Genes in the Service of Therapeutic Index: Progress for Virus-Directed Enzyme Prodrug Therapy
Authors: Edward A. Sausville
Journal: Journal of Clinical Oncology (2004)

It has been a difficult past half-decade or so for would-be gene therapists. In contrast to the rather heady prospects in the early 1990s of using “gene surgery” to approach everything from congenital disease to cancer and HIV infection, recent reversals (including unforeseen toxicities encountered with adenovirus vectors and secondary lymphoproliferative disorders encountered with retroviral vectors) have tempered enthusiasm for these approaches in the clinical investigation community. Despite these unfortunate outcomes, we cannot lose sight of the opportunities afforded by gene therapy approaches. Increased understanding of the biology of potential vectors for gene therapy, and our continuous advances in understanding the molecular basis for cancer will clearly lead to the design of new cancer treatments predicated on the expression of introduced genes into a tumor or its host. Gene therapy can broadly be understood as promoting three types of outcomes. In the first, the gene(s) introduced into the host or tumor directly causes tumor cell death. The most frequently pursued paradigm is that of a replicationcompetent virus administered intralesionally. Replication of the virus in tumor cells, but not in normal host cells, leads to tumor cell death. Strategies employing this approach include the ONYX-015 adenovirus, which could be considered prototypic for the field. This virus was engineered with a deletion in its E1B gene. Since the E1B protein product binds to normal p53 to allow virus replication, it was hypothesized that this might result in ONYX-015 replicating in and destroying only p53-deficient cells, a circumstance that is very common in human tumors. ONYX-015 has been safely administered in several intratumoral early phase trials. We now understand that ONYX-015 can actually replicate in cells with wild-type p53. In addition, it has been hypothesized that other functional defects in the p53 pathway, particularly involving deletion of p14ARF, might allow its replication in those cases. Recent evidence, however, suggests that the basis for its selective replication is more complex. Other “oncolytic” virus strategies are also in development. These include Newcastle disease–related virus PV701, administered systemically and associated with some responses in early clinical trials; G207, a herpes virus already studied in a locally administered phase I trial in glioma; and a variety of vector systems in advanced preclinical or early clinical trials, including polio virus and other RNA virus– derived constructs. For this type of application, the key requirement is that the virus naturally or by alteration of its regulatory features cannot replicate in the host, or its replication in normal host cells conveys no adverse organismic effect. A frequent basis for the success of such strategies is that tumor cells display altered regulation of growthregulatory pathways that also are important in virus replication, not only of p53, as discussed above in the case of adenoviruses, but also the protein kinase R and interferonresponsive pathways in the case of RNA viruses. In a second application, the genes introduced into host or tumor cells are expressed, and the resulting protein evokes an immune response directed against the tumor. In this connection, genes can either be introduced as naked DNA, commonly as plasmids containing the gene of interest, or as viruses that are replication incompetent, such as adenoviruses or pox viruses, but still capable of infecting cells and expressing genes, including a transgene that encodes the immunogenic protein. In this application, key variables in addition to assuring lack of gene replication potential in the host or transmission through the host germ line, are the level of target protein production, how the protein(s) of interest are presented to the host immune JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 9 MAY 1 2004