Review: Oncolytic Herpes Simplex Viruses for Treatment of Glioma

Oncolytic viruses, first clinically evaluated in the 1950s but only genetically engineered in 1991, have two unique mechanisms of action: they directly kill tumor cells, replicate, and spread in the tumor while sparing normal cells, and they induce an inflammatory tumor microenvironment and antitumor immune responses, thus serving as in situ vaccines.

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In Frontiers in Cellular and Infection Microbiology, physicians at Massachusetts General Hospital recently reviewed the genetic alterations used to engineer oncolytic herpes simplex viruses (oHSVs) and the current state of oHSV therapy for glioblastoma.

The authors are Kimia Kardani, PhD, and Judit Sánchez Gil, PhD, research fellows in the Molecular Neurosurgery Laboratory in the Department of Neurosurgery, and Samuel D. Rabkin, PhD, Thomas A. Pappas chair in Neurosciences and professor of Neurosurgery in the Brain Tumor Research Center.

Making HSV Oncolytic

HSV-1 and HSV-2 have very similar genomes and are lytic viruses that efficiently infect tumor cells and proliferate. Many of their genes are non-essential for replication and thus can be deleted to allow the insertion of therapeutic transgenes. Moreover, antiviral drugs (e.g., acyclovir) are available to treat unforeseen virus replication.

In marked contrast to other cancer therapeutics, no case in which cancer cell resistance to oHSV developed during treatment is known. Glioblastoma has been a favored disease target for oHSV both preclinically and clinically.

Three Generations of oHSVs

The gene that principally drives HSV neuropathogenicity is γ34.5. Deleting this gene provides cancer selectivity and significant safety in the brain. The design of oHSVs targeting glioblastoma has evolved over the past three decades:

γ34.5 deletion

HSV1716 (seprehvir) was the first oHSV to enter glioblastoma clinical trials in Europe. No patient in any of the three clinical trials experienced adverse events attributable to the virus, but there was concern about the safety of only a single genetic alteration. This prompted the development of multimutated oHSVs, of which G207 is the exemplar.

γ34.5 deletion and ICP6 inactivation

G207 is derived from recombinant HSV3616 with γ34.5 deleted and a reporter transgene, LacZ, inserted into another pathogenicity gene, ICP6, to inactivate it. Those two pathogenicity genes are broadly spaced in the genome, making recombination/reversion highly unlikely. Other important safety features of G207 are hypersensitivity to antiviral nucleoside analog drugs, temperature sensitivity to compromise replication under fever conditions, and the fact that it kills glioma cells, not astrocytes or neurons.

G207 was well tolerated in early clinical trials and is still in clinical trials. However, glioblastoma stem-like cells (GSCs) were discovered several years after they began. These have features such as self-renewal and tumorigenicity and have been linked with tumor heterogeneity, therapy resistance, and tumor recurrence. They are, therefore, a critical therapeutic target.

In three different GSC-derived preclinical models of glioblastoma, G207 did not replicate well and did not significantly extend survival.

γ34.5 and ICP47 deletion

The third generation of γ34.5-deleted oHSVs was designed to overcome attenuated virus replication without significantly increasing pathogenicity. G47Δ (teserpaturev) is engineered from G207 by deletion of ICP47 and the Us11 promoter. It kills glioma cells, including GSCs, and inhibits tumor growth more effectively than G207.

In a single-arm phase 2 trial of teserpaturev in 19 patients with recurrent glioblastoma, published in Nature Medicine, 84% of patients met the primary endpoint of one-year survival. The median overall survival was 28.8 months from the first surgery/diagnosis, and three patients were alive more than three years from the last dose. These findings led to the approval of teserpaturev in Japan for treating malignant glioma.

Features identified and likely characteristic of oHSV therapy in glioblastoma include an extended survival benefit with an unremarkable overall response rate of only 5.3% and delayed treatment responses detected by MRI of many months.

Other γ34.5-deleted oHSVs currently in clinical trials for glioblastoma are C134 (MB-108) expressing a γ34.5 homologue, M032 (NSC-733972) expressing IL12, and rQNestin34.5v.2 (CAN-3110), like G207 but with a stem cell promoter driving γ34.5 expression.

"Armed" oHSVs

A powerful way to enhance oHSV activity is to "arm" the virus with therapeutic transgenes. HSV-1 and HSV-2 can accommodate large or multiple therapeutic transgenes or sequences, up to ~30kb, that can target uninfected cells in the tumor.

The authors detail the many choices of transgenes, including cytokines, chemokines, immunomodulatory factors, anti-angiogenic factors, tumor microenvironment inhibitors/degraders, and cytotoxic proteins.

The first and so far only oncolytic virus approved in the U.S. is an armed oHSV, talimogene laherparepvec (T-Vec), that expresses GM-CSF. Like teserpaturev, T-Vec has γ34.5 and ICP47 deleted, but there is some concern about its safety in the brain.

Combination Therapy

Adding low-dose radiation to G207 has been safe in clinical trials for adult and pediatric gliomas while increasing virus replication and postulated immune responses. The reviewers conclude by discussing preclinical research into combinations of oHSVs and pharmacologic agents that target GSCs.

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