Clinical experience with gene therapy for the treatment of prostate cancer

Abstract

Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients.

Figure 1

The classic cancer vaccine. Cancer cells are grown in culture from individual patients and infected with a retrovirus that expresses GM-CSF. Cells expressing GM-CSF, a cytokine that enhances antigen presentation, are expanded and lethally radiated to ensure they cannot grow when injected back into the subcutis.

Figure 2

How the HSV-tk plus prodrug system kills cells. GCV, ganciclovir; HSV-tk, herpesvirus.

Figure 3

Mechanism of action for CG7870. This vector is a replication-competent adenovirus. The genes that control replication have been placed under the control of a prostate-specific enhancer. Therefore, this virus can infect any cell, such as a hepatocyte, but cannot replicate. When it infects a prostate cancer cell anywhere in the body it replicates until the cell lyses and hundreds of new viral particles can infect surrounding cells, again replicating and killing only prostate cells.

Figure 4

Cellular binding sites for adenovirus. Adenovirus gains entry to cells via a 2-step process: the knob at the end of the fiber binds to the coxsackie-adenovirus receptor (CAR) followed by interactions from the base of the fiber with integrins in the cellular membrane. Genetically, the sequences for the H1 loop, which binds to CAR, can be removed and replaced with sequences that bind to other surface proteins, thus reprogramming binding. Alternatively, the entire knob can be replaced with knobs from other serotypes of adenovirus that have natural predilection for certain cell types.