Cancer cell therapy innovator shifts focus toward treatment of solid tumors
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Crystal L. Mackall, MD, believes she has an "unusual pedigree" for someone in her position.
Mackall — the Ernest and Amelia Gallo family professor of pediatrics and medicine at Stanford University School of Medicine and founding director of Stanford Center for Cancer Cell Therapy — grew up on the border of Northeast Ohio and Pennsylvania.
Mackall opted for an affordable medical school close to home via a combined 6-year BS/MD program at University of Akron and Northeast Ohio Medical University, a state school with the aim of turning out primary care physicians for the region that — as she noted — is hardly part of the pipeline for academics who end up at NIH or Stanford.
Despite a lack of name recognition among her educational institutions, Mackall said her interest in being a physician came early, as did her desire to work in the field of cancer care and research.
“There was never anything but oncology for me,” she told Healio. “I knew early that I wanted to be an oncologist. I felt that cancer was the biggest problem to solve from a clinical point of view.”
At NIH, Mackall melded her intellectual curiosity in basic science with a desire to improve the lives of those with cancer.
“I was 29 years old and done with all my medical training before I got the chance to embark on my academic career,” she said. “I’m forever indebted to NIH for giving me that opportunity because mine was not the typical pedigree for somebody who has been groomed for an academic career.”
A pioneer with a purpose
After spending considerable time at NIH studying immunologic principles related to cancer, Mackall became chief of NCI’s pediatric oncology branch.
She “brilliantly led” the unit to “become the leaders in the application of cell therapy to pediatric malignancies,” according to Steven A. Rosenberg, MD, PhD, chief of the surgery branch and head of the tumor immunology section of NCI’s Center for Cancer Research.
Rosenberg — a man with his own seat at the pantheon of immune-oncology — was one of Mackall’s early mentors and collaborators in the cancer cell therapy space.
Mackall, he noted, was “instrumental” in helping to develop the techniques of modern adoptive cell transfer for younger patients with both hematologic malignancies and solid tumors.
Rosenberg and others worked with Mackall to apply NIH’s CD19-directed chimeric antigen receptor T-cell technology in younger patients with B-cell acute lymphoblastic leukemia. “With the great innovation and tireless effort of Dr. Mackall, NIH was among the first to apply this kind of genetic engineering to treat patients in the pediatric sphere,” Rosenberg said.
“[She] is an outstanding pediatric oncologist, an inspiring leader and has developed many of the careers of those involved in the use of immunotherapy for the treatment of pediatric cancer, where she's been a pioneer.” Rosenberg told Healio. “She’s already been responsible for major advances in the field, and I would expect to see a lot more advances emanating from her work in the future.”
Robbie Majzner, MD, assistant professor of pediatrics at Stanford University School of Medicine, trained in Mackall’s lab at Stanford. Now — as leader of his own lab — he collaborates with Mackall on a novel cellular therapy to treat a deadly form of pediatric brain cancer.
When asked to describe Mackall’s greatest professional asset, Majzner starts with just one word: synthesis.
“Crystal brings a combination of scientific expertise and creativity with real-world insight into what happens with patients in the clinic,” he told Healio. “Because she's got her foot in both worlds and is able to synthesize things that come from all different directions, she's able to create these very strong, biologically reasoned and well-designed early-phase trials that end up being extremely impactful.”
In a profession where most people are proficient at basic science or the ability to translate those findings into clinical relevance, Mackall is special for her rare ability to do both, Majzner said.
“She has a 360-degree view of the field,” he said. “She loves basic biology, but it's always with an eye on the clinic and a focus toward improving outcomes for children with cancer.”
A doctor first
Although Mackall infrequently sees patients in a clinical setting, she said she was a doctor first and a scientist second. This is the core of the approach she takes to her ongoing professional pursuits.
“In my work, you will see there's a very clear thread of pragmatism through it all,” she told Healio. “I'm interested in advancing the field of science, but not as an end unto itself. What I really want to do is improve cure rates for patients, and that potential is what excites me most.
To that end, Mackall echoed the words of her mentee. Making advances in pediatric oncology and the use of cellular therapy requires her to be a synthesizer of scientific discovery who can unbiasedly communicate its relevance for patient care, she said.
“Science is complicated and it's fast moving,” she said. “What's dogma today might be rethought tomorrow.”
When it comes to the scientific advances in which she has played a role, Mackall said those that have helped contribute to or change the overall narrative about how a problem is approached remain the most indelible in her memory.
She cites, for example, her work on the value of lymphodepletion in adoptive cellular therapy that started in the 1990s as a part of her early bench research.
