Stories of progress, inspiration, and information in overcoming osteosarcoma.

Dr. Crystal Mackall and her lab at Stanford University, smiling and looking into the camera.

Targeting the Cancer Cells in Solid Tumors

Crystal Mackall, MD, shares how cell and gene therapies show promise for a potential breakthrough in osteosarcoma treatment.

While drug therapies for adult cancers like breast cancer and lung cancer have improved over the last few decades, advancement in pediatric cancer medicine has been slow, says Crystal Mackall, MD, the Ernest and Amelia Gallo Family Professor and Professor of Pediatrics and Medicine at Stanford University.

“You see the advertisements on television of a grandma out with her grandkids, rowing in a canoe on her medication for triple negative breast cancer. On the advertisements for pediatric cancer, you still see children linked up to IV poles with bald heads,” says Dr. Mackall. In fact, treatments for osteosarcoma, a bone cancer that primarily affects children and adolescents, are as limited as they were 35 years ago.

Dr. Mackall, a leading expert in cancer cell therapy, spoke with The Frontline to explain why solid tumor immunotherapy for osteosarcoma has been challenging and to share about promising immunotherapies in the pipeline.

Challenge #1: Finding the Right Targets for Osteosarcoma Immunotherapy

One form of cancer immunotherapy involves activating T-cells, a part of the body’s immune system, to target and destroy cancer cells. For osteosarcoma, a challenge is developing T-cells that can tell the difference between cancer cells and normal tissue. Scientists first need to determine specific targets, or characteristics that set cancer cells apart. Then, they need to engineer the T-cells to focus on eliminating cells with those targets.

“The targets are the biggest barrier,” says Dr. Mackall. “To develop more effective cell and gene therapies for osteosarcoma, we need to identify better targets and we need to launch and conduct early phase trials to find the winners.”

“To develop more effective cell and gene therapies for osteosarcoma, we need to identify better targets and we need to launch and conduct early phase trials to find the winners.” — Crystal Mackall, MD, the Ernest and Amelia Gallo Family Professor and Professor of Pediatrics and Medicine at Stanford University

Challenge #2: A Lagging Pediatric Cancer Drug Market

The second major challenge, says Dr. Mackall, is that drug development for childhood cancers has been slow. New drugs are developed regularly for many adult cancers, but the biology of osteosarcoma is very different from these cancers. “The fact that the biology is so different in pediatrics makes the requirement for drug development more difficult,” says Dr. Mackall. “We have to develop drugs specifically for pediatrics. We cannot wait for it to come from adult cancers.”

Even after drugs are developed and tested in clinical trials, they need to be commercialized for patients to access them. Dr. Mackall says, “What we need is bench-to-market. Unless we have a way to commercialize the products, they are not going to get to the patients.”

Promising New Immunotherapies for Pediatric Cancers

Dr. Mackall is determined to be part of the solution to these challenges. She has patented more than a dozen different cancer treatments. After 27 years at the National Institutes of Health, she transitioned to Stanford University, where she leads an internationally recognized translational research program focused on immune-oncology.

Dr. Mackall and her lab are not the only ones working on developing cell and gene therapies for patients with pediatric and rare diseases. In a recent study published in the New England Journal of Medicine, patients with neuroblastoma showed impressive responses to a CAR-T cell therapy that targets a tumor-associated antigen called GD2 that is expressed on tumor cells.

“We have evidence that these cells can work in solid cancers,” says Dr. Mackall. “My lab has been working on using similar cells targeting GD2 in a devastating brain tumor, diffuse midline glioma. If those CAR T-cells work in that brain tumor, and if they can work in neuroblastoma, maybe they can work in osteosarcoma. We are all anxiously awaiting that information.”

Collaborating for Progress

Dr. Mackall says that collaboration remains central in the fight against osteosarcoma and other pediatric cancers.

“Scientists working on pediatric cancer learned early on that you need to do large pivotal trials to know whether something works. We were forced to collaborate because we had to, but the truth is that pediatricians are that way by nature. That spirit of collaboration continues to ring true throughout everything we do.”