Former refugee feels ‘blessed’ to make positive impact on people with cancer
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A young girl growing up in revolutionary-era Iran had a clear but lofty goal — cure cancer.
Many decades later, on the other side of the world, Katy Rezvani, MD, PhD, continues that quest.
Rezvani holds several appointments at The University of Texas MD Anderson Cancer Center, including Sally Cooper Murray endowed chair in cancer research and chief of the section of cellular therapy in the department of stem cell transplantation and cellular therapy.
During her time at MD Anderson, Rezvani has used her expertise in cellular immunotherapy and stem cell transplantation to expand into an emerging branch of cancer cell therapy that shifts focus away from the T cell as the primary delivery vessel.
“I work within a field that could potentially result in a cure for at least a subset of patients with cancer,” Rezvani told Healio. “I am blessed to do something that I absolutely love and can see the impact that it potentially has on the lives of our patients.”
Life-shaping events
Although she was in primary school, Rezvani has vivid memories of the Iranian Revolution in 1979.
Her father was a general in the Shah's army, and their closeness to the previous regime required an exit.
Rezvani’s family escaped Iran and received asylum in the U.K., where she remained for some time.
“Throughout the different periods of your life, events shape you in many respects,” she said. “What happened with the revolution was, of course, very traumatic in many ways — being uprooted, losing everything we had and having to start all over again.”
Rezvani recently came across a yearbook from her childhood in Iran.
“I was probably 8 or 9 years old at the time, and there were these entries from my friends saying ‘I hope you grow up and fulfill your dream of curing cancer,’” she said.
Although Rezvani doesn’t remember making that exact statement, she does remember her fondness for school and science at a young age.
Despite having other far-ranging interests — French literature to psychology — the fragileness of having to adjust to life in a new country likely had an impact on Rezvani’s decision to pursue a career in medicine.
“Had the revolution not happened, and had I not had this insecurity of an immigrant, then I’m not sure whether I would have become a physician,” she said.
The insecurity her parents faced in life meant they wanted their daughter to have a future that offered greater stability. Being a physician provided that opportunity.
“Both my school and my parents wanted me to [go into] medicine, and it worked out perfectly because I really loved science and immunology,” Rezvani said. “Both are very intuitive to me.”
Finding your calling
Rezvani knew cell therapy would become her future during a rotation in the 1990s with the bone marrow transplant service at Hammersmith Hospital in London.
While there, she had what she described as an “inspirational early-career mentor” in John M. Goldman, MD, a British hematologist recognized as a pioneer in the clinical application of hematopoietic stem cell transplantation for the treatment of chronic myeloid leukemia.
Transplant was the only known cure at the time for CML.
“When I started rounding on the transplant floor, that’s when I knew I had found my calling,” Rezvani told Healio.
“I loved the high-intensity aspect of looking after these patients, but also the fact that allogeneic transplant relied so much on the immune system of a healthy donor to induce remission in a patient,” she added. “It just made a lot of sense to me, and that’s when my interest in immunotherapy really started.”
When Rezvani started her transplantation fellowship in the early 2000s, her cellular immunotherapy research “was all about the T cells,” she said.
Rezvani spent approximately 7 years working on ways to enhance T-cell responses against leukemia while serving as a postdoctoral and subsequent senior research fellow at NIH. In 2008, she found herself back at Hammersmith Hospital, where she set up her own lab and continued her clinical work with HSCT.
Despite no formal training with natural killer (NK) cells, Rezvani became intrigued about their possible use in cancer immunotherapy.
“[NK] cells have innate receptors that are expressed on the cell surface,” she said. “They distinguish themselves from T cells by their ability to recognize and kill their tumor targets without prior antigen priming.”
NK cells are also “clever” because of their ability to identify and destroy abnormal cells that have downregulated expression of major histocompatibility complex (MHC) class I, Rezvani said.
“This allows NK cells to kill those abnormal cells — whether they’re tumor cells or virally infected cells — that have downregulated MHC class I to escape T-cell recognition,” she said. “What’s more amazing is that NK cells do not cause graft-versus-host disease.”
