HSV1716 clinical trial for childhood cancer receives FDA grant

A clinical trial testing a genetically reprogrammed herpes simplex virus as treatment for deadly forms of childhood cancer has received a U.S. Food and Drug Administration grant to support the research.

The Phase I trial at Cincinnati Children's Hospital Medical Center currently focuses on testing the safety of the agent HSV1716 in patients. The study includes young patients with solid tumors such as rhabdomyosarcoma or Ewing's sarcoma. These cancers have limited treatment options and survival rates under 30 percent when the cancers recur and spread to other parts of the body.

Survival curves for stubborn, metastatic childhood cancers have leveled off in the last decade, underscoring the need for new therapeutic approaches, says Timothy Cripe, M.D., Ph.D., principal investigator on the trial and a physician/researcher in division of Hematology/Oncology at Cincinnati Children's.

"We've exhausted our ability to improve cure rates with existing conventional therapies and we need new solutions," he said. "This is why we are testing HSV. It's a potent virus that has been manipulated genetically with the intent of making it safe for the patient. When you're trying to fight fire with fire you need something that is strong."

The $600,000 grant from FDA is part of a program encouraging clinical development of "orphan drugs" as new treatments for rare diseases or conditions. The HSV1716 virus being tested in this trial was developed by Crusade Laboratories of Glasgow, Scotland.

HSV1716 is similar to other viruses now under development by Dr. Cripe and colleagues at Cincinnati Children's in that certain genes are removed so the virus does not infect healthy dormant cells or cause the disease in the recipient. Instead, the genetic manipulation is designed to prompt the virus to target, infect and degrade only rapidly dividing cancer cells.

Genetic information also can be added to HSV that programs the virus to attack cancer cells in other ways - such as activating certain types of chemotherapies in a one-two punch or destroying blood vessels that feed tumors. Research in mouse models of human cancer by Cripe's laboratory has shown oncolytic HSV agents to be effective at shrinking a variety of modeled tumor types, suggesting a possible approach for treating human disease.

"Our goal in the current HSV1716 trial is to light a fire to the cancer so that the virus replicates and spreads to the cancer cells," Dr. Cripe explained. "We have to take this one step at a time and the initial phase of the trial focuses on making sure the virus doesn't cause adverse side effects. It has been tested in Europe in adults with brain cancer, squamous cell carcinoma and melanoma and shown in those trials to be safe."

HSV1716 has also been tested extensively for safety in animal models at Cincinnati Children's Hospital by Dr. Cripe and in Europe prior to it being tested in people.

The Phase I trial will include up to 18 patients and is expected to last three years. The optimum safe dosing for this virus is unknown, so the study will sequentially increase dosing levels in small groups of patients and observe for side effects as the trial proceeds. This earliest phase tests the lowest dose on older children and young adults with solid tumor cancers who have limited or no standard therapy options available.

The researchers plan to add younger patients with earlier stages of cancer as the trial proceeds. They will not be able to determine if the safety trial is successful until all patients have received treatment and the results analyzed. As with all clinical trials of new anticancer therapies in patients, many factors can influence the risk for severe side effects and anticancer activity. Even though HSV1716 may cause tumor shrinkage in mouse models of pediatric cancer, it may not have antitumor effect in patients.