Treatment of Canine Glioma with Combination Gene Therapy

Status –
Approved

What is “combination gene therapy” and how is it used in this study?

Gene therapy is a relatively new treatment method that uses the recent advances of molecular biology in which particular pieces of DNA or genes that cause the production of specific proteins are inserted into tumor cells. Once the bits of DNA are inserted into the tumor cell's own DNA, the tumor cell begins to produce the specific protein. A virus that has been modified so that it does not cause any disease is used to carry the gene into the tumor cells. The two genes that will be used in this study work together to make the tumor cells more “visible” to the brain's own immune response to kill the tumor cells. The body's immune system prevents or rids the body of disease by destroying foreign material (bacteria) and abnormal cells (tumor cells) and producing antibodies. One gene called “Ftl3L” stimulates the brain’s most powerful immune cell, a dendritic cell. These cells can kill tumor cells independently and signal other immune cells that tumor cells are present and need to be removed. The second gene to be used called “HSV-tk” is a "suicide gene". When this gene is added to the DNA of a tumor cell, the tumor cell dies when it tried to divide and also kills other nearby tumor cells in a process called the "bystander effect". This gene combination had a 70% cure rate when given to rats with large brain tumors, although neither gene was very effective when given alone. Because the tumor cells are attacked by several methods simultaneously, this combination gene therapy has the potential to remove the tumor and prevent it from recurring. This therapy has the potential to reduce or eradicate the tumor in patients suffering from brain cancer.

Which animals are eligible for enrollment in this study?

Any dog with a specific aggressive brain tumor called a glioma that is healthy enough to undergo the surgery and radiation therapy can be included in this study. The brain tumor is initially found by a CT scan or an MRI and may be tentatively diagnosed as a glioma. The tumor must then be verified as a glioma with a magnetic resonance imaging (MRI) or computed tomography (CT) guided brain biopsy before your dog can receive treatment.

How much does the treatment of the glioma cost?

Once the brain tumor is diagnosed as a glioma, the ensuing treatments will be performed at no cost to the dog's owners up to a maximum $12,000, which is the estimated financial value of the entire treatment protocol. In addition, the value of prolonging your pet's life and of contributing to the efforts to find a cure for brain cancer in both dogs and people is invaluable.

How are animals being chosen to enroll in this study?

Dr. Pluhar, a veterinary surgeon and Principal Investigator of this study, one of the veterinary oncolgists, Dr. Mike Henson and Dr. Brian Husbands, or a veterinary neurologist, Dr. Alistair McVey will perform a thorough physical and neurological examination of your dog. Blood will be drawn for screening tests to make sure your dog is healthy enough to undergo the general anesthesia for surgery and subsequent radiation therapy. A small amount of this blood will be stored for our glioma DNA bank. If an MRI has not already been done, your dog will be placed under general anesthesia under direct supervision of board-certified anesthesiologists and certified technicians for a brain MRI to determine the location, size, and imaging characteristics of the mass. If the tumor has an appearance consistent with that of a glioma, a piece of the tumor (biopsy) will be taken. A small sample of cerebrospinal fluid (CSF) will be collected for analysis after the MRI. Any dog that has a biopsy that confirms the brain tumor is a glioma can be enrolled in the study.

What is the course of therapy for the dogs?

Dogs that are enrolled in this clinical study will help to establish the safety and effectiveness of a novel cancer treatment. This is an experimental treatment in dogs that has been shown to be very effective in killing large brain tumors that were artificially induced in rats' brains. If this therapy is effective in reducing or completely removing the tumor in dogs, it will be continue to be offered as a treatment for other dogs with the tumor and will be offered as a treatment for people with this type of brain cancer. To determine if this gene therapy has a significant effect in dogs with glioma, a two-arm clinical study will be conducted. Dogs enrolled in the study will receive the highest current level of care, surgical removal of the tumor and a full course of radiation therapy or the combination gene therapy in addition to this same standard of care. Treatment will include surgical removal of as much of the tumor as possible, followed by whole brain radiation therapy that will be specifically planned for your dog. All dogs under anesthesia will be monitored and supervised by a board-certified veterinary anesthesiologist at the Veterinary Medical Center (VMC). The surgery will be performed by Dr. Pluhar, a board-certified veterinary surgeon at the VMC, and may be assisted by Dr. Stephen Haines, MD, neurosurgeon at the Fairview-University of Minnesota Medical Center. Prior to surgery, each dog will be randomly-assigned to receive either the virus-delivered combination gene therapy or the virus with an inactive gene. Each dog will have the tumor removed completely, if possible, or debulked and then the virus with or without the therapeutic genes will be placed into the brain where the tumor was removed.

