UAB Initiates Novel Bench-to-Bedside Study

Ovarian cancer remains the leading cause of death from gynecologic cancers in women. Advances achieved through taxane and platinum-based therapies and combinations of intraperitoneal (IP) therapy with standard intravenous therapy have lengthened remissions. Yet despite improved treatments and aggressive surgical debulking, only limited gains have been made in 5-year survival, which remains at <40%. A new genetically modified, viral-based therapy may provide much needed investigative and therapeutic options for women with recurrent ovarian cancer.

UAB Gene Therapy Center (GTC) Director David T. Curiel, MD, PhD, and Ronald D. Alvarez, MD, director of UAB’s Division of Gynecologic Oncology, have labored for more than 6 years to see their phase 1 study of an infectivity enhanced, conditionally replicative adenovirus (CRAd) begin in spring 2007.

Although viral therapies have been used for more then 60 years, “this is the first trial in humans using a virus with an altered affinity for cancer cells,” Curiel says. The study features Ad5-∆24RGD, a CRAd designed by GTC scientists for enhanced infectivity, potency, and tumor-specific replication — novel properties that may improve clinical outcomes, Curiel says. “These changes in tropism modify the way the virus sees the cell and increase its ability to preferentially enter ovarian tumor cells.” Alvarez emphasizes viruses used in the study are modified to restrict replication to cancer cells. Scientists engineered this aspect of the virus’s biology to avoid replication in healthy tissue.

Passage of extensive preclinical hurdles led to endorsement from the Food and Drug Administration and the National Institutes of Health (NIH) to initiate this trial, which will determine the maximum tolerated dose, side effects, and clinical activity. A follow-up study employing a noninvasive fluorescing imaging system compatible with current clinical imaging modalities and capable of evaluating viral replication and spread during treatment is in development.

Clinical Translation
Following precedents endorsed by the National Cancer Institute in 2006 advocating IP administration of chemotherapy, this trial will deliver the CRAd via IP infusion. Clinicians will treat seven groups of women for 3 days and monitor patients for toxicity and clinical responses. Women participating in this clinical trial are true pioneers.

Curiel notes the use of a CRAd codesigned in UAB laboratories and administered to UAB patients during a clinical trial fully illustrates the bench-to-bedside concept emphasized by the NIH. “Industry-developed pharmaceuticals typically require 10 to 15 years and a half billion dollars to reach clinical practice,” he says. “In an academic medical center you can take much greater conceptual leaps, and the rewards are shared by all — patients, scientists, and clinicians.”

With new knowledge of cancer biology leading to innovative treatments, Alvarez hopes this unique trial will add to incremental advances extending ovarian cancer patients’ lives. “While we often are not able to cure recurrent disease, we can perhaps help patients reach whatever their next life milestone may be, such as the marriage of a child or the birth of a grandchild.”

For more information
Dr. Ronald Alvarez
Dr. David Curiel
1.800.UAB.MIST
mist@uabmc.edu