An Unlikely Match: Bacteria + Immunotherapy

When it comes to having a successful research collaboration, human chemistry plays an equally important role as the science itself.

Sreyan Chowdhury (left), Tal Danino (center), and Nicholas Arpaia in the lab. Credit: Jane Nisselson/Columbia Engineering

This stands true for frequent collaborators Nicholas Arpaia, PhD, Tal Danino, PhD, and their joint PhD student, Sreyan Chowdhury. This summer, the trio’s Nature Medicine paper grabbed wide media attention and accolades from the scientific community for its innovation and incredible promise in the cancer immunotherapy space. 

In fact, it was their co-mentee and student, Chowdhury, who got this dream team together in the first place. 

Inspired by the recent explosion of cancer immunotherapy studies, Chowdhury, a third-year PhD student in Columbia’s Integrated Program, began brainstorming ways to couple his interest in synthetic biology with cancer immunotherapy. At the time, Chowdhury had been rotating in the Danino lab, and Danino, assistant professor of biomedical engineering, had been investigating strains of bacteria for a programmable delivery system to kill cancer cells.

“I wondered whether we could use these programmable bacteria to home to tumors, grow, and release waves of potent immunotherapeutics exclusively within the cores of tumors,” says Chowdhury. “The hope was that we could sustainably deliver high-dose immunotherapy within the tumor, while preventing off-target toxicity and side effects. For this, Tal and I both knew we needed an expert in immunology.” 

The beauty of Columbia’s Integrated Program in Cellular, Molecular, and Biomedical Studies (CMBS), is that as an interdepartmental program it allows for graduate students in their first year to rotate in any Columbia lab involved in biomedicine broadly. While on rotation at the Danino lab on the Morningside campus, Chowdhury traveled uptown every Tuesday and Thursday for a graduate immunology course at the Columbia University Irving Medical Center (CUIMC) campus. A module of the course was taught by Arpaia, assistant professor of microbiology & immunology. Chowdhury began learning more about Arpaia’s research, including his graduate work in understanding immune factors governing virulence of pathogens and his postdoctoral work on the diverse roles of regulatory T cells in health and disease.

“Inspired by Nick’s papers and lectures in immunology, I brought up the idea of setting up a meeting between the three of us. Tal is super supportive of his trainees forging new research directions for the lab so he instantly agreed,” says Chowdhury. 

One morning in February 2017, Arpaia hopped off the subway at W. 116th, stopped at Danino’s lab on the Morningside campus, and from there, the three formed what has become a tightly knit research team, with their eyes set on cutting-edge cancer research. Both Arpaia and Danino are members of the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia, and lean to out-of-the-box ideas that meld bacterial cancer therapy and immunotherapy in a way to increase its efficacy as a therapeutic and also enhance its safety. 

In the Nature Medicine paper, the researchers demonstrate a novel engineered system to deliver immunotherapy from bacteria, which is priming the patient’s own immune system to fight the cancer. In a mouse model of lymphoma, the therapy led not only to complete regression of treated tumors, but also demonstrated it could prime the immune system to seek and treat distant untreated tumors.

The team’s first grant came from Columbia donors Roy and Diana Vagelos and their Precision Medicine Pilot award in the spring of 2018. This award specifically went to a collaboration between investigators on the two different campuses, and to support the team’s ongoing work in programmable probiotics for personalized cancer immunotherapy. The team has since continