Novel therapeutic approach against Epstein-Barr virus-associated tumors

EBV infects about 95% of the human population and causes more than 200,000 cases of cancer each year and that around 2% of all cancer deaths are due to EBV-attributable malignancies. EBV-associated tumours include Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, gastric tumour and post-transplant lymphoproliferative disease, etc. Current treatment options for EBV-associated tumours are limited with considerably unwanted off-target toxicities and incomplete effectiveness for relapsed or refractory disease. V?2-T cells are innate-like T cells with anti-tumour potentials against EBV-associated tumours. Unfortunately, its clinical translation is limited because V?2-T cells from some cancer patients are difficult to be expanded. Exosomes are endosome-originated small extracellular vesicles that mediate intercellular communication. Compared with cell-based therapy, cell-free exosomes have advantages with higher safety, easier storage, and lower costs. However, the anti-tumour activity of exosomes derived from V?2-T cells (Vδ2-T-Exos) remains unknown.

Research findings

Herein, the team found that Vδ2-T-Exos contained death-inducing ligands (FasL and TRAIL) and immunostimulatory molecules (CD80, CD86, MHC class I and II). Vδ2-T-Exos targeted and efficiently killed EBV-associated tumour cells through FasL and TRAIL pathways and promoted EBV antigen-specific CD4 and CD8 T cell expansion. Administration of Vδ2-T-Exos effectively controlled EBV-associated tumours in immunodeficient and humanized mice. Because expanding V?2-T cells and preparing autologous Vδ2-T-Exos from cancer patients ex vivo in large scale is challenging, the team further explored the anti-tumour activity of allogeneic Vδ2-T-Exos in humanized mouse cancer models. Interestingly, the team found that allogeneic Vδ2-T-Exos had more effective anti-tumour activity than autologous Vδ2-T-Exos in humanized mice; the allogeneic Vδ2-T-Exos increased the infiltration of T cells into tumour tissues and induced more robust CD4 and CD8 T cells-mediated anti-tumour immunity. Compared with exosomes derived from NK cells with direct cytotoxic anti-tumour activity or dendritic cells that induced T-cell anti-tumour responses, Vδ2-T-Exos have dual anti-tumour activities by directly killing tumour cells and indirectly inducing T cells-mediated anti-tumour responses, thus resulting in more effective control of EBV-associated tumours.

"Our study provides the first evidence about the anti-tumour activities of Vδ2-T-Exos against EBV-associated tumours. These exosomes could effectively control EBV-associated cancers in multiple mouse models. More importantly, allogeneic Vδ2-T-Exos had higher therapeutic efficacy than autologous Vδ2-T-Exos to control EBV-associated tumours. Therefore, the Vδ2-T-Exos prepared from healthy donors can be used to treat patients with EBV-associated tumours, which is highly beneficial to the clinical application of this novel approach," said Professor Tu Wen-wei, Antony and Nina Chan professor in Paediatric Immunology, Department of Paediatrics and Adolescent Medicine, HKUMed, who led the research.

Significance of the study

The findings of the study have significant implications in cancer immunotherapy. Firstly, the identification that Vδ2-T-Exos has potent immunostimulatory property suggests that they could be designed as a cancer vaccine by serving as immune adjuvant and delivering immunogens. Secondly, the Vδ2-T-Exos has advantages over other exosome-based therapies (e.g. NK-Exos and DC-Exos) by displaying dual anti-tumour activities and are easier in preparation. Thirdly, the results that allogeneic Vδ2-T-Exos have higher anti-tumour efficacies than autologous Vδ2-T-Exos can greatly enhance the clinical feasibility of Vδ2-T-Exos, because the preparation of allogeneic exosomes does not require personalized procedures and is easier in quality control, standardization and centralization for clinical application.