Gene Therapy for Malignant Glioma: Current Clinical Status

Abstract

Glioblastoma is an aggressive brain tumor with a dismal prognosis. Gene therapy may offer a new option for the treatment of these patients. Several gene therapy approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly used approach, but oncolytic conditionally replicating adenoviruses and herpes simplex virus mutant vectors, p53, interleukins, interferons, and antisense oligonucleotides have also been used. During the past few years, adenoviruses have become the most popular gene transfer vectors, and some recent randomized, controlled trials have shown significant anti-tumor efficacy in clinical use. However, efficient gene delivery into the brain still presents a major problem, and there is a lack of definitive phase III trials, which would avoid potential problems associated with a small number of patients, inadvertent patient selection, and overinterpretation of results based on a few long-time survivors. For clinical efficacy, median survival is one of the most rigorous endpoints. It is used here to evaluate the usefulness of various treatment approaches and current clinical status of gene therapy for malignant glioma.

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

“…This is exemplified by two unsuccessful phase III randomized controlled trials of gene therapy16, 17 and variable responses in other smaller clinical studies 6, 18, 19, 20, 21…”

Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth

“…18,19 The most common therapeutic transgene used for glioma gene therapy, both experimentally and in clinical trials, has been the herpes thymidine kinase (HSV-tk) gene. [20][21][22] The product of the HSV-tk gene transforms the prodrug ganciclovir to a precursor that arrests DNA replication, inducing cell death. Interestingly, the effects of this type of vectors are amplified by the bystander effect, caused by the passage of the toxic metabolites to cells connected by gap junctions.…”

Clinical trials of gene therapy, virotherapy, and immunotherapy for malignant gliomas

“…Results are now available from several clinical trials. Unfortunately, they are rather disappointing in terms of clinical response, even though treatment procedures and gene transfer have been generally proven to be safe and well tolerated 4,5 (Table 1). Reasons for such failure have been mainly ascribed to inefficient transduction of target tumor cells (as reported for other types of cancers), rather than to the gene therapy strategy per se.…”

“…4 With a few anecdotal exceptions, lack of efficacy was particularly observed in clinical trials based on the use of RVPCs as gene transfer tools. 5 In a total of 79 evaluable patients with recurrent GBM enrolled in nine phase I/II studies of retroviral vectormediated HSV-TK gene therapy, complete or partial responses were observed in 13% of cases, and minor responses or stable disease in 18% (Table 1). In most studies, treatment consisted in injection of RVPCs into the surgical cavity after tumor debulking and not in direct intratumor injection of the RVPCs.…”

“…Therefore, response to treatment was difficult to assess. In the studies of HSV-TK gene therapy based on intratumor injection of RVPCs, 5,7 tumor regression was observed in a relatively high percentage of patients, especially in those with small tumor recurrences. Unfortunately, tumor responses were limited to the site of RVPC injection, whereas untreated tumor masses progressed rapidly.…”