‘Very much a calling’: one clinician’s journey from solving word problems to curing cancer
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Nirali N. Shah, MD, MHSc, was a self-proclaimed “big math nerd” growing up.
The St. Jude Math-A-Thon fundraiser became the perfect outlet for a young girl with a knack for solving word problems and an early budding interest in medicine.
“Whenever I would see those St. Jude commercials, I knew I wanted to be a doctor, and I knew I wanted to take care of children,” Shah told Healio. “It was very much a calling from the beginning.”
Shah now is head of the hematologic malignancies section in the pediatric oncology branch at NCI, as well as an NIH Lasker Clinical Research Scholar.
Her role as an NCI clinical investigator put her on the front lines of chimeric antigen receptor T-cell therapy development, where she was among the first to witness the promise the modality provided to the sickest, most difficult-to-treat patients.
She also strives to conquer the formidable challenges related to therapeutic development in pediatric oncology.
“I’ve always had a passion for medicine’s approach to complex problem solving and wanting to merge that with the compassionate care that is required when treating pediatric patients,” Shah said. “I knew I had to work with children in some capacity and — for me — it’s a privilege to talk to families and have them be a part of a patient’s care.”
An ‘indefatigable’ force
Shah’s mentors at NIH have included some of the biggest names in cell therapy.
Her initial draw to hematologic malignancies came via intellectual curiosity surrounding the practice of hematopoietic stem cell transplantation — both its ability to cure and its complexities.
She completed her fellowship from 2009 to 2012, when CAR-T therapies were just starting to evolve.
Shah collaborated with her colleagues in the pediatric oncology branch as part of the clinical research team using CD19 CAR-T in pediatric patients with B-cell acute lymphoblastic leukemia. The trial used a CAR-T construct developed at NIH by NCI surgery branch chief Steven A. Rosenberg, MD, PhD, and senior investigator James N. Kochenderfer, MD.
The early results bordered on magical, Shah said.
“I remember one of our early patients who was chemotherapy refractory — resistant to all of the best available therapies,” she said. “Looking at her [bone] marrow in remission after CAR-T was an amazing experience.”
Shah landed as a fellow at NCI after being recruited by Alan S. Wayne, MD, fellowship director, and Crystal L. Mackall, MD, who — at the time — served as chief of the pediatric oncology branch.
Mackall — now 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 — mentored Shah during her fellowship and early independent research phase at NCI.
She called Shah “a stellar clinician” who maintains true dedication to her patients.
“Nirali is a natural leader and has a fierce determination to improve health outcomes for children,” Mackall told Healio. “She is one of those indefatigable people who finds a way to overcome barriers rather than allowing barriers to stop her.”
‘No matter how long it takes’
Shah’s involvement with CAR-T from its early clinical research stages makes her “one of the leading trialists” in the field, Mackall said.
Mackall noted one of Shah’s major contributions was leading a team that identified hemophagocytic lymphohistiocytosis (HLH) as a toxicity related to treatment with CD22-targeted CAR T cells — distinct from cytokine release syndrome — that requires a unique approach to management and grading.
Shah considers the CD22 CAR-T developed at NIH — and the science around its progress — her most impactful scientific endeavor to date.
Another of Shah’s mentors — Terry J. Fry, MD — initiated the program, which includes a first-in-human, first-in-children trial that continues to enroll patients (NCT02315612).
“It was the first time we attempted an alternate CAR-T target for B-cell acute lymphoblastic leukemia or used it as a salvage therapy for those who had previously received CAR-T,” Shah said. “We learned so much about why certain CD22 CAR T cells worked and others didn’t, in addition to exploring a new toxicity.”
“I’m very much hoping that the efforts that started here at the NCI within our group ultimately will be carried forward,” Shah said.
The baton has been passed to Mackall’s group at Stanford, which is conducting a trial for a CD22-directed CAR-T grounded in the work done by researchers within the pediatric oncology branch at NIH.
The investigational therapy is undergoing commercial development and — if it receives regulatory approval — Shah said she hopes a pediatric indication “could piggyback on that registration.”
Mackall gave an unrestrained assessment of Shah’s impact on CD22-directed CAR-T development.
“Nirali shepherded the clinical development of the CD22-CAR for children, which is the only agent beyond CD19-CAR that has demonstrated irrefutable efficacy in the space,” Mackall said.
This included managing the challenges associated with a novel therapy and sustaining it in an academic setting until it earned breakthrough therapy designation from the FDA and the attention of industry, Mackall added.
“Bottom line: She kept the drug alive and carried it over the valley of death,” Mackall said. “That’s the mark of a great clinical investigator.”
“CD22-CAR is my professional baby,” Shah said. “No matter how long it takes, I want it to become commercially available for patients.”
A teacher at heart
One of the biggest professional challenges Shah faces is gaining support to move promising therapies toward commercialization for pediatric populations.
Part of overcoming this hurdle involves mentoring the next generation of researchers and clinicians, but it’s a role that suits her.
If she hadn’t pursued a career in medicine, she would’ve become a teacher.
She spent her last year as an undergrad completing a secondary education certification to teach chemistry.
“I want to teach,” Shah said. “I want to promote young minds, support them and help them advance in their careers.”
For the past 5 years, Shah has mentored medical students who take a year off from their normal curriculum to pursue research projects at NCI. She previously led the pediatric hematology/oncology fellowship program for several years.
“I continue to mentor, either directly in working with a group of advanced fellows in immunotherapy learning about cell therapy, or by providing indirect mentorship in the sense that I will often talk to trainees about personal reflections and professional growth,” she said.
Despite the high proportion of women in the field of pediatrics, there continues to be a need for young female physician-scientists who are interested in specializing in cellular therapy for the treatment of cancer, Shah said.
It also is important to increase the number of women in leadership roles throughout health care, she added.
“Women should definitely have a seat at the table when big decisions are being made,” she said. “We need better advocacy to ensure greater funding from pharma for pediatric causes.”
Treating children with cancer requires a certain amount of dedication, so anyone considering a career in pediatric oncology must be motivated by the work, Shah said.
“Professional success depends on personal happiness,” Shah told Healio. “Ultimately, good work will drive professional success, but it is the approach taken that determines whether you achieve personal happiness.”
The payoff from the dedication displayed by clinical researchers like Shah is just now coming due. If she and her contemporaries can continue to develop and strengthen the pipeline of new investigators, the successes achieved thus far may prove to be a starting point.
“The possibilities for CAR T cells are tremendous, and I would love to see them expand into diseases that affect younger patients for which we do not have any good therapies,” Shah said. “I want to see how we can take this potent therapy and get it into other realms.”
References:
Lichtenstein DA, et al. Blood. 2021;doi:10.1182/blood.2021011898.
Shah NN, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03279.
For more information:
Crystal L. Mackall, MD, can be reached at cmackall@stanford.edu.
Nirali N. Shah, MD, MHSc, can be reached at nirali.shah@nih.gov.
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