This became particularly intriguing to Rezvani, who — given her background as a transplanter — has treated many HSCT recipients who subsequently developed GVHD.
Life-changing decisions
She had become frustrated with her ability to advance her scientific interests in the U.K. and — with the support of her husband, Richard — decided to make a change.
Rezvani described her choice to return to the United States by way of a faculty position at MD Anderson as the best decision she ever made.
“I knew I wanted to come back to the states because the opportunities available for a researcher living in the U.S. are unmatched anywhere else in the world,” she said. “The move to MD Anderson changed the path of my career.”
Right around that time, preliminary data were published on the effectiveness of chimeric antigen receptor T cells.
“It made sense to take natural killer cells from healthy donor umbilical cord blood and see whether we could engineer them to express a CAR because they were unlikely to cause GVHD in the allogeneic setting,” Rezvani said. “They already had their own machinery for tumor killing, so by inserting a CAR they become more antigen-specific.”
The preliminary work to develop CAR-NK cells began at Rezvani’s lab at MD Anderson in 2012. Five years later, the first patient underwent treatment developed based on those efforts.
In 2020, her research group published a proof-of-principle study in The New England Journal of Medicine showing that their CD19-directed CAR-NK cell therapy induced high response rates akin to CAR T cells among individuals with advanced non-Hodgkin lymphoma or chronic lymphocytic leukemia.
The agent exhibited anticancer effects while avoiding the toxicities commonly associated with CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity. More important, Rezvani and colleagues reported no cases of GVHD after treatment with CAR-NK cells.
Rezvani also expressed excitement about results from an ongoing phase 1/phase 2 trial using donor-derived NK cells preactivated with cytokines and then expanded and precomplexed with a bispecific antibody for treatment of advanced CD30-positive lymphoma.
Preclinical research conducted in her lab showed that the NK cell-bispecific antibody combination induced much greater responses in mouse models than either preactivated NK cells or the bispecific alone.
More recently, Rezvani presented results of a novel CD70-directed CAR-NK cell therapy that she called “simply mind boggling” at this year’s European Group for Blood and Marrow Transplantation Annual Meeting in Paris.
“I have amazing collaborators at MD Anderson,” Rezvani said. “I am fortunate to work with this incredible team of researchers, and everybody's working with the thought that the therapies we develop could help our patients.”
Looking forward
In a field often chided for its glacial-like pace of progress, Rezvani expressed gratitude about how quickly the NK cell program developed at MD Anderson.
“It was all very rapid,” she told Healio. “There was a lot of support from the institution and expertise that came together to get these clinical trials started.”
The CD70-targeted CAR-NK cells her lab developed are the result of years of refinement to optimize everything about the clinical protocol — from the most suitable target, to the cell manufacturing process, to the proper cryopreservation method.
“I am honestly excited about all of our NK cell approaches,” Rezvani said. "We can start mixing and matching strategies to develop therapies that are much more potent.”
Safety also is a differentiating factor for NK cells.
“We haven't seen those kinds of toxicities with our CAR-NK cell that have been observed with use of CAR T cells,” Rezvani said. “The safety profile of NK cells is a huge advantage and allows us to treat individuals as outpatients.”
Now that the safety and efficacy of CAR-NK cells have been established, Rezvani’s focus has shifted to increasing their durability.
Another area of concentration in her lab is making cell therapies more effective for solid tumors. She believes this is possible, despite the frequently cited challenges that still must be overcome.
“We currently have the tools we need to edit genes of interest,” she said. “The opportunities available for cellular genetic engineering mean that the sky is the limit for what is possible.”
Rezvani shares the scans of patients who respond to their therapies as part of weekly meetings to ensure everyone on her team knows they are making tangible positive impacts on patients’ lives.
“For every patient who responds to our therapies, it makes me feel like I have achieved my dream,” she said. “The goal is to keep doing that for as many patients as we possibly can.”
References:
- Liu E, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1910607.
- Nieto YL, et al. Abstract CT003. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
For more information:
Katy Rezvani, MD, PhD, can be reached at krezvani@mdanderson.org.
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