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UCLA is testing an investigational gene transfer technique on a form of brain cancer


CU-Brain Cancer GeneUCLA is conducting a clinical trial to test the efficacy of a promising gene transfer technique for patients with glioblastoma multiforme (GBM), an aggressive and deadly form of brain cancer. GBM affects glial cells, the support structures in the brain that manufacture myelin coating and provide nutritional support for neurons.

About 20,000 people each year are diagnosed with GBM, making it the most common type of primary brain cancer. With a one-year survival rate of 33 percent and a five-year survival rate of 4 percent, GBM is the most fatal form of all primary brain cancers. Although it does not spread to other organs, GBM produces tumors that create pressure on vital brain structures. Depending on their location in the brain, the tumors can cause a range of symptoms including seizures, degeneration of memory or speech, personality changes, nausea, vomiting, headache and muscle weakness.

There is no means of early detection for GBM, nor can it be prevented. While it affects people of all ages, it is the second leading cause of cancer deaths in young adults and is on the rise in patients over age 65. Patients are treated with surgery, radiation and chemotherapy using temozolomide — a palliative treatment regimen that temporarily relieves symptoms but only improves average survival by about one year.

Novel gene transfer technique may overcome obstacles

In the past 20 years, there have been many unsuccessful attempts to treat disease by correcting or replacing abnormal or non-functioning genes with normal ones. The corrective genes are generally introduced into tumors through a vector such as a virus. The technique has had limited success because (a) the weakened viruses typically used as vectors don’t spread throughout the tumor and (b) the patient’s immune system often recognizes the virus as foreign and attacks it.

UCLA is testing a novel gene transfer technique that addresses these obstacles and may improve outcomes for patients suffering from GBM. The new treatment uses a genetically altered retrovirus called Toca 511, a virus that can cause leukemia in newborn mice but is not known to cause disease in humans. In mice, Toca 511 has the ability to replicate within a brain tumor without being inhibited by the immune system. It has been altered to contain a so-called “suicide gene” that produces a powerful chemotherapy drug inside the cancer cells infected with the virus, killing tumor cells without harming healthy tissue.

How Toca 511 works

Engineered at UCLA, Toca 511 is a self-replicating retrovirus — meaning it contains RNA and becomes a permanent part of the host cell’s DNA and all of its daughter cells — that is designed to make cytosine deanimase, an enzyme found in yeast. The virus is delivered into the tumor through a transcranial injection using a biopsy needle. After a three-week wait for the virus to replicate throughout the tumor, the patient receives a six-day oral course of an anti-fungal drug that is usually well tolerated by patients. In the malignant cells infected with Toca 511, the cytosine deanimase converts the anti-fungal drug into 5-FU, a powerful chemotherapy drug that can destroy the tumor cells infected with the virus. Because the virus targets rapidly dividing tumor cells, healthy brain cells, which divide slowly if at all, should remain unaffected. As the virus is not intrinsically oncolytic (cell-destroying), it also is designed to escape detection by the patient’s immune system. To ensure all the malignant cells are treated with 5-FU, the oral anti-fungal treatment is repeated every four weeks for six cycles.

UCLA is enrolling patients in a clinical trial of the technique

While three centers have received FDA approval to test the gene transfer technique, UCLA is the only facility that has currently recruited patients for the Phase 1 clinical trial. The study will enroll approximately 30 patients, who will receive one of four concentrations of the virus.

Only patients with glioblastoma who have already undergone surgery, radiation, and chemotherapy with temozolomide (Temodar) are eligible to participate in the trial. Patients must be between the ages of 18 and 75, have a single glioblastoma lesion between 1 and 3 cm in its longest dimension and be at least 12 weeks from their latest radiation treatment. Patients who are HIV-positive, have poorly controlled seizures, or ventricular involvement of the tumor are not eligible for the study.

Toca 511’s “suicide” gene represents a new era in gene transfer medicine

In one disappointing study after another, gene transfer has not lived up to its promise as an anti-cancer therapy. The weakened viruses used as vectors have been largely ineffective at infecting tumors and are usually attacked by the patient’s immune system before they can deliver their payload.

Toca 511, a replication-competent retrovirus, has been engineered to manufacture an enzyme that helps deliver chemotherapy to malignant brain tumors, and may overcome many of the obstacles that have hampered gene transfer therapies in the past.

“The vector contains what we call a ‘suicide gene’ and is a clever way of delivering medicine to kill the tumor,” says UCLA’s Neuro-Oncology Program Director Timothy F. Cloughesy, M.D., who is the study’s principal investigator.

“This is a new type of therapy that is pushing the boundaries of gene therapy,” Dr. Cloughesy says. “I’m incredibly hopeful that it could eventually lead to a cure.”

Participating Physicians

Timothy F. Cloughesy, M.D.
Professor of Neurology
Department of Neurology
Director, Neuro-Oncology Program

Linda M. Liau, M.D., Ph.D.
Professor and Vice Chairman,
Neurological Surgery

Bob B. Shafa, M.D.
Assistant Professor Neurological Surgery

Albert Lai, M.D., Ph.D.
Assistant Professor UCLA Neuro-Oncology Program

Leia Nghiemphu, M.D.
Assistant Clinical Professor UCLA Neuro-Oncology Program

William Yong, M.D.
Professor Pathology and Laboratory Medicine,
Surgical Pathology Director Brain Tumor Translational Resource

Whitney Pope, M.D., Ph.D.
Assistant Professor Radiology,
Section of Neuroradiology

Contact Information
UCLA Neuro-Oncology Program
710 Westwood Plaza, Suite 1230
Los Angeles, CA 90095
Phone: (310) 825-5321
Fax: (310) 825-0644

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