Prostate Cancer Gene Therapy: Attempts to Innovate

I n contrast to hematopoietic tumors few solid tumors, especially after they metastasize, can be cured by conventional therapy. Prostate cancer is one of the most common types of cancer in men in the United States, with 186,000 new cases in 2008 and 28,600 deaths. It is the second leading cause of cancer death in men after lung cancer. Standard therapies include surgery, radiation, hormonal therapy, and chemotherapy. Curing cancer is the ultimate goal and therefore new, innovative approaches must be tested.

Several therapeutic approaches have been investigated using small molecules, antibodies, antiangiogenic molecules, cell therapy, and gene transfer methods. None has succeeded so far. More than 90 clinical protocols using gene transfer in prostate cancer patients can be found in the NIH database and the majority use adenoviral vectors as delivery methods. Most approaches are in early-phase testing or were terminated early on. Four approaches progressed to phase III. Trying to force the immune system to fight cancer has been a tantalizing and often frustrating project for many scientists and it is not clear why the trial failed.

Adenoviral gene transfer strategies in patients with prostate cancer have achieved a particularly outstanding safety record. All trials using adenoviral vectors administered as a single agent or in combination with other modalities, in localized disease or in patients with metastatic disease, have demonstrated low toxicity. But this cannot be the purpose. Significant antitumor activity is the ultimate goal and strategies must be reconsidered and improved. So far adenoviral vectors armed with immunostimulatory genes or prostate-derived antigens, or with oncolytic properties, are the leading strategies. The debate is still on concerning which of these approaches should primarily be pursued. It is clear that this debate can be settled only in the clinic after randomized and well-controlled phase III trials have been completed. To get to this point several issues must be addressed: Are the vectors delivering the genes to a sufficient amount of target cells? Are the levels and timing of transgene expression appropriate? Are the preclinical models able to predict which strategy will work in cancer patients?

Human Gene Therapy presents a series of three reviews that discuss clinical status and the preclinical development of gene therapy of prostate cancer. Schenk and colleagues set the stage and summarize the clinical experiences (and in part disappointments) both with replication-deficient and replication-competent adenovirus vectors and consider which directions should be pursued to overcome current limitations and improve efficacy.

De Vrij and colleagues review recognized in vivo barriers for adenoviral vector delivery to prostate cancer and tumor cells in general and discuss current approaches to improve vector potency both after direct tumor injection and systemic delivery. Inefficient vector delivery to tumor cells and, in the case of oncolytic vectors, poor intratumoral spreading remain the major shortcomings of current technologies.

Last, Maitland and colleagues address potentials and limitations of available preclinical cellular and tumor models for prostate cancer gene therapy and suggest that improved testing systems mimicking more closely the clinical situation are urgently needed to facilitate translation of preclinical research to clinical trials.

Although these reviews focus on gene therapy of prostate cancer with one particular vector type, it is obvious that many, if not most, issues discussed are of similar significance for clinical and preclinical gene therapy development for many other solid malignancies with the same or other viral and nonviral vectors.