Children's of Alabama is home to one of the most exciting studies underway in pediatric cancer: evaluating the use of a cold sore virus to treat children with progressive malignant brain tumors.
The approach is based on the finding that pediatric brain tumors are highly sensitive to genetically engineered oncolytic HSV-1 G207, the same virus responsible for the common cold sore.
University of Alabama at Birmingham (UAB) and Children's are the only places in the world where this type of virus has ever been used to help pediatric brain cancer patients. Gregory Friedman, M.D., an associate professor, Pediatric Hematology-Oncology and director of Developmental Therapeutics at UAB who treats patients at Children's, says it's still early in the study, but it's already showing major promise. Friedman's team has treated 10 patients from across the United States – and some internationally – with promising preliminary results.
We do get a lot of looks when we say we're going to be using the herpes virus, but what we've learned is that we can engineer these viruses so that they're safe and can actually be directed, targeted therapy to kill cancer cells."
Gregory Friedman, M.D., associate professor, Pediatric Hematology-Oncology and director of Developmental Therapeutics, UAB
Here's how it works.
Once a biopsy is done to confirm a recurrent tumor is present, doctors place catheters directly into the tumor. Then the catheters are externalized out through the patient's scalp similar to an IV.
"Then the following day, the virus is infused over six hours through the catheters," he says.
Doctors then remove the catheters, the patient is monitored for a few days in the hospital, and then followed intermittently in the outpatient clinic.
This one-time treatment is shown to not only kill cancer cells but also to stimulate the patient's immune system.
Friedman noted that the primary purpose of this initial study is to demonstrate safety and thus far the virus has been safe and tolerable in children with progressive malignant brain tumors.
The following is a Q and A with Dr. Friedman about the study.
Q: What is pediatric virotherapy/immunotherapy as it relates to your research of recurrent brain tumors?
A: Virotherapy is a type of immunotherapy that utilizes a virus to kill cancer cells and to stimulate the child's immune system to attack the tumor, providing a "one-two punch" at attacking the tumor. There are many different viruses that are being studied as possible cancer treatments. Some of the viruses do not typically produce disease in humans, and others, like the cold-sore virus that we are researching, have to be altered so that the virus cannot harm normal cells but can kill cancer cells. We think the cold-sore virus is an ideal virotherapy/immunotherapy agent for a number of reasons. It can infect and kill cancer cells while stimulating a robust immune response against the tumor. The virus has been studied extensively so that the essential and nonessential genes have been identified. Nonessential genes can be replaced with foreign human genes. As the virus replicates, the foreign gene can result in the production of substances that enhance the immune response against the tumor. Lastly, unlike other viruses, there are drugs available to treat infection in the unlikely event that the altered virus causes problems.
Q: Describe the attributes of children who are generally diagnosed with malignant brain tumors.
A: When a child is diagnosed with a brain tumor, the symptoms can vary depending on the location of the tumor. Commonly children will experience headache, nausea, vomiting, and difficulty with balance. Occasionally, a tumor can cause seizures, weakness, numbness, vision changes, or difficulty with speech or swallowing.
Q: What is a typical treatment plan for a child with malignant brain tumors?
A: The treatment depends on the type of tumor and location of the tumor, but in general, malignant brain tumors in children are treated with a combination of surgery, chemotherapy, and radiation. These therapies are very damaging to a child's developing brain and can result in lifelong disability in survivors. Unfortunately, many children do not survive a malignant brain tumor. This is why novel, targeted therapies are greatly needed to improve outcomes and lessen toxic side effects of current therapies.
Q: What is the prognosis of someone with malignant brain tumors?
A: The prognosis depends on the type of malignant tumor, the location, and the molecular genetics of the tumor. Some tumor types, like brainstem gliomas and glioblastoma, have very poor outcomes with survival rates of 0–10%. Survival rates for medulloblastoma, the most common malignant brain tumor in children, range from 50–80%. Overall, malignant brain tumors are the leading cause of death from cancer in children.
Q: What happens when a patient relapses?
