Originally appeared on ASCO Daily News
Crystal L. Mackall, MD, the Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine at Stanford University and Founding Director of the Stanford Center for Cancer Cell Therapy, is the recipient of the Pediatric Oncology Award for her research in immuno-oncology. Dr. Mackall will present a lecture in support of the award during the 2021 ASCO Annual Meeting.
First delivered in 2002, the Pediatric Oncology Award recognizes someone who has demonstrated outstanding leadership or achievement in the field.
“I'm honored and privileged, and I'm just humbled by it all,” Dr. Mackall said. “This is an amazing honor, and I truly didn't expect it.”
Dr. Mackall trained in internal medicine and pediatrics. She knew from the start that she wanted to be an oncologist and at the time her career was launching in the late 1980s, pediatric cancer medicine was thought to be “so much more advanced” than adult oncology.
“We were doing so much better with children's cancers at the time,” she said. “Intellectually, in many ways, pediatric oncology was more vibrant and more academically stimulating. I became very focused on immunotherapy” in the 1990s. At the time, a small number of people were working on immunotherapy, and predominantly in adult cancers.
Pediatric Cancers and Immunotherapy
Dr. Mackall said that, unfortunately, the evolution of treatment for childhood cancers has slowed over the past 30 years, compared to the rapid evolution early in the field—a testament to how effective chemotherapy-based treatments have been. In contrast, she said, during the last 30 years there has been exponential change in how adult cancers are treated, a true “payback from fundamental research and the development of targeted therapeutics, including small molecules, and more precise disease stratification,” she said.
The reason for the “plateau” in advancing childhood cancer treatments is multifactorial, Dr. Mackall said. Although significant advances have come in adult cancers by targeting mutant kinases, most oncogenes that drive childhood cancers cannot be targeted in this fashion, including those that alter the epigenome, as well as fusion proteins, which are notoriously undruggable,” she said.
“Pediatric oncology was so successful early on with multimodal chemotherapy that, despite the toxicities of these treatments, the cure rate was around 80%. That didn't leave a lot of room for improvement,” she said, which in turn made it more difficult to develop and test more targeted therapeutics. “It's a valid argument that our glass was already more than half full.”
The introduction of immunotherapy, however, has shown some very impressive early signals of success in pediatric cancers.
“Although we can't use immune checkpoint inhibitors for most pediatric cancers, which have driven the field of adult immuno-oncology, proof of concept that immunotherapy can be very potent has come from several different arenas,” she said.
The majority of new drugs approved for childhood cancers in the last decade have been immunotherapies. In fact, some of the first approved immunotherapies (CAR T cells) were approved for childhood cancers, Dr. Mackall noted, “and arguably some of their most exciting impact has been in children.”
Dr. Mackall “holds out hope that immunotherapy will be the thing that helps pediatric cancer treatment become more targeted and less toxic.” Current therapies can produce approximately 80% survival rates, but they also subject the patient to lifelong toxicities.
Much of a pediatric oncologist's time is spent treating those toxicities.
“We've figured out how to give a poison at a dose that allows the patient to survive, and much of what we do is deal with the toxicities of our therapies, both short- and long-term,” she said. “We have to be able to do better.”
An ‘A-Ha’ Moment
Dr. Mackall spent a good part of her early career arguing that the role for immunotherapy should be in a setting of minimal disease burden.
Dr. Mackall spent a good part of her early career arguing that the role for immunotherapy should be in a setting of minimal disease burden.
“But when I saw what CAR19 could do…” she said, and spoke of one boy age 4 with refractory acute lymphoblastic leukemia who enrolled in the National Cancer Institute study on CAR19, which Dr. Mackall chaired.
“I felt guilty enrolling him because I just didn't believe that his immune system, which had been so beat up for so long, was going to be able to have the power to eradicate what was a packed marrow,” she said. By day 4, the child's fever had spiked, and stayed high for about a week.
“But at day 28, the cytokine release dissipated, and he didn't have any leukemia anywhere,” she said. “I realized then that I had underestimated the power of the immune system.”
What the Future May Bring
Dr. Mackall sees her purpose in the field as continuing to push for more targeted, less toxic therapies that work, and she believes immunotherapy has that potential. Chemotherapy will continue to be a treatment option, but, for example, in the case of bone marrow transplantation, “there is a lot of long-term late effects that increase over time. Hopefully, we can figure out how to use immunotherapy in a way that we change the way we treat children's cancers,” she said.
— Michelle Dalton, ELS