She was investigating how to transfer cells and engraft them into a patient, and the role lymphodepleting chemotherapy could play in that process. By understanding how lymphodepletion affected the immune system, her group’s research gave rise to the notion that a host immune system needed to be prepared in such a way to make it more receptive to cell engraftment.
“This has been an area where I contributed a lot — not only in terms of data and papers, but mostly I think around the idea itself,” she said.
“Now we all get it: Lymphodepletion really matters, and we use lymphodepletion to create space for the cells to take hold,” Mackall added. “We don't fully understand it all, but that was an example of something that I feel very proud about, because I helped contribute to the larger understanding of this phenomenon.”
A new calling
Mackall said her latest focus is to help those in the field of cell therapy remain patient while innovation takes hold and allows the technology to successfully translate into effective treatments for solid tumors.
“I see this as my greatest calling,” she said. “We all know CAR-Ts work for B-cell malignancies, but now we are learning a lot about their limits and why they fail.”
Mackall said her lab’s focus is to “craft a new narrative” about the utility of CAR-T in solid tumors and contribute to an ongoing conversation about what works and what doesn’t, despite a fair number of skeptics who lack confidence in CAR-T’s ability to make effective inroads in this area.
“All the evidence demonstrates that CAR-T could work for solid tumors,” she said. “We must understand their limitations and have a conversation about how we can chip away at these in an intellectually honest way.”
Majzner said the work done in Mackall’s lab has already “changed the trajectory of cell therapy.” This is especially true for solid tumors, where her lab’s research is driving the field forward to the benefit of patients, he added.
“The insights gained from her laboratory around T-cell exhaustion and its effects on CAR T-cell efficacy has started to change how we started to manufacture CARs,” Majzner said. “Biologic insights from her laboratory about the importance of antigen density has altered the way we select targets for CARs and the disease that we go after.”
These two insights have been incorporated with positive clinical effects as part of Stanford’s trial of GD2-directed CAR-T for younger patients with diffuse midline gliomas, Majzner said.
“We were able to bring these insights into patient care and, as a result of what we learned from Crystal’s lab, for the first time we've seen regressions in a disease that is basically untreatable,” he said.
Preparing for the future
Mackall said the most important thing she can do at this point in her career is to help the next generation of clinician-scientists.
“I benefited immensely from wonderful mentors at every stage of my career, and this is the single most important thing that I can do right now — not only for the field, but for my own legacy,” she said.
Her lab has “become a bit of a magnet” for younger female investigators, Mackall noted. However, she said she strives to bring a mix of younger minds into her organization.
Diversity takes on many forms, and people across the spectrum can benefit from the guidance of a good mentor — especially one who can identify with the struggles of others, Mackall said.
“I am also a gay woman, so I’ve been on the outside of a lot of things in society,” she told Healio.
“I look at diversity broadly and want to mentor women, but also sexual minorities, or people who come from circumstances that would typically make them feel uncomfortable in the rarefied ivory tower,” Mackall said.
Mackall said her current role at Stanford has been “gratifying” because of the top-tier research done there, and because many leadership positions are filled by women.
Despite witnessing great progress for women in science over her career, she said there is unfinished work when it comes to placing women into positions where most decisions are made.
“It's great to recruit young women into STEM fields, but having those role models at the top, making decisions and inspiring the younger age group is so important,” she said. “More progress in this area is definitely needed.”
As for the next chapter in an already accomplished career, Mackall said the focus is on helping her institution develop effective therapeutics to treat cancer.
“It is more about innovation than discovery,” she said. “If you look at the way things are invented, novelty is kind of overrated because you often have to iterate and make slight changes to existing technology while being orderly about it, so you can look at the effect of these small changes.”
Mackall said she does not want to look back and think that cell therapy for solid tumors was not given a fair chance. Her lab will continue to try new things, understand why they worked or failed, and use what they have learned to create the next iteration of cancer therapeutics.
“You can study things in mice all day long, but it's really what you learn from when you're treating patients that matters, and that’s what the center I have helped create at Stanford is all about,” she said.
“When things fail, then we go back to the drawing board and make a better mousetrap,” Mackall added. “We keep our eyes on the prize, we don't get distracted, and we don't get demoralized.”
For more information:
Crystal L. Mackall, MD, can be reached at cmackall@stanford.edu.
Robbie Majzner, MD, can be reached at rmajzner@stanford.edu.
Steven A. Rosenberg, MD, PhD, can be reached at sar@mail.nih.gov.
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