Introduction:
Diffuse midline glioma (DMG)/diffuse intrinsic pontine glioma (DIPG) are deadly childhood gliomas with median survival of less than 12 months and a 2 year survival of 10%. D24, a genetically engineered adenovirus specific for glioma, has anti-tumoral effect in a phase 1 study when given by direct intratumoral injection. Our preliminary work has shown endovascular super-selective intra-arterial delivery of D24 packaged in mesenchymal stem cells (MSC-D24) is feasible and safe in patients.
Objective:
We hypothesize that endovascular intra-arterial delivery of MSC-D24 will be safe and effective for treatment of DMG/DIPG.
Methods:
In vitro killing assays were used to assess the tumoricidal effects of MSC-D24 against DIPG using TP54, DIPG 36, and SF8628 cell lines (from 102 to 105 cells). Transwell migration assays were performed to test homing of MSC (105 cells) to the same cell lines. To assess safety of infusion in the vertebrobasilar circulation, a rabbit survival model (7 days) was used and 0.4 mL of 107 MSC-D24 cells were infused into the basilar artery. Clinical examination, histology, angiography, and MRI were used to assess stroke and other complications after infusion. The efficacy of MSC-D24 against will be tested in-vivo using a mice xenograft model of DIPG.
Results:
Transwell killing assays showed a dose dependent tumoricidal effects of MSC-D24 against all 3 DIPG cell lines. MSCs successfully homed to TP54 in the migration assay. Rabbits (n=3) did not exhibit neurologic deficits after the MSC-D24 intra-arterial infusion and MRI, histology, and angiography post-infusion did not show any strokes or other evidence of tissue injury. Bioluminescent imaging of DIPG bearing mice showed tumor reduction and improved survival.
Conclusion:
Endovascular vertebrobasilar intra-arterial infusion of MSC-D24 is safe and the oncolytic virus appears effective against DIPG in both in vitro and in vivo models. The results support a phase 1 trial of MSC-D24 for patients with DMG/DIPG.