The ASPECT study,1 a randomized, open-label, phase III trial examining adenovirus-mediated gene therapy with sitimagene ceradenovec followed by IV ganciclovir for patients with operable high-grade glioma, is an important achievement for both neuro-oncology and gene therapy. As vector engineering became more sophisticated in the 1990s and the molecular bases of disease were beginning to become unraveled, great enthusiasm drove the field of gene therapy as the expected therapeutic approach of the future for much of disease, including cancer. This enthusiasm was significantly dampened by the initial clinical experiences, which were hampered by lack of efficacy, low transduction efficiency of the targeted cells, and occasional severe toxicities, including treatment-associated mortality.2
Suicide Gene
The delivery of the HSV thymidine kinase (HSV-tk) suicide gene as an anticancer therapeutic is a concept that has been examined preclinically and in clinical trials for nearly 20 years, and is attractive for several reasons. The tk gene, when delivered to cancer cells, phosphorylates the prodrug ganciclovir to ganciclovir triphosphate, which is a directly cytotoxic nucleoside analog. Cells expressing tk are therefore killed after administration of drug; also, the toxic metabolite can be passed to adjacent cells via gap junctions, which allows for further spread of the effect. This is mechanistically straightforward and nontoxic to neurons and normal glia that are not undergoing cell division.
The HSV-tk/ganciclovir paradigm has been previously examined in a randomized clinical trial in patients undergoing surgery for newly diagnosed glioblastoma.3 In 2000, Rainov and colleagues reported a phase III trial in which the treatment group underwent post-resection intracavity injection of vector-producing cells that released retrovirus- expressing HSV-tk into the surrounding environment. There was no impact of the therapy on either progression-free or overall survival. The authors deduced that treatment failure was due to low genetic transduction of the tumor cells, which was likely limited by the inability of the vector-producing cells to migrate.
Replication-Deficient Adenovirus
Concurrently, replication-deficient adenovirus was being developed as an alternative vector, and preclinical data showed improved transduction efficiency as compared to retroviruses. After dosing and in vivo transduction were established in early-phase trials,4,5 a replication-deficient adenovirus containing the cDNA for HSV-tk was examined in a randomized phase II study,6 confirming safety and showing improved survival using the composite end point of time to death or surgery for recurrence, and leading to the current phase III study.
In summary, the much-anticipated findings of this trial are that the study treatment of sitimagene ceradenovec followed by IV ganciclovir was associated with improved time to death or reintervention, the primary endpoint. Overall survival, however, was not significantly improved. Treatment had a greater effect on the subset of patients with unmethlyated MGMT promoters as measured by the primary endpoint. There were more significant adverse events in the treatment group, most consisting of neurologic morbidity. In the experimental group, having elevated antiadenovirus antibodies prior to treatment was associated with better outcome.
Design Limitations
Though the ASPECT Study Group is to be commended for executing this randomized study, there are two design issues that are of concern. First, as enrollment began in 2005, the use of temozolomide was left to the discretion of the treating physicians, and the distribution of temozolomide use was unequal between the two arms (49% in the treatment arm vs 65% in the control arm). However, we would expect this to bias outcome against the therapy.
Second, the fact that this was an open-label study might bias the time to reintervention. An aptly named “reintervention committee”—members of which were blinded to treatment—retrospectively analyzed decision-making at the time of perceived progression and reintervention and determined that there was no bias.
While the authors offer an explanation as to why a blinded trial was not feasible, there may have been alternatives. Ideally, patients in the control arm would have received injections of a replication-deficient adenovirus that did not express HSV-tk, followed by ganciclovir. Currently, we could postulate that the observed effect was secondary to an adenovirus-induced inflammation.
Noteworthy Sidelights
Several noteworthy sidelights further support activity of the treatment. Unexpected radiographic changes in the treatment group were regularly present at 19 days and were classified as pseudoprogression, necessitating a change in the radiographic interpretation of disease activity. Also, while preexisting antiadenoviral humoral immunity might be expected to abrogate the effects of treatment, subjects with the highest antiadenoviral antibody titers were more successfully treated than those without baseline responses. Patients with more active immune systems (that are able to overcome glioblastoma-mediated immunosuppression) may more effectively mount antitumor immune responses after treatment, a phenomenon that has been observed in patients undergoing HSV-tk/ganciclovir treatment for malignant glioma.7
On balance, while sitimagene ceradenovec followed by IV ganciclovir will not become the standard of care for patients with newly diagnosed resected glioblastoma, this trial is an important advance and legitimizes a gene therapy approach for brain tumors. More robust efficacy will likely require vectors that more efficiently transduce target cells, stimulate antitumor immunity, or utilize vehicles that home to infiltrating tumor cells, such as mesenchymally derived stem cells.8
Viral oncolytic approaches, as opposed to the use of replication-deficient vectors, are under intensive study and have shown activity in a phase III trial in patients with advanced melanoma.9 With the appropriate technology and study design, gene therapy approaches to glioblastoma are deserving of serious attention and further investigation in large-scale clinical trials. ■
Disclosure: Dr. Curry reported no potential conflicts of interest.
References
1. Westphal M, Ylä-Herttuala S, Martin J, et al: Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): A randomised, open-label, phase 3 trial. Lancet Oncol 14:823-833, 2013.
2. Marshall E: Gene therapy death prompts review of adenovirus vector. Science 286:2244-2245, 1999.
3. Rainov NG: A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11:2389-2401, 2000.
4. Sandmair AM, Loimas S, Puranen P, et al: Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther 11:2197-2205, 2000.
5. Puumalainen AM, Vapalahti M, Agrawal RS, et al: Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 9:1769-1774, 1998.
6. Immonen A, Vapalahti M, Tyynelä K, et al: AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: A randomised, controlled study. Mol Ther 10:967-972, 2004.
7. Floeth FW, Shand N, Bojar H, et al: Local inflammation and devascularization--in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma. Cancer Gene Ther 8:843-851, 2001.
8. Murphy AM, Rabkin SD: Current status of gene therapy for brain tumors. Transl Res 161:339-354, 2013.
9. Andtbacka RHI, Collichio FA, Amatruda T, et al: OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol 31(suppl):Abstract LBA9008, 2013.
