CAR-T pioneer a ‘galvanizing’ force in research community
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Perhaps no one has been better prepared to become a leader in the field of cancer cellular immunotherapy than Marcela V. Maus, MD, PhD.
She grew up in and around the clinic, accompanying her pediatrician mother and neurologist father on patient visits.
Her early mentors and collaborators included some of the biggest names in the cell therapy field, including Carl H. June, MD, of University of Pennsylvania’s Perelman School of Medicine, Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Katherine A. High, MD, emeritus professor of pediatrics and director of the Center for Cellular and Molecular Therapeutics at Children’s Hospital of Philadelphia and a pioneer in gene therapy.
“I have been trained by an amazing set of people,” Maus — director of the cellular immunotherapy program at Mass General Cancer Center, associate professor of medicine at Harvard Medical School and member of the Healio | Cell Therapy Next Peer Perspective Board — told Healio.
But perhaps the most important aspect of Maus’ development came from her early curiosity about finding answers to questions about the forces that drive life.
“I'm very much a biologist at heart, and I see everything through the lens of biology,” she said. “From a young age, I was very much about finding solutions to medical problems.”
During her youth, the HIV/AIDS epidemic often dominated news headlines. Maus recalled learning about Ryan White, an American teenager with hemophilia who became infected with HIV from a contaminated factor VIII blood treatment. His story helped combat the fear, stigmatization and misinformation about the virus.
“I remember thinking that something like this should be fixable,” she said. “If we know about RNA and DNA, and we know about how viruses infect cells, then why can't we just use these to deliver genes that we need either to make cells resistant to viruses or to make them produce things we want?”
Mother and father know best
Except for some time in Chile and suburban Philadelphia, Maus spent her formative years in New York City, where she attended the renowned Stuyvesant High School.
As the child of two physicians, Maus grew up in an environment that supported her scientific curiosity. However, her parents didn’t steer toward a career as a physician-scientist.
“I definitely didn't feel pressure to follow in their path,” Maus said.
Maus said she was not one of those “super gifted people” who earned a perfect score on her SATs or who became valedictorian of a graduating class. Instead, her talent emerged through the marriage of motivation and hard work.
“I had a lot of fire in the belly,” Maus said.
A typical day included school, followed by gymnastics practice, and volunteer service at Beth Israel Medical Center.
While volunteering, Maus often spoke with patients on the geriatric floors, where visitors were less common.
“It was New York, so everybody had interesting stories,” Maus said.
Around this time — during the summer between eighth and ninth grades — Maus began to develop an interest in research. She worked in a lab that was conducting basic molecular biology, and the experience helped lead her to the intersection of oncology and immunology.
A career in ‘fringe’ science
Maus attended Massachusetts Institute of Technology. She later moved back to Philadelphia and University of Pennsylvania for a combined MD/PhD program, where she worked in June’s lab.
She found herself torn between wanting to work in both immunology and gene therapy.
“It turns out they're related, and I could do them both,” she said.
Her ability to pursue both interests helped “keep the fire in my belly alive,” Maus said.
That led her to June’s lab.
“[The research] wasn't about gene transfer into T cells yet,” she said. “It was about growing T cells and figuring out how to make immune cells grow in a way that we could transfer them into patients with cancer and the T cells would be able to reject the patient's cancer.”
At this point in the early 2000s, the field of cellular therapy was extremely niche. Maus recalled cell therapy presentations taking place in the smallest rooms at the end of major hematology and oncology conferences.
“Excitement about cell therapy was limited to the people who were working in it,” she told Healio. “We were definitely at the fringe of science.”
Concerns about the viability of gene transfer had led many to give up after the initial hype of gene therapy, she added.
Early immunotherapy — such as interleukin-2 for melanoma — showed anticancer capabilities but only resulted in cures for a small percentage of patients, while leading to high levels of treatment-related toxicity, Maus said.
“It was much more appealing to give chemotherapy and see tumors shrink in a large number of patients,” she said. “And it was much more appealing to use targeted therapies in the form of a pill that makes tumors go away.”
However, such successes are temporary for many patients, and those whose tumors develop resistance to these therapies require alternative treatments to achieve long-term remissions.
The cellular immunotherapy believers thought they could address this need.
“I was told [cell therapy] was a ‘religion’ in a negative way,” Maus told Healio. “It wasn’t even a standard religious belief, but rather like a cult in that only the faithful believe that immune cells would be able to do anything against cancer.
“I was told that it was like career suicide to chase something that was really just a fringe belief,” she added. “I suppose you could say I'm stubborn and persistent, because [cell therapy] was really what interested me and I decided to chase it.”
A ‘galvanizing’ force
After completing her residency, Maus went back to New York City for a fellowship at Memorial Sloan Kettering. She returned to University of Pennsylvania in 2012 to become assistant professor and director of translational medicine.
Her next move — becoming leader of the cellular immunotherapy program at Mass General Cancer Center — launched perhaps the most impactful stage of her career, June said.
“Dr. Maus has had a galvanizing effect on the local regional Boston [research] community by being the first to start [chimeric antigen receptor T-cell therapy] clinical trials in the Harvard system,” June told Healio. “She has boundless energy and enthusiasm that motivates the team of scientists, technicians and physicians that she leads.”
Maus has made other significant contributions to the growing body of scientific knowledge around cellular therapy, June added.
“As a physician-scientist, her major impact for the field is in brain cancer,” he said. “She was the first to lead CAR-T trials for glioblastoma, and her seminal report in Science Translational Medicine in 2017 has set the standard in the field for translational medicine.”
June said his ongoing collaboration with Maus has been fruitful.
One notable project he recalled resulted in a 2013 publication that described a patient’s allergic reaction to a CAR T-cell infusion. The paper showed that, under certain circumstances, CAR T cells could lead to anaphylaxis.
Frederick L. Locke, MD, co-leader of the immune-oncology program and vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center, called Maus a true "cell therapist" who is an effective leader due to her ability to connect with people and remain involved with the clinical side of their profession.
"Not only is Marcela Maus a wonderful person and one who is easy to collaborate with from a professional standpoint, she has helped bring together the thinking behind two of the groups that helped develop second-generation CAR-T and bring these therapies to more patients,” Locke — a member of the Healio | Cell Therapy Next Peer Perspective Board — told Healio. “Her lab has informed the field with some very important findings about how other drugs — such as [Bruton tyrosine kinase] inhibitors — can improve the function of CAR T cells, as well as providing significant insights in what works and what doesn’t in trying to translate CAR-T into use for solid tumors.”
A woman in science
Although Maus acknowledged that women in science face gender bias, she said she has overcome obstacles through perseverance and the help of supportive family and colleagues.
“I have three children and, when I was pregnant, I definitely got the sense that I wasn't being taken seriously as someone to invest in in terms of intellectual mentorship,” she told Healio. “There were times when I wasn't as productive. I could go back to Carl and talk to him, and he showed that he had faith in me because he had already seen what I was capable of.”
Ironically, the time around one of her pregnancies became one of the most fruitful of Maus’ career.
She worked in an office that allowed her to bring her newborn to work with her. She contributed to several scientific publications that year.
Maus said that over time, what starts out as a fair number of women working together in the lab as part of academic training programs gets whittled down to just a few, as female colleagues are presented with numerous life decisions and opportunities to engage in different career paths.
“I'm not sure that I was really paying attention to the trend, perhaps because I was in my own little bubble,” Maus told Healio. “There's been attrition over the years, and it all seems reasonable as we go through life, but then you sort of emerge from that bubble, look around and think to yourself, ‘Where did all of the women go?’”
‘Oddball in the room’
Despite spending most of her time in the lab, Maus does maintain some clinical duties. On those occasions, lab work becomes secondary.
“I'm all about the patients when I'm somebody's doctor,” she told Healio. “I really love taking care of patients, and I'm kind of emotional and intense about it. It's probably for the better for my own sanity to have it be restricted to a couple of weeks out of the year.”
Although she is not anyone’s personal or specialist physician, Maus said she continually receives emails from patients who are interested in accessing CAR-T clinical trials, and she helps connect them with experts in their specific disease type.
Her current research work includes T-cell lymphoma, acute myeloid leukemia and glioblastoma.
When asked whether any of the research projects she oversees is particularly promising, she said that would be like having to pick her favorite child.
“I am excited about all of them,” Maus said. “I'm excited about what we can do for patients with different kinds of cancers with this kind of therapy.”
Maus considers herself a cell therapy specialist rather than a disease specialist; however, first and foremost, she is an oncologist.
“I am more about the modality,” Maus said. “I dedicate all my time to cell therapy.”
People who work at her institution specialize in disease types, but her department is the only one that focuses on a specific treatment type.
“This makes me the oddball in the room,” Maus said.
Maus believes the modality offers tantalizing promise to not only treat cancer but to potentially cure some patients.
“I remember trying to talk about cures once in fellowship and I was shut down,” she told Healio. “I was told that talk like that was arrogant, even obnoxious — and so taboo — which I found rather interesting because the goal has always been to cure cancer and save a life.”
Maus pointed to the successes seen thus far in leukemia and lymphoma as proof that cures with cell therapy are possible.
“Cell therapy holds that promise,” she said. “Going forward, we need to make it safer and accessible to more people, and that’s what we're working on.”
Maus marvels at how the pendulum of cell therapy’s promise has swung so dramatically over the past couple of decades, from once being considered fringe science to now being a field that so many are eager to enter.
However, the increased interest comes with increased expectations, she said. Some attempts to treat diseases using gene-edited cellular therapy are abandoned before the scientific community has the chance to evaluate and refine the approach.
Maus is thankful that — with more than 25 years’ worth of data — cancer cell therapy continues to advance even if numerous novel approaches fizzle out.
“There's a lot of people entering the field and there's a lot of movement, which can be both exciting and disruptive,” Maus said. “But I think we're in a good place right now. It's a very exciting time to be a part of this field.”
Reference s :
- Maus MV, et al. Cancer Immunol Res. 2013;doi:10.1158/2326-6066.CIR-13-0006.
- O'Rourke DM, et al. Sci Transl Med. 2017;doi:10.1126/scitranslmed.aaa0984.
For more information:
Carl H. June, MD, can be reached at Smilow Center for Translational Research, 3400 Civic Center Blvd., Philadelphia, PA 19104-5156; email: cjune@upenn.edu.
Frederick L. Locke, MD, can be reached at Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612; email: frederick.locke@moffitt.org.
Marcela V. Maus, MD, PhD, can be reached at Massachusetts General Hospital, 149 13th St., Room 3.216, Charlestown, MA 02129; email: mvmaus@mgh.harvard.edu.
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