TNFerade to the rescue? Guidelines for evaluating phase I cancer gene transfer trials.

In this issue of the Journal of Clinical Oncology, Senzer et al [1] describe the results of their phase 1 gene transfer trial of TNFerade. The goal of this trial was to take advantage of the well-known antitumor effects of tumor-necrosis factor alpha (TNF), while avoiding the considerable systemic toxicities that currently limit its use. This was accomplished by injecting tumors with a replication deficient adenovirus encoding the human TNFgene driven by a radiation-inducible promoter, followed by treatment with external beam radiation. The trial showed that repeated intratumoral injection of TNFerade in combination with external beam radiation was safe. A significant proportion (43%) of patients demonstrated objective tumor responses, although it is unclear how many responses would have been achieved with radiation alone. In some cases, it was possible to compare the size of “control” lesions that were only radiated with those treated with TNFerade plus radiation in the same patient. For the most part, lesions treated with TNFerade and radiation showed more response than these “control” lesions. Before discussing this study, we should comment on our choice of describing this study as a gene “transfer” trial rather than gene “therapy” trial. The US Food and Drug Administration (FDA) and the National Institutes of Health have concerns that references to gene therapy trials, particularly in the phase I stage, implies a therapeutic benefit from the transfer of genetic material that has not yet been proven. This may pose a problem for the consent form in these studies, particularly for patients with advanced cancers who are desperate for novel and more effective treatments. Accordingly, we recommend the use of the terminology gene transfer or gene delivery, until well-designed controlled studies have clearly demonstrated therapeutic efficacy. Is this a good phase 1 cancer gene transfer study? Although, for the most part, this trial should be evaluated like any other standard phase I trial of an experimental antineoplastic agent, there are additional criteria that should be considered when evaluating a cancer gene transfer trial. Any good clinical study must meet certain well-accepted standards. Patient inclusion and exclusion criteria must be clearly stated and explained. The trial protocol must be logical and understandable. Dose-limiting toxicities should be defined. A reasonable number of patients should be studied, and the numbers of patients who dropped out of the study and the reasons for these dropouts should be stated. All regulatory and informed consent issues must be addressed. In gene transfer trials, in addition to standard institutional approvals, review by the Recombinant DNA Advisory Committee and the FDA is required. The TNFerade trial performed well in all these areas. Good clinical studies need to begin with a well-reasoned hypothesis and a thorough understanding of the limitations of the therapeutic agent. Given the current limitations of cancer gene therapy vectors, this latter point is especially important. All of the currently available vectors (ie, adenovirus, herpes simplex virus, retrovirus, lentivirus, adeno-associated-virus, and liposomes) have the ability to transduce only a small minority of cells within a tumor, and none is currently effective in targeting tumor after systemic administration. To achieve any sort of efficacy, these limitations require that gene therapy agents induce strong “bystander effects.” This term refers to the ability of a transgene, expressed in transduced cells, to affect other nontransduced cells, both neighboring and distant. Examples of transgenes with bystander potential include: “suicide” genes, such as cytosine deaminase or herpes simplex thymidine kinase, in which a toxic product is secreted or moves from cell to cell; genes encoding for secreted proteins that induce death of tumor cells or tumor vasculature, such as antiangiogenic compounds; genes that stimulate immunologic effects, such as cytokines; or genes encoding for JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 4 FEBRUARY 15 2004