A: When a patient relapses with a malignant brain tumor, there are very few effective treatment options. If it is possible for the neurosurgeon to remove the recurrent tumor, surgery may be performed. If it has been a long enough interval from the initial course of radiation, another course of radiation may be used. There are a few traditional chemotherapy agents that can be used as a second line of treatment as well. Unfortunately, these type of treatments tend to only temporarily control the disease; recurrent malignant tumors are very rarely curable and almost always fatal over time.
Q: How has treatment for pediatric malignant brain tumors changed in the last 30 years?
A: The main changes to standard therapies have been improvements in surgical techniques, new strategies for delivering radiation, and a few new traditional chemotherapy agents. More recently, there has been a scientific boom in understanding the molecular characteristics of tumors, which has helped to define tumor behavior and provide new targeted avenues for treatment. This has led to the development of many different types of therapies, including antibodies, small molecule inhibitors, and immunotherapies.
Q: Why did you choose to research malignant brain tumors?
A: While overall survival rates for childhood cancers have improved greatly, unfortunately, outcomes for malignant pediatric brain tumors have lagged behind other types of cancer. Also, those that survive often suffer long-term disability from the treatments and the disease itself. There is an incredibly great need for new, targeted, less-toxic agents for this vulnerable population of patients, and that need is really what attracted me to research in this area.
Q: Are there any current research projects that are promising? If so, can you provide high-level/layperson details of the research?
A: To me, the most exciting and promising research projects currently are immunotherapies. Immunotherapies harness the patient's own immune system to attack the tumor. There are many different approaches being tested, including antibodies to block proteins that tumors use to evade the immune system attack, tumor vaccinations, immune cellular therapies such as chimeric antigen receptor (CAR) T cells or natural killer cells, and virotherapy. Likely a combination of these approaches will be most effective. The first step is to get the child's immune system to recognize the tumor as abnormal and to begin to attack it. Then the goal is to increase and maintain the attack on the tumor. Even if the immune system can just keep the tumor in check and keep it from growing, this would provide significant benefit for the patient.
Q: In lay terms, describe your research and the potential outcomes.
A: My overarching goal is to improve outcomes for children with brain tumors by developing and improving novel, targeted immunotherapies in the lab and then translating these therapies to clinical trials. We are currently studying a cold-sore virus that has been genetically altered so that it cannot harm normal brain cells but can infect and kill tumor cells while stimulating the patient's own immune system to attack the tumor. Our first-generation virus is currently in a Phase 1 clinical trial for children with brain tumors and has shown great promise thus far. It has been safe and tolerable in all patients with evidence of efficacy in many, including a patient over two years out from the treatment without any additional therapy. We are taking what we are learning from the current clinical trial back to the lab (bedside-to-bench) to improve the therapy further by developing newer viruses, unique routes of delivering the virus, and unique combination therapies with the virus to maximize the anti-tumor response from the immune system. We will then take our discoveries from the lab back to the clinic (bench-to-bedside) to conduct new clinical trials to hopefully improve outcomes and lessen side effects for children in desperate need of better therapies.
Q: What have you learned from the patients with malignant brain tumors you have treated?
A: I have learned something from every patient I have treated. These lessons have ranged from how to handle adversity to communicating more effectively with children and families to managing unexpected side effects to considering and offering new treatment approaches. My goal is to treat each patient and family like I would want my own child and family members treated.
Q: Is there one child or family in particular about whom you could share a story of the way they impacted your passion to continue your research?
A: One of the first children with a brain tumor I took care of was a 3-year-old with a highly aggressive ependymoma. The tumor wrapped around the brainstem, and during the surgery to remove the tumor, the child suffered a brain injury and was in the ICU for months. The child lost the ability to talk and walk, and we were not certain if any recovery was possible. Against all odds, the child made a miraculous recovery, and through hard work and determination of the child and family, the child returned to walking, talking and playing. Unfortunately, the disease was a really bad disease, and the tumor returned. When it did, we lacked effective treatment options, and ultimately, the disease took the child's life. This was incredibly difficult for everyone involved-;to watch the child courageously fight back only to lose the battle against the disease. This definitely heightened my passion to fight for these children and their families and develop improved, targeted therapies.
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