasculature.
Contributed by Lauren Hitchings
(1) Qiu L (2) Huang Q (3) Pan X (4) Chen G (5) Liu W (6) Wang K (7) Zhou Y (8) Xie R (9) Dong X (10) Wu Q (11) Li Z (12) Zeng Y (13) Ji H (14) Cai Z (15) Liu X
In a phase 2 clinical trial in 37 patients with advanced HCC, Qiu et al. observed that adding s.c. Poly(I:C) to hypofractionated radiotherapy (HFRT) was well tolerated, and evaluable patients had better overall responses (54.5% vs. 21.2% with HRFT alone), abscopal responses, 6-month disease control, PFS, and OS, with even more pronounced benefits in subset of patients treated with a TKI (mostly lenvatinib, but also soratenib). Systemic responses were associated with increases in circulating CD28+CD8+ T cells. In mice, CD8+ T cells and CD28 co-stimulation were required for abscopal effects, and lenvatinib enhanced T cell infiltration by normalizing the tumor vasculature.
Contributed by Lauren Hitchings
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.
Author Info:
(1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 35002
5, China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350025, China. (2) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. (3) The 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. (4) The 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. (5) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. (6) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. (7) The 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. (8) The 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. (9) The 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. (10) The 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. (11) The 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. (12) The 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. (13) Department of Radiotherapy, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, China. Electronic address: fjjhb8@sina.com. (14) The 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. Electronic address: caizhixiong1985@163.com. (15) The 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. Electronic address: xiaoloong.liu@gmail.com.
