Genetic theraphy for cancer: hurdles remain
Authors: David Kirn
Journal: Molecular Therapy (2005)

Approved targeted therapies for cancer have to date included small molecule drugs and monoclonal antibodies. Although generally less toxic than standard chemotherapeutics, these agents have had relatively modest single-agent efficacy against the common carcinomas, and tumor resistance universally develops. Advances in cancer therapy will require novel agents with new mechanisms-of-action, multiple modes of cell destruction and synergy with standard treatments. Genetic therapies have the potential to fit this profile. These therapies include oncolytic viruses (virotherapy), therapeutic gene transfer and nucleic acid therapeutics. A key advantage of genetic agents is that they can be targeted to cancer cells in a highly specific fashion. For example, in this issue of Molecular Therapy, Nasimuzzaman et al. show that a dominant-negative EBNA1 protein can inhibit the growth of Epstein-Barr virus (EBV)-transformed cells, while leaving EBV-negative cells unharmed. Although genetic therapeutics for cancer have been in clinical trials for over fifteen years, none of these agents has been approved for commercialization in the US or EU. A number of hurdles have been identified. First, systemic antitumoral efficacy is critical to maximize clinical benefit. New approaches are being developed, such as the use of viruses that are inherently able to target tumors intravenously or the coating of viruses with cationic polymers to improve intravenous circulation times. The resulting improved circulation times and higher intravenous doses may require that cancer-cell selectivity be improved. For example, promoter-dependent control of oncolytic virus replication may need to be optimized (see Pico et al., this issue). A second hurdle is getting the therapeutic agent to sufficient numbers of tumor cells at sufficient doses once it has reached the tumor mass. The rate of spread of viruses within a tumor is still a critical limiting determinant—as demonstrated through both direct experimentation and mathematical modeling. Intratumoral spread can be enhanced by using viruses that inherently spread rapidly, such as poxviruses, by engineering viruses to spread more quickly or by expressing proteins that reduce barriers to spread within the tumor, such as fibrosis. Engineering viruses to avoid rapid immune clearance will also increase tumor cell exposure. Gene transfer approaches will also have to surmount the hurdle of resistance. The development of resistance is driven by heterogeneity in cancer cell populations. Resistance can be addressed through killing cells by multiple nonoverlapping mechanisms. Oncolytic viruses, for example, can also kill by apoptosis-independent mechanisms such as direct cell lysis or necrosis. Virotherapy agents can also induce tumor-specific cell-mediated immunity and antivascular effects. To further augment these effects, oncolytic viruses can be genetically “armed” with therapeutic transgenes, such as prodrug-activating enzymes, immunostimulatory cytokines and antivascular peptides (see Liu et al., this issue). Finally, perhaps the greatest barrier to success is getting new agents into clinical trials designed to answer fundamental questions for the field. Hurdles to entry into the clinic include the need for toxicology and biodistribution studies, myriad regulatory submissions, and manufacturing and product release testing. Once in the clinic, the development of genetic agents can be substantially improved. Randomized Phase II trials will be necessary to determine the optimal Phase III dose. Optimal treatment regimens must be defined for each agent, including infusion duration, frequency per treatment cycle and cycle duration. Validated endpoints such as survival and quality-of-life will be critical for product approval. Finally, the field will benefit greatly from an improved understanding of viral replication and kinetics in patients. Genetic therapy agents such as armed oncolytic viruses will eventually become integral parts of the cancer treatment armamentarium. However, it is clear that important hurdles to their development remain to be overcome. The editors of this journal would like to reinforce to our readers our intention to recruit and publish studies that address these key issues in the development of genetic agents to treat cancer.