A clinical trial at the National Cancer Institute was a huge success for the patients suffering with primary CNS lymphoma - but with a catch.
The patients were getting a BTK inhibitor - a targeted drug to stop an enzyme which would arrest the B-cells, thus curtailing the cancer’s strategic assault on the body. Ninety-four percent of the patients went into remission, with a full 86 percent having no recurrence. But close to half (39 percent) developed an invasive fungal infection, called aspergillosis, despite the germs having no seeming connection to the drug’s target.
For Jigar Desai, then a fellow at NIH, he was fascinated - and determined to get to the root cause. A painstaking investigation of several years solved it; the findings are being submitted for publication soon.
Desai and his laboratory investigate fungi and their health impacts, from acute infections to systemic spread, along with concurrent effects on other diseases, including cancer. Desai, now at the Hackensack Meridian Center for Discovery and Innovation (CDI), is publishing papers furthering the science about the emerging science of fungi like Candida albicans, Candida auris, and Aspergillus fumigatus, among other germs which are taking larger and larger roles in post-COVID-19 health care settings. At the core of it all is the “complement system” - the dozens of distinct plasma proteins which work together to jump-start immune responses.
“Our goal is to figure out what the protective mechanisms and their specific molecular pathway - particularly against this really-high-mortality, invasive fungal infection,” said Desai, Ph.D., assistant member at the CDI, and assistant professor of medical sciences at the Hackensack Meridian School of Medicine. “We’re also looking at how the fungus-and-complement system act together in some other diseases such as colorectal cancer, inflammatory bowel diseases, and others, where together they may promote pathogenic inflammation, and may provide an opportunity for an adjunctive therapeutic intervention.”
“Jigar’s work nicely complements and expands our emphasis on applied immunology for infectious diseases and cancer at the CDI,” said David Perlin, Ph.D., chief scientific officer and executive vice president of the CDI. “His unique training and vantage point elevates our overall program, and we’re glad to have brought him into the fold.”
The Mycobiome, and is Immediate Impact
A seven-year stint of work for Desai and his colleagues just produced a paper which could make an immediate clinical impact. The paper “C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection” appeared in the journal Cell on May 22. Their findings: that certain advanced immunotherapies actually open the door to fungal infections by inhibiting the protective immune response. The team of scientists established that the C5a protein, the penultimate effector constituent of the complement pathway, is key to the body's innate ability to fight systemic fungal infections. Additionally, the team also identified enhanced complement pathway signature acts as a predictive biomarker for systemic candidiasis. With the use of animal models, patient data and sera, the team showed how C5a and its downstream effects are crucial for the body’s immune cells, specifically neutrophils and macrophages, to clear the fungus Candida albicans, when it gains access to the bloodstream.
Put another way: clinicians using these certain immunotherapies will now be better forewarned and forearmed to monitor their patients for invasive fungal infections, which can prove life-threatening to immunocompromised people.
“Our findings will assist clinicians in their understanding of how these life-threatening infections are emerging,” said Desai. “These findings may help doctors and scientists alike to better understand how some of these cases arise - and how to avoid them.”
The microbiome, the collection of microbes (mostly bacteria) which impact a wide array of factors affecting human health, has entered common knowledge, and the public lexicon. Less well known is the mycobiome - the fungal part of the microbiota that also resides within the human body, which is less prevalent. But its impact is huge - since fungi are eukaryotes, they are a complex piece of the puzzle when it comes to disease and wellness. Studying the intricacy of fungi is a monumental part of Desai’s work.
For instance, Desai is working to assess how, following hematopoietic stem cell transplants, the donor cells themselves may open recipients up to susceptibility of fungal outbreaks, based on the donor-intrinsic genetic factors, such as the complement proteins.
Fungal blooms also appear in certain phases of cancer, and could be connected with either fallout from the disease development - or could play an active part in tumor growth and evolution. Desai is studying these nuances with other CDI experts like Kevin Tong, Ph.D., and Alvin Makohon-Moore, Ph.D.
Underlying all this is the complement system, which Desai has spent years testing and assessing by increments.
“So what we are doing in the lab is to understand how this complement system is regulated by these fungi at diverse body sites, and how we can utilize that information,” he said. “For instance, when it comes to the pulmonary mucosa - which is the primary site for protecting against inhaled opportunistic pathogens, including fungi, we are investigating how the complement is activated in lungs by the fungi and how it can promote protection against invasive infections but may predispose the patients to asthma or chronic bronchopulmonary disease.”
Coming to the CDI
Prior to joining the CDI last year, Desai was a research fellow in the Fungal Pathogenesis Section of the National Institute of Allergy and Infectious Diseases at the NIH in Bethesda, MD.
“The transition has been really great,” he said. “Being here at the CDI, utilizing clinical resources and being surrounded by really smart people with whom you can collaborate - it’s really the point to all of the work.”
His career high point was the aforementioned recent paper, which capped more than six years of labor detailing the fungal-immune system dynamic. But he’s in the process of doing more to go further, and higher: several collaborative projects and grant applications are pending, and he’s looking to move scientific understanding further.
The ultimate goal is to raise awareness in the scientific field - and beyond - about fungi and these complex interactions which could be driving health outcomes in overlooked ways.
“Next we want to understand possible ways that the fungi interact with the human body and learn to protect against them in case of infection, and harness their ability to condition our immune system to improve outcomes during cancers and the autoinflammatory diseases of the gastrointestinal tract,” he said.
Both Sides of the Globe
Desai grew up in India, in Surat, a city on the west coast of the country about 250 kilometers north of Mumbai. His family, including parents and a younger sister, are still there. Desai did his bachelor’s in pharmacy in India, but came to the U.S. to pursue his graduate work.
He spent two years at Virginia Commonwealth University and then Carnegie Mellon University, where he met his wife. From there, he kicked his research work into high gear at the NIH.
Currently he and his wife live in suburban New Jersey, and travel back to India every year or so to see family; flights from Newark are a relatively quick 14 to 15 hours.
But he is building his future here, at the CDI.
His free time is spent reading, especially science fiction and fantasy novels; among his favorites is the Hitchhikers’ Guide to the Galaxy. Desai also seeks time at home to cook meals: a science of another kind.