Cancer Gene Therapy: Present and Future

G ene therapy was originally intended to treat congenital diseases by introducing the missing gene into appropriate target cells. However, as soon as technologies and protocols were developed, it became clear that many acquired diseases could benefit from this therapeutic modality. Today, more than 60% of ongoing gene therapy clinical trials are designed to treat cancer (Edelstein et al., 2007). This high figure is the result of medical need: despite the fact that several mechanisms of oncogenesis are now understood, cancer is still a major cause of morbidity and mortality worldwide. The high incidence of cancer has encouraged extensive scientific effort, and the high mortality associated with advanced disease urges a rapid clinical translation of novel therapeutic approaches, with appropriate assessment of the risk/benefit ratio.

In this scenario, several therapeutic approaches, alternative to gene therapy, including small molecules, antiangiogenic compounds, antibodies, hematopoietic stem cell transplantation, cell therapy, and immunotherapy, have been investigated at preclinical and clinical levels, with the ultimate goal of increasing the rate of response obtained by conventional chemoradiotherapy. The majority of these approaches produced clinical success to various degrees, at least in selected tumors. On the other hand, the initial clinical experience with biodrugs, cell therapeutics, and small molecules revealed their limitations. Several small molecules are highly active, but only in selected subsets of patients affected by a specific disease. Adoptive cellular immunotherapy is highly active, but can be offered only in the small subset of cancer patients from whom tumor-specific lymphocytes can be identified and expanded in vitro. Allogeneic stem cell transplantation is highly effective against several hematologic malignancies, but is affected by a high rate of transplant-related mortality, largely due to graft-versus-host disease. The high rate of clinical response to antibodies is often transient.

The transfer and expression of genes, the common motif of a wide range of therapeutic approaches included in the definition of gene therapy, have tremendous potential to overcome the limitations of standard and more innovative drugs. To move from the pioneering stage to a mature clinical phase, gene therapy is today required not only to compete with, but often to synergize and sometimes to enable, established and novel therapeutic platforms.

On the basis of these considerations, we reasoned that a series of reviews covering topics related to the therapeutic application of gene therapy to cancer should be implemented. In the next four issues of Human Gene Therapy, we will learn how gene transfer technology allows us to overcome the intrinsic limitations of cancer immunotherapy, by producing, for every candidate patient, virtually infinite numbers of tumor-specific lymphocytes, by transferring tumor-specific T cell receptor genes into the patient's cells. In addition, the review series will focus on how the specificity of antibodies can be exploited to obtain long-term clinical responses by transferring chimeric antigen receptor genes into human lymphocytes, and on the advantages of introducing a gene encoding an entire antigen into human dendritic cells to prepare potent cancer vaccines. We will also explore the complex activity of oncolytic vectors in cancer cells, the tumor environment, and innate and adaptive immunity and learn how the transfer of a suicide gene into donor lymphocytes enables haplo-identical stem cell transplantation, by taming its side effects. Finally, we will explore the potential of gene transfer to inhibit tumor angiogenesis and discuss the advantages offered by gene therapy as compared with antibodies and small molecules in treating head and neck cancer.

Undeniably, gene therapy is limited by its high technological complexity and subsequent costs. This is a highly relevant limitation for a novel therapeutic approach, still in need of support from the proper business models. This challenge needs to be met and will be faced by appropriate clinical trials and competitive clinical results.