The dogs will be kept in the intensive care unit of the VMC with constant monitoring and care given by Dr. Pluhar and the ICU doctors and staff. Analgesia (pain relief) and management of any seizure activity will be given on an individual basis under the direction and supervision of the trained doctors and staff. When fully recovered, each dog will be released to their owners’ care.

Every dog will have whole brain radiation therapy (RT) beginning 1 week after surgery. The radiation dose and plan will be designed by Dr. Elizabeth McNiel, a veterinary oncologist and radiation oncologist, or the veterinary radiologists at the VMC, Dr. Dan Feeney and Dr. Kari Anderson. Each dog will receive a standard dose of radiation (51Gy) administered in small fractions (19 2.7Gy doses) daily, Monday through Friday, to minimize the side effects. The dogs will be under general anesthesia for RT and will again be under the supervision of the veterinary anesthesiologists in the VMC.

There will be regular rechecks of the dog by Dr. Pluhar, Dr. Henson, Dr. Husbands or Dr. McVey. Complete physical and neurological examinations and a quality of life assessment will be made 2 weeks after surgery. At 1, 6, and 12 months after surgery, an MRI will be performed in each dog in addition to these tests.

The decision to euthanize your dog will ultimately rest with you; however you will be required to donate your pet’s remains so tissue samples can be obtained for further testing and research studies.

What are the risks to the patients?

There are several risks involved in this study. First, we do not know whether the combination gene therapy will be more effective than surgery and radiation therapy alone. Although this is pilot study and this particular gene therapy has not been used in dogs with glioma, it has greatly increased survival time when given to rodents with large gliomas without appreciable side effects. This type of gene therapy caused either no or temporary side effects in normal dogs. Finally, other types of gene therapy are currently used in people with brain tumors with minor adverse effects such as headache and mild fever.

General anesthesia, in and of itself, can be dangerous. Although it is rare, animals can have unexpected reactions to the anesthetic drugs. Tests will be run to minimize your dog's chance of having problems with anesthesia. Drugs that are most safe for dogs with brain masses and are reversible will be used and the anesthesiologists are always on hand in case of an emergency.

Although the surgery to remove the tumor is a major procedure, tumor removal will be limited to an amount that can be accomplished without causing more damage. Tumors close to the surface of the brain or in the forebrain are easier to remove. State of the art preoperative planning and postoperative care will also be used to minimize the chance of complications.

Radiation therapy has inherent risk as well. Since all radiation treatments must be performed under anesthesia, the aforementioned risk of anesthesia is present. Radiation side effects include moist sloughing of skin, alopecia (hair loss), redness, irritation and pain over the radiation field. This normally occurs 2-3 weeks into therapy and may persist for 2-3 weeks. Another unlikely but possible side effect is radiation myelitis (neurological abnormalities due to the treatment). When this occurs, it tends to be several weeks to months after radiation therapy. Unfortunately, there is no definitive treatment for it other than symptomatic care. Once the radiation has been given, there is no way to prevent radiation side effects. Even when we do not see radiation effects during the course of therapy, we still expect them to occur at some point. Not all animals will have the same sensitivity to radiation effects and so there is wide variation in the time to and degree of radiation side effects between animals. The side effects can be minimized by proper pre-radiation planning and fractionated dosing.

How can I find out more?

If you or your veterinarian thinks that your pet could benefit from enrollment in this study, or if you would just like more information about gliomas or any of our studies, please contact Dr. Pluhar at 612-626-8387 (referral center), 612-625-1162 (office) or by email

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