Cristina Bergamaschi, PhD, a molecular immunologist and vaccine biologist at the National Cancer Institute (NCI), specializes in the development of immunomodulatory cytokine therapies for cancer treatment and improved vaccination strategies.
Born and raised near Italy's fashion-forward city of Milan, Bergamaschi credits her parents for teaching her the importance of an inquisitive mind.
"I know it's a cliche, but my parents taught me to be a seeker, to really look around, ask questions, and be curious about the world," she said. "That was the foundation of my career as a scientist."
Believing medicine a worthy science to pursue, she earned a doctorate in molecular medicine specializing in immunology from the University of Milan.
Exploring Interleukin-15
"It wasn't until I came to the United States in 2005 to work with a great mentor, George Pavlakis, MD, PhD, in the Vaccine Branch at NCI's Human Retrovirus Section, that I started working on interleukin-15 (IL-15). I was extremely fortunate to be offered a senior position as a staff scientist in 2012 within the lab of another very supporting mentor, Barbara Felber, PhD, in NCI's Human Retrovirus Pathogenesis Section, Vaccine Branch. The lab is heavily focused on immunotherapy, with an emphasis on the development of a vaccine for HIV, and now, of course, for SARS-CoV-2."
Granted freedom to pursue some of her own interests, Bergamaschi continued to work on IL-15 as it relates to the cancer immunotherapy field.
"At NCI, I investigated the regulation of expression of the IL-15 and IL-12 family of cytokines and their function in regulating anti-viral and anti-tumor activities of leukocytes in a variety of cellular and animal models," she detailed further. "That presented a great opportunity; the lab allowed me to gain experience in tissue culture, mouse models, macaque monkey models, and finally clinical trials in patients."
In fact, Bergamaschi was responsible for a major discovery on IL-15 that would allow her to take her research project from bench to bedside, and from the discovery of a molecular mechanism to the design of in vivo proof of concept studies, all the way to a clinical trial in cancer studies.
Putting a Discovery to Work
In a look back, Bergamaschi noted, "We wanted to use IL-15 in cancer patients, for cancer immunotherapy intervention, hoping the molecule could stimulate the immune system and kill cancer cells and eventually provide a response that is durable, even if the tumor would reoccur. IL-15 promotes proliferation, survival, migration, and killing capabilities of lymphocytes, including NK and CD8 T cells and it has shown promises as immunotherapeutic intervention against cancer and infectious disease."
Of course initially there was no way to test theories in people, "... so we started from a very basic place. A lot of molecular designing and experimentation in vitro led to my important first discovery pertaining to the molecular mechanism of efficient physiological production of IL-15 in the body. IL-15 is produced and functions as a heterodimeric complex of two polypeptide chains, IL-15 and IL-15 receptor alpha (IL-15R[alpha]) (J Biol Chem 2008; doi: 10.1074/jbc.M705725200; J Immunol 2009; doi: https://doi.org/10.4049/jimmunol.0900693).
"Together they form what we call heterodimeric IL-15. This was a really important discovery," stressed Bergamaschi, "because until then everybody was using IL-15 as a single chain, but this molecule is very unstable and didn't have a favorable way to be delivered in people. By using IL-15 in the real form that is produced in the body, as a heterodimer, we were able to produce efficient tools for the safe and effective clinical use of the molecule."
Describing her work in greater technical detail, Bergamaschi explained, "The membrane bound IL-15R[alpha] is responsible for IL-15 retention on the cell surface, where it is transpresented to adjacent responding cells expressing IL-2/15[beta][gamma] receptor. In addition, after proteolytic cleavage of the IL-15R[alpha], a soluble heterodimeric form of IL-15 circulates in the blood, is stable and biologically active in vivo (Blood 2012; doi: 10.1182/blood-2011-10-384362).
"This discovery allowed the production of DNA vectors for the efficient expression of heterodimeric IL-15 upon in vivo delivery. The results show that transient expression of IL-15 heterodimers by nucleic acid delivery in the muscle is a valid procedure to obtain bioactive levels and represent an important advancement in the field, as therapeutic nucleic acid delivery is a new and relatively unexplored set of technologies (Gene Ther 2015; https://doi.org/10.1038/gt.2014.84)."
