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Jingjun Huang,1,* Yongjian Guo,1,* Wensou Huang,1,* Xiaotao Hong,2 Yi Quan,3 Liteng Lin,1 Jingwen Zhou,1 Licong Liang,1 Yaqin Zhang,4 Juan Zhou,5 Mingyue Cai,1 Kangshun Zhu1 1Department of Minimally Invasive Interventional Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province, People’s Republic of China; 2Department of Interventional Medical Center, Jieyang People’s Hospital, Jieyang City, Guangdong Province, People’s Republic of China; 3Department of Oncology Medical Center, The First People’s Hospital of Zhaoqing, Zhaoqing City, Guangdong Province, People’s Republic of China; 4Department of Radiology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai City, Guangdong Province, People’s Republic of China; 5Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kangshun Zhu; Mingyue Cai, Department of Minimally Invasive Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, 250 East Changgang Road, Guangzhou City, Guangdong, 510260, People’s Republic of China, Tel +86-20-34156205, Fax +86-20-34153709, Email zhksh010@163.com; cai020@yeah.netPurpose: To evaluate the safety and efficacy of regorafenib combined with anti-PD-1 antibody sintilimab (rego-sintilimab) as a second-line treatment for advanced hepatocellular carcinoma (HCC).Methods: This multicenter retrospective study evaluated consecutive patients with advanced HCC who received rego-sintilimab (rego-sintilimab group) or regorafenib alone (regorafenib group) as a second-line treatment from January 2019 to December 2020. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Uni- and multi-variable analyses of prognostic factors for OS and PFS were performed using Cox proportional hazard regression models.Results: In total, 113 patients were included in the study: 58 received rego-sintilimab and 55 received regorafenib. The rego-sintilimab group had higher ORR (36.2% vs 16.4%, P = 0.017), longer PFS (median 5.6 vs 4.0 months; P = 0.045), and better OS (median 13.4 vs 9.9 months; P = 0.023) than the regorafenib group. Regorafenib alone, Child-Pugh B, and neutrophil-to-lymphocyte ratio (NLR) > 3.6 were independent prognostic factors for poor OS. Regorafenib alone, α-fetoprotein level, and NLR > 3.6 were independent prognostic factors for poor PFS. Subgroup analyses showed a survival benefit of rego-sintilimab in patients with NLR ≤ 3.6 (hazard ratio 0.518 [95% CI, 0.257– 0.955]) but not in those with NLR > 3.6 (0.852 [0.461– 1.572]); P = 0.002 for interaction. The difference in incidence of grade 3/4 adverse events between the two groups was not statistically significant (39.7% vs 30.9%; P = 0.331).Conclusion: Rego-sintilimab was tolerated and led to better OS than regorafenib as a second-line treatment for advanced HCC patients, especially in those with NLR ≤ 3.6.Keywords: liver cancer, regorafenib, anti-PD-1 antibody, second-line treatment, overall survival, neutrophil-to-lymphocyte ratio

Jingjun Huang,1,* Wensou Huang,1,* Meixiao Zhan,2,* Yongjian Guo,1 Licong Liang,1 Mingyue Cai,1 Liteng Lin,1 Mingji He,3 Hui Lian,3 Ligong Lu,2 Kangshun Zhu1 1Department of Interventional Radiology, Minimally Invasive and Interventional Cancer Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province, People’s Republic of China; 2Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai City, Guangdong Province, People’s Republic of China; 3Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou City, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kangshun ZhuDepartment of Interventional Radiology, Minimally Invasive and Interventional Cancer Center, The Second Affiliated Hospital of Guangzhou Medical University, 250 East Changgang Road, Guangzhou City, Guangdong, 510260, People’s Republic of ChinaTel +86-20-34156205Fax +86-20-34153709Email zhksh010@163.comLigong LuZhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, 79 Kangning Road, Zhuhai City, Guangdong Province, 519000, People’s Republic of ChinaTel +86 7-56-2222569Fax +86 7-56-2162086Email lu_ligong@163.comPurpose: To evaluate the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with oxaliplatin plus fluorouracil and leucovorin (FOLFOX)-based hepatic arterial infusion chemotherapy (D-TACE-HAIC) for unresectable large (5.1– 10 cm) or huge (> 10 cm) hepatocellular carcinoma (HCC).Methods: This retrospective study evaluated consecutive patients with unresectable large or huge HCC who underwent D-TACE-HAIC (D-TACE-HAIC group) or DEB-TACE (DEB-TACE group) from January 2017 to December 2020. At imaging, tumor infiltrating appearance was classified into smooth tumor margin, non-smooth tumor margin, and macrovascular invasion. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups.Results: A total of 133 patients (mean age, 53 years ± 12; 117 men) were included: 69 underwent D-TACE-HAIC and 64 underwent DEB-TACE. The patients who underwent D-TACE-HAIC had higher ORR (71.0% vs 53.1%; P = 0.033), longer PFS (median, 9.3 vs 6.3 months; P = 0.005), and better OS (median, 19.0 vs 14.0 months; P = 0.008) than those who underwent DEB-TACE. In subgroup analysis, patients with non-smooth tumor margin (median, 20.8 vs 13.0 months; P = 0.031) or macrovascular invasion (median, 15.0 vs 11.0 months; P = 0.015) had significantly longer OS in D-TACE-HAIC group than in DEB-TACE group; but in patients with smooth tumor margin, OS between the two groups was similar (median, 37.0 vs 35.0 months; P = 0.458). DEB-TACE, non-smooth tumor margin, and macrovascular invasion were independent prognostic factors for poor OS in uni- and multivariable analyses. The incidence of grade 3/4 adverse events was not statistically different between the two groups (37.7% vs 28.1%; P = 0.242).Conclusion: D-TACE-HAIC was tolerable and led to better OS than DEB-TACE in patients with large or huge HCC, especially in those with non-smooth tumor margin or macrovascular invasion.Keywords: liver cancer, high tumor burden, chemoembolization, drug-eluting beads, hepatic arterial infusion chemotherapy, survival analysis

Zhimei Zhou,1,* Liteng Lin,1,* Yongcheng An,1,* Meixiao Zhan,2 Ye Chen,1 Mingyue Cai,1 Xiaojing Zhu,1 Ligong Lu,2 Kangshun Zhu1 1Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China; 2Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong Province, 519000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kangshun ZhuLaboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, 250 Changgang East Road, Guangzhou 510260, People’s Republic of ChinaTel +86-20-34152264Fax + 6-20-34152281Email zhksh010@163.comLigong LuZhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, 79 Kangning Road, Zhuhai, Guangdong Province 519000, People’s Republic of ChinaTel +86 7-56-2222569Fax +86 7-56-2162086Email lu_ligong@163.comBackground: The response rate of immunotherapy via immune checkpoint blockade in hepatocellular carcinoma (HCC) is limited due to multiple immune evasion mechanisms. OX40 is a T cell co-stimulating molecule which suppresses the cancer immune evasion by activating effector T cells (Teffs) and counteracting regulatory T cells (Tregs). TLR9 belongs to the toll-like receptor superfamily which promotes tumour antigen presentation by stimulating the maturation of dendritic cells. Though the combination immunotherapy of TLR9 agonist (CpG) and OX40 agonist (anti-OX40 antibody) has shown encouraging efficacy in various tumours, its effect on HCC remains unknown.Materials and Methods: Orthotopic and ectopic HCC models were constructed by implanting Hepa1-6 cells at different body sites of the mice. Immune agents were administrated via three ways, including intratumoural injection into one site of the tumour, intraperitoneal injection, and subcutaneous injection. The anti-tumour immune response was evaluated by the regression of both the local treated tumour and distant untreated tumour. The ratio and function of CD4+ T cells, CD8+ T cells, Tregs and myeloid-derived suppressor cells (MDSCs) were analyzed by flow cytometry.Results: CpG via intratumoural injection remarkably upregulated the weakly expressed OX40 of intratumoural T cells. The combination immunotherapy of CpG and anti-OX40 antibody via intratumoural injection significantly inhibited the growth of local and distant tumours, and also effectively prevented their recurrence. Excitingly, drug administration via intratumoural injection, rather than via intraperitoneal or subcutaneous injections, induced potent anti-tumour immune response. Furthermore, we demonstrated that the combination immunotherapy promoted CD8+ and CD4+ T cells, and inhibited Tregs and myeloid-derived suppressor cells, contributing to the effective inhibition on HCC. Noteworthily, the combination immunotherapy also induced an immune memory response.Conclusion: The intratumoural administration of combined CpG and anti-OX40 antibody serves as a promising immunotherapy against HCC.Keywords: hepatocellular carcinoma, immunotherapy, combination therapy, toll-like receptor, intratumoural administration

Min Shen,1,* Faming Gong,3,* Pengfei Pang,1,* Kangshun Zhu,1 Xiaochun Meng,1 Chun Wu,1 Jin Wang,1 Hong Shan,1,2 Xintao Shuai3,41Molecular Imaging Lab, Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; 2Institute of Intervention Radiology, Sun Yat-sen University, Guangzhou, China; 3PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China; 4Center of Biomedical Engineering, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China*These authors contributed equally to this workAbstract: Polyethylene glycol-grafted polyethylenimine (PEG-g-PEI) which was functionalized with a neuroblastoma cell-specific ligand, the GD2 single chain antibody (scAbGD2), was synthesized in order to effectively deliver Bcl-2 siRNA into neuroblastoma cells. This polymer was complexed first with superparamagnetic iron oxide nanoparticle (SPION) to get a MRI-visible targeted non-viral vector (scAbGD2-PEG-g-PEI-SPION) and then with Bcl-2 siRNA to form nanoparticles showing low cytotoxicity. The targeting capacity of scAbGD2-PEG-g-PEI-SPION was successfully verified in vivo and in vitro by magnetic resonance imaging. The single chain antibody encoded targeted polyplex was more effective in transferring Bcl-2 siRNA than the nontargeting one in SK-N-SH cells, a human neuroblastoma cell line, resulting in a 46.34% inhibition in the expression of Bcl-2 mRNA. Consequently, a high level of cell apoptosis up to 50.76% and a significant suppression of tumor growth were achieved, which indicates that scAbGD2-PEG-g-PEI-SPION is a promising magnetic resonance imaging-visible non-viral vector for targeted neuroblastoma siRNA therapy and diagnosis.Keywords: tumor targeting, GD2, non-viral vector, Bcl-2 small interfering RNA, magnetic resonance imaging