Advances in local therapy for glioblastoma - taking the fight to the tumour

Abstract

Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.

Fig. 1 |. Methods of local treatment in glioblastoma.

In laser interstitial thermal therapy, tumour tissue is heated with a laser probe, destroying the tissue and disrupting the blood–brain barrier (BBB), usually under MRI guidance. Various compounds can be injected via stereotactic injections directly into the tumour with the aid of neuronavigation, frequently coupled with intraoperative CT or MRI. Convection-enhanced delivery involves continuous injection of various compounds using a pressure gradient to improve distribution. Ommaya or Rickham reservoirs can be implanted, enabling intermittent injections of therapy over an extended period of time. Catheters can be placed in the tumour or resection cavity or in the cerebral ventricles. For intra-a rterial delivery, catheters can be positioned directly into the feeding arteries, allowing local delivery of high-dose therapeutics. This technique can be combined with BBB disruption. CAR, chimaeric antigen receptor.

Fig. 2 |. Tumour cavity treatments for glioblastoma.

Injection of iron oxide nanoparticles (1) enables magnetic hyperthermia. In photodynamic therapy (2), photosensitizing agents are applied to the cavity and are activated by light at a specific wavelength to generate reactive oxygen species. Implantation of wafers (3) designed to release chemotherapy. Injection of viral vectors (4), immune-s timulating oligodeoxynucleotides (5), engineered neural stem cells (6) or chimaeric antigen receptor (CAR) T cells (7) into the cavity wall.

Fig. 3 |. Mechanisms of local viral therapies in development for glioblastoma.

AdvHSV-t k is a replication-incompetent adenoviral vector that delivers herpes simplex virus type 1 (HSV-1) thymidine kinase (TK). The transgene is introduced to the cell, and TK is produced. TK phosphorylates systemically administered ganciclovir (GCV) to generate GCV-p, which interferes with DNA repair and replication, eventually leading to tumour cell apoptosis or necrosis. Ad-RTS-hIL-12 is a replication-incompetent adenoviral vector that encodes human IL-12 preceded by a RheoSwitch Therapeutic System (RTS). The DNA construct is introduced into the cell, but can only be transcribed in the presence of veledimex (VDX). When VDX is administered systemically, IL-12 is produced. IL-12 activates T cells and generates an antitumour microenvironment. PVSRIPO is a replication-competent oncolytic polio–rhinovirus chimaera. PVSRIPO enters the cell via CD155, which is abundantly expressed in most glioblastomas. The virus then replicates in the tumour cell, leading to apoptosis and spreading of the virus. G207 is a replication-competent, oncolytic HSV-1 virus that is designed to replicate in tumour cells, causing apoptosis and viral spread. DNX-2401 is a replication-c ompetent adenovirus. The virus enters the cell via αvβ3 and αvβ5 integrins, which are present on glioma stem cells, and cannot replicate when a functional retinoblastoma pathway is present. As this pathway is often inactivated in tumour cells, the virus can cause selective apoptosis or necrosis of these cells.