Additionally, Bergamaschi played a critical role in securing a source of heterodimeric IL-15 protein for clinical trials through the development of human-based cell line overproducing the molecule. She also had a leadership role in the design, execution, and interpretation of pre-clinical experiments to test the bioactivity of heterodimeric IL-15 in mice (J Biol Chem 2013; doi: 10.1074/jbc.M113.461756) and macaques (Cytokine 2018; doi: 10.1016/j.cyto.2018.01.011).
"With these studies, we really investigated how heterodimeric IL-15 promotes proliferation or activity of the target cells, and we also looked at the pharmacokinetics, pharmacodynamics, and the toxicity of the molecule, especially when we moved up to a macaque model," Bergamaschi noted.
"In the mouse model, we started to explore the efficacy of heterodimeric IL-15-based therapy in different cancer types-breast cancer, colon carcinoma, melanoma, pancreatic cancer. We identified the major function of IL-15 is really to convert a tumor that is poorly immunogenic into a tumor that has a lot of T and NK cells, equipped with killing capabilities. The presence of immune infiltrate is usually considered a really important prognostic factor for a successful therapy of cancer," she explained.
The research team found that IL-15 affects the production of chemokines, molecules that attract more immune cells within the tumor.
"By inflaming the tumor, heterodimeric IL-15 promotes an interaction between the T cell and dendritic cell that leads the way and teaches the T cell how to kill and what to kill, providing a durable response," said Bergamaschi. These results were recently published in the Journal of Immunotherapy of Cancer (2020: doi: 10.1136/jitc-2020-000599).
Of interest in the mouse studies, Bergamaschi and colleagues also used heterodimeric IL-15 in conjunction with adoptive cell transfer therapy in mice.
"We took T cells that have specificity toward killing a cancer cell and transferred them in a mouse. Usually these approaches must be combined with chemotherapy or radiation to deplete the immune system and provide an advantage to the cell. But we found that by providing IL-15, we can reproduce some of the benefit of irradiation. The ability to avoid irradiation and the associated downside effects for the patient in clinic will be an important advantage," she stated.
"Overall, these studies have allowed the effective bridging of basic and translational research by using a detailed understanding of post-transcriptional and post-translation regulation in an applied manner toward the development of improved immune interventions in the clinic," she explained. "Indeed, the discovery on heterodimeric IL-15 was moved forward to create a novel cytokine therapy that was tested in a Phase I clinical trial (NCT02452268)."
What's Next?
Bergamaschi, who is married and mother to two young children, said her next focus will be personalizing the use of IL-15 in cancer therapies.
"Heterodimeric IL-15 may have many possible applications. The obvious next step is to look at the application of IL-15 in combination with other treatments, such as checkpoint inhibitors, CAR T-cell therapy, and vaccination. Maybe one checkpoint inhibitor works well with it, maybe one doesn't, depending on the tumor's molecular signature. Maybe if you want to combine it with vaccination, we should look at certain molecules called tumor antigens expressed specifically in that patient...these are examples of personalization that will be considered," said the researcher.
"So the immediate goal is working toward a combination vaccination for cancer that will also lead to a more personalized type of intervention. Fortunately, the NIH community offers the possibility to continue to work to translate scientific breakthrough into new cancer treatments and develop new technologies to improve the efficacy of therapeutic and diagnostic tools. I feel lucky to be here."
Asked to encapsulate the major thrust of her work, Bergamaschi said, "The major takeaway is that if we understand how our immune system works, we can really begin to attack cancer. Cancer is not one disease; every patient has a different disease. However, you need an immune system and immune system response for all types of tumors.
"Heterodimeric IL-15 helps because it pushes the T cells into the tumor, and fortifies them with the killing molecules so they can kill more effectively. It promotes an interaction between T cell and antigen-presenting cells to develop a durable response. All of this could be sufficient in certain tumors, but combined with other intervention in certain tumors, it could be even more powerful and effective. The bottom line, eventually, will be a cancer vaccination."
Valerie Neff Newitt is a contributing writer.
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