Local Delivery Of Herpes Simplex Virus Into Gliomas

Herpes simplex virus type I (HSV-1) is an enveloped, double-stranded, linear DNA virus with a genome of 152 kb which encodes more than 80 genes. About one half of the genes are essential for viral replication whereas the other (nonessential) genes encode proteins which support the viral life cycle within the host cell. The major advantages and disadvantages of HSV-1 for tumor oncolysis are illustrated in Table 1.

Several different strategies have been applied to generate tumor-selective HSV-1 vectors, as first shown by Martuza et al. It appears that most oncolytic viruses may ultimately be targeting cells, which have altered signal-transduction pathways that promote tumorigene-sis. This can occur spontaneously as is the case for reovirus (10-12) or can occur by genetic re-engineering. In the latter case, mutations or deletions in the viral genome are commonly introduced to eliminate the expression of specific viral proteins, which renders the mutant vector dependent on the tumor cells for viral propagation. Some ofthese viral proteins are also associated with neurotoxicity and a dual beneficial effect is obtained by mutating these genes. One of these mutants (designated 1716) has progressed to phase 1 clinical trial in 2 studies which include 21 patients altogether (13,14). In both studies patients with recurrent malignant glioma, refractory to conventional therapy, were treated. The HSV-1 vector was well tolerated at doses up to 105 infectious particles after stereotactic intratumoral injection, and no adverse events were reported. In the first trial, multiple injections of a 1-mL total volume were performed. No viral DNA was detected by polymerase chain reaction (PCR) in serum and buccal swab samples taken from five patients. Four out of nine patients were alive at 14 mo after the treatment (13). In the second trial, patients were injected with virus followed by tumor resection after 4 to 9 d, which showed virus replication in the tumor tissue. In some patients the amount of recovered virus exceeded the input dose (14). 1716 has also been clinically tested for advanced melanoma (15). In three patients receiving multiple intranodular injections, histopathological analyses revealed tumor necrosis and HSV-antigen presence in the tumor only.

Table 2

Potential Advantages and Disadvantages of AAd as an Oncolytic Virus

Potential advantages of Ad as an oncolytic virus

• Can be genetically re-engineered to render it selective for specific tumor-suppressor pathways

• Can take 24-48 h to kill tumor cells, but can produce several thousand progeny viruses

• Can deliver/express in tumors 1 or 2 additional anticancer transgenes.

• Does not randomly insert into the cellular genome, minimizing the risk for additional mutagenesis events

• Has been used in human clinical trials for gliomas Theoretical disadvantages of Ad as an oncolytic virus

• Some of the more attenuated and less toxic mutants are difficult to produce to very high titers

• Encephalitis, meningitis, and inflammation are likely dose-limiting toxicities in humans

• The mutant viral genome could recombine with wild-type adenovirus and added transgenes could be passed onto a wild-type Ad

• There are no effective antiadenoviral agents for aborting viral infection/replication, if necessary

• The adenoviral receptor (CAR) is poorly expressed in gliomas, thus limiting efficient infection.

Using a single mutant, HSV-1 vectors are potentially associated with the risk of restoring a wild-type phenotype (16). Concern about this risk led to the design of an oncolytic virus with dual mutations: G207. G207 has been tested in a phase I clinical trial in patients with recurrent glioma (17). Twenty-one patients were included and single injections of doses up to 3 x 109 infectious particles were administered. No adverse events were observed and the virus was well tolerated to the extent that no maximum tolerated dose was achieved. Promisingly, 2 patients were still alive 4 yr after the treatment.

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