| Summary: | <p>Glioblastoma (GBM) is a highly aggressive brain tumour in adults, often becoming resistant towards conventional therapy of radiotherapy and temozolomide (TMZ) chemotherapy. The oncolytic herpes simplex virus-1 (oHSV- 1) G207 is a promising approach for GBM immunotherapy, capable of selective infection, replication and causing cell lysis within GBM but not healthy cells. However, G207 has demonstrated only limited efficacy in GBM clinical trials.</p>
<p>The Natural Killer Group 2 Member D (NKG2D) receptor plays a key role in the innate immune control of cancers. The ligands for this receptor (NKG2DLs) are minimally expressed or absent on healthy cells, while stressed or malignant cells upregulate NKG2DLs, resulting in innate immune activation. We have developed a strategy targeting upregulated NKG2DLs on GBM cells with a bispecific T cell engager (BiTE) consisting of a recombinant NKG2D receptor linked to an anti-CD3 domain. Simultaneous binding of the NKG2D BiTE to NKG2DLs on GBM cells and CD3 on T cells causes antigen-independent T cell activation, pro-inflammatory cytokine release, and tumour cell death.</p>
<p>Here, we engineer G207 to express the NKG2D BiTE from infected GBM cells, allowing the G207-NKG2DBiTE virus to combine direct viral oncolysis and BiTE- mediated cytotoxicity via activation of local T cells. NKG2DL expression was elevated on GBM cells following pre-treatment with sublethal doses of TMZ and radiation, sensitising them to NKG2D BiTE activity and achieving synergistic cytotoxicity with G207-NKG2DBiTE virus.</p>
<p>We also demonstrate a novel strategy for targeting glioma stem-like cells (GSCs), which are a source of resistance to conventional therapies. In contrast to differentiated GBM cells, GSCs are non-permissive to G207 infection, but they remain sensitive to NKG2D BiTE. Therefore, we propose a potential model for targeting GSCs in heterogeneous tumours, whereby differentiated GBM cells infected with G207-NKG2DBiTE virus produce NKG2D BiTE locally, directing T cell cytotoxicity towards the GSC sub-populations in the tumour microenvironment.</p>
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