Immunotherapy: A New Weapon in Childhood Cancer Treatment Arsenal
A new warrior has emerged in the war against pediatric cancer. Immunotherapy, prompting the immune system to fight cancer, is the newest of the existing treatments. American Family Children’s Hospital and the UW Carbone Cancer Center have become two of the key battlegrounds, by developing unique therapies for children with cancer.
For the past 70 years, surgery, chemotherapy and radiation have been the mainstays of cancer treatment. All three have improved cancer survival rates. But despite being life-saving for many children, these therapies are not always effective and can carry life-long, serious side effects and quality of life issues. Immunotherapy offers great promise for improvement on this front.
"Immunotherapy is not without side effects," says Dr. Paul Sondel, head of Pediatric Hematology and Oncology at American Family Children’s Hospital. "But unlike chemotherapy that affects normal as well as abnormal cells, immunotherapy is designed to target only cancer cells."
The primary goal of immunotherapy is to stimulate or enhance the natural immune system to prevent or fight cancer. Scientists are studying several ways to manipulate the immune system including infusion of antibodies, infusion of activated or genetically modified white blood cells (such as T cells or natural killer cells) and use of cell-signaling/activating drugs.
The human papillomavirus (HPV) vaccine is an example of immunotherapy that has recently come into standard clinical use as an effective immunotherapeutic means to prevent the development of cervical cancer.
Other methods, focused more on the treatment of existing cancers, are being developed or are in clinical trials that are offered only at specialized centers such as American Family Children’s Hospital.
Sondel and other researchers, including his colleague Dr. Ken DeSantes, head of the Bone Marrow Transplant program at American Family Children’s Hospital and clinical director of Hematology/Oncology, lead interdisciplinary teams that work with the Children’s Oncology Group (COG), a network of more than 250 children’s hospitals, cancer centers and universities that collaborate on pediatric cancer research.
As they have for the past four decades, researchers are playing a significant role in the most recent COG pediatric cancer therapy innovations. The COG collaboration developed a new form of immunotherapy for neuroblastoma, a cancer of the nervous system outside of the brain and spinal cord. Neuroblastoma is the second most common solid tumor form of childhood cancer; up until 2009, children with the high risk form of this disease had a survival rate of only 40 percent, or about one-half that of all childhood cancers. A recent COG study has improved those numbers.
The COG research collaboration, lead by Dr. Alice Yu of the University of California-San Diego, developed a combination of three separate drugs based on separate lab and clinical studies being investigated by Dr. Yu in California and Dr. Sondel in Wisconsin. The protocol combines MAB 14.18, an antibody that seeks out cancer cells, with Interleukin-2 (IL-2), a white blood cell activator investigated by Sondel’s team, and GM-CSF a second activator that was being studied by Dr. Yu’s team. The goal is to activate several types of white blood cells to attack the cancer cells that have MAB 14.18 on them.
In 2001, COG researchers including Sondel began a nine-year clinical trial that enrolled 226 children with high-risk neuroblastoma who responded to initial therapy. The children were randomly assigned to receive isotretinoin, a chemotherapy drug, or a combination of isotretinoin, the MAB14.18 antibody and the immune-boosting drugs. The trial showed strong positive results; the children receiving the immunotherapy did better than those that didn’t. The children who were on the standard therapy were given the option to switch to immunotherapy.
The clinical trial findings, published in the September 30, 2010, edition of New England Journal of Medicine, showed that the percentage of children who survived two years without disease progression increased from 46 percent to 66 percent because of the immunotherapy. The U.S. Food and Drug Administration currently is considering approval for use of the antibody as part of a standard treatment for children with neuroblastoma.
"Immunotherapy has been more than 85 years in the making," Sondel said. "And now it’s becoming standard therapy for certain childhood cancers and for some cancers affecting adults as well."
Sondel says several new directions for immunotherapy research have developed. They include new white blood cell activators that have been created and will be studied, genetically- engineered antibodies, and infusions of tumor-reactive white blood cells. Similar methods of immunotherapy are being investigated for other forms of cancer.
Dr. DeSantes and his team are currently running a clinical trial at UW to study the use of natural killer (NK) cells. Natural killer cells are white blood cells that don’t require activation and are preprogrammed to recognize their targets. In the trial, NK cells are taken from donors and infused into cancer patients as part of a bone marrow transplant regimen.
Other UW pediatric cancer researchers are also pursuing lab approaches directed towards future advances. Dr. Christian Capitini is investigating how to direct the immune cells in a bone marrow transplant against the tumor in a "graft-versus-tumor" reaction. The research in mice uses approaches that could soon move to clinical trials. Dr. Mario Otto is studying how antibodies similar to MAB14.18 might be able to deliver nanoparticles to cancers in order to maximize immune-directed tumor attack.