4-1BBL-Armed Oncolytic Herpes Simplex Virus Exerts Antitumor Effects in Pancreatic Ductal Adenocarcinoma

Overview

Journal Vaccines (Basel)

Date 2025 Jan 8

PMID 39771971

Authors

Wenrui Gao

Zhuoqian Zhao

Ying Bi

Jinghua Li

Na Tian

Cuizhu Zhang

Shuyuan Pan

Li Deng

Yuntao Zhang

Affiliations

Soon will be listed here.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a notably poor response to therapy due to its immunosuppressive tumor microenvironment (TME) and intrinsic drug resistance. The oncolytic virus (OV) represents a promising therapeutic strategy capable of transforming the "cold" immunological profile of PDAC tumors to a "hot" one by reshaping the TME. 4-1BB (CD137), a crucial member of the tumor necrosis factor receptor superfamily, plays a significant role in T-cell activation and function. In this study, we constructed an oncolytic herpes simplex virus armed with 4-1BBL (oHSV-4-1BBL), the ligand for the 4-1BB receptor, and investigated its therapeutic effects in two mouse models of pancreatic cancer, Pan02_HVEM and KPC. We found that oHSV-4-1BBL remarkably inhibited tumor growth and extended the median survival time in both models. To amplify the therapeutic effect, we further combined oHSV-4-1BBL with PD-1 antibody. This combination therapy not only further suppressed tumor growth but also extended the median survival time by an additional 11 days compared to oHSV (armed with GFP as a control) combined with PD-1 antibody treatment, with some mice achieving complete tumor regression. Our findings confirm the potential of combining oncolytic viral therapy with 4-1BB targeting in enhancing the treatment of pancreatic cancer.

References

Sledge Jr G, Toi M, Neven P, Sohn J, Inoue K, Pivot X . The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019; 6(1):116-124. PMC: 6777264. DOI: 10.1001/jamaoncol.2019.4782. View

Vazaios K, van Berkum R, Calkoen F, van der Lugt J, Hulleman E . OV Modulators of the Paediatric Brain TIME: Current Status, Combination Strategies, Limitations and Future Directions. Int J Mol Sci. 2024; 25(9). PMC: 11084613. DOI: 10.3390/ijms25095007. View

Hansen T, Bouvier M . MHC class I antigen presentation: learning from viral evasion strategies. Nat Rev Immunol. 2009; 9(7):503-13. DOI: 10.1038/nri2575. View

Teague A, Lim K, Wang-Gillam A . Advanced pancreatic adenocarcinoma: a review of current treatment strategies and developing therapies. Ther Adv Med Oncol. 2015; 7(2):68-84. PMC: 4346211. DOI: 10.1177/1758834014564775. View

Jennings V, Ilett E, Scott K, West E, Vile R, Pandha H . Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites. Int J Cancer. 2013; 134(5):1091-101. PMC: 4321045. DOI: 10.1002/ijc.28450. View

Ye K, Li F, Wang R, Cen T, Liu S, Zhao Z . An armed oncolytic virus enhances the efficacy of tumor-infiltrating lymphocyte therapy by converting tumors to artificial antigen-presenting cells in situ. Mol Ther. 2022; 30(12):3658-3676. PMC: 9734027. DOI: 10.1016/j.ymthe.2022.06.010. View

Menk A, Scharping N, Rivadeneira D, Calderon M, Watson M, Dunstane D . 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 2018; 215(4):1091-1100. PMC: 5881463. DOI: 10.1084/jem.20171068. View

Kaufman H, Bines S . OPTIM trial: a Phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 2010; 6(6):941-9. DOI: 10.2217/fon.10.66. View

Cheng W, Kang K, Zhao A, Wu Y . Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J Hematol Oncol. 2024; 17(1):54. PMC: 11283714. DOI: 10.1186/s13045-024-01581-2. View

10.

Ducreux M, Cuhna A, Caramella C, Hollebecque A, Burtin P, Goere D . Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v56-68. DOI: 10.1093/annonc/mdv295. View

11.

Lin C, Li H, Hao M, Xiong D, Luo Y, Huang C . Increasing the Efficiency of CRISPR/Cas9-mediated Precise Genome Editing of HSV-1 Virus in Human Cells. Sci Rep. 2016; 6:34531. PMC: 5054376. DOI: 10.1038/srep34531. View

12.

Eissa I, Bustos-Villalobos I, Ichinose T, Matsumura S, Naoe Y, Miyajima N . The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Cancers (Basel). 2018; 10(10). PMC: 6210336. DOI: 10.3390/cancers10100356. View

13.

Toda M, Rabkin S, Kojima H, Martuza R . Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. Hum Gene Ther. 1999; 10(3):385-93. DOI: 10.1089/10430349950018832. View

14.

Kim H, Park S, Jeong S, Lee Y, Lee H, Kim C . 4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8 T Cells in Hepatocellular Carcinoma. Hepatology. 2019; 71(3):955-971. PMC: 7154753. DOI: 10.1002/hep.30881. View

15.

Wang R, Chen J, Wang W, Zhao Z, Wang H, Liu S . CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model. J Immunother Cancer. 2022; 10(1). PMC: 8796271. DOI: 10.1136/jitc-2021-003809. View

16.

Palanivelu L, Liu C, Lin L . Immunogenic cell death: The cornerstone of oncolytic viro-immunotherapy. Front Immunol. 2023; 13:1038226. PMC: 9899992. DOI: 10.3389/fimmu.2022.1038226. View

17.

Long A, Haso W, Shern J, Wanhainen K, Murgai M, Ingaramo M . 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015; 21(6):581-90. PMC: 4458184. DOI: 10.1038/nm.3838. View

18.

Liu B, Robinson M, Han Z, Branston R, English C, Reay P . ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003; 10(4):292-303. DOI: 10.1038/sj.gt.3301885. View

19.

Zhao J, Wang H, Chen J, Wang C, Gong N, Zhou F . An oncolytic HSV-1 armed with Visfatin enhances antitumor effects by remodeling tumor microenvironment against murine pancreatic cancer. Biochem Biophys Res Commun. 2024; 718:149931. DOI: 10.1016/j.bbrc.2024.149931. View

20.

Wherry E . T cell exhaustion. Nat Immunol. 2011; 12(6):492-9. DOI: 10.1038/ni.2035. View