Potential Side Effects

Apart from the limited efficacy, cancer gene therapy also faces the concern of toxicity. Although no cases of treatment-related death have been reported in cancer patients under gene therapy trials, a few cases of treatment-related severe adverse effect (SAE) were documented. Moreover, death and SAE have been reported from gene therapy studies for other diseases. The first fatal case directly linked to gene therapy was of a patient with ornithine carbamyltransferase (OTC) deficiency, who received replication-deficient adenovirus-mediated OTC gene delivery via the hepatic artery. Investigation into this case pointed out an extremely high level of interleukin-6 (IL-6) postinjection in this patient and associated disseminated intravascular coagulation (DIC), which was not suppressed by a simultaneous rise in IL-10 (34); whether IL-6 elevation was the cause or effect is unclear. Although it is uncertain whether this resulted from patient- or disease-specific idiosyncrasy to adenovirus, the tragedy has prompted investigators and patients to be more cautious in designing and participating in gene therapy trials (35).

Another important report came from a X-linked severe combined immunodeficiency (SCID) trial in which patients without a matched bone marrow donor available underwent ex vivo retrovirus-mediated Yc (common chain) gene delivery into autologous CD34+ bone marrow cells (36). Among more than 30 patients who entered the trial, 2 were found to develop acute leukemia after 2.5 to 3 yr (37,38). Although gene integration is a hallmark of retrovirus based gene delivery, it has never been shown to promote insertional oncogenesis in rodent, dog, and nonhuman primate models, as well as in many other patients who previously received retrovirus-based gene therapy (39,40). Moreover, the two patients who developed leukemia were both on the highest dose level, both among the youngest in the trial, but notably, they had the same locus of gene insertion (37,38). A series of extensive investigations have been carried out, and several potential mechanisms were proposed to explain the SAE (41-43). Some proposed that the activation of a yet poorly defined group of high risk proto-oncogenes (represented here by the gene LMO2 activated in both patients) was sufficient to induce premalignant transformation and further events (e.g., transgene expression and other signal alterations) would promote malignant progression. The other hypothesis suggested that non-physiologic transgene expression evoked a signal alteration that specifically cooperated with the activated oncogenes in the initiation of disease. Subsequent "hits" were also required in this model. However, it is unclear at this moment whether the transgene level at the local environment plays an equally critical role as proto-oncogene activation.

It is clear that current preclinical models are not ideal for predicting the type, frequency, and severity of toxicity, including insertional mutagenesis. Species difference between human and mouse or human and nonhuman primates is the major reason. For cancer gene therapy, animal models face another specific problem: most published preclinical models are human tumor-mouse xenograft systems and involved the use of athymic or even SCID mice. Thus, the results obtained from these studies may be misleading because one of the most crucial players in the cancer-vector-host interplay, the host immune system, is missing. In terms of the risk to humans, it is also unknown whether other patients who received retrovirus-based gene therapy developed leukemic disorders in the long term and whether the administration dosage, route, and duration have any impact on the development of these potential SAEs.

For studies involving the use of replication-deficient viruses, one potential concern is the recombination of replication-competent viruses. Similarly, for oncolytic viruses the risk of wild-type virus recombination (reversion) is another concern. Whereas herpesvirus can be eliminated by acyclovir, effective antibiotics are not readily available for other virus species, and the sequelae of circulating wild-type virus in patients are largely unknown, especially with HIV-based lentivirus. Although recombination has not been shown in preclinical and clinical studies, patients undergoing viral vector-mediated gene therapy should be closely monitored for replication-competent and wild-type virus recombination.

An equally important factor is the route of administration. Although systemic delivery is the ultimate goal for metastasing cancer cells, it is also likely to induce the highest immune reaction, and potential toxicity. To this end, "staged" clinical research and development approaches can ensure safety of the agent tested (44). The goal of this approach is to increase systemic exposure to the test article sequentially only after safety with more localized delivery is demonstrated (see Fig. 1). Following demonstration of safety and biological activity by the intratumoral route, trials can sequentially be initiated to study intracavitary (e.g., intraperitoneal), intra-arterial (e.g., hepatic artery), and eventually intravenous administration. Finally, clinical trials of combinations with chemotherapy or radiotherapy will be initiated only after the safety of the test article as a single agent is demonstrated by the relevant route of administration.

In order to predict any potential toxicity to patients, proper preclinical toxicology testing is critical. However, the currently available preclinical models do not fully reflect clinical settings. In addition, because the latent period of the insertional muta-genesis in patients was more than 2 yr, long-term safety evaluation, which is not always practical for preclinical testing, needs to be improved. Furthermore, a large proportion of cancer patients have other comorbid diseases that might affect the biodistribution and toxicity of these gene therapy agents. Patients with liver function impairment (e.g., liver cirrhosis and/or chronic hepatitis) might have an impaired hepatic clearance of viral vectors; in contrast, pulmonary uptake might be increased in these patients, as shown in animal models (45). It is also unknown whether patients with chronic viral infection (hepatitis B virus [HBV], Epstein-Barr virus [EBV], etc) will have acute exacerbation resulting from activation by viral genes and/or therapeutic transgenes. Indeed, age, comorbid index, and surgery were found to be risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors (46). These need to be addressed in preclinical toxicity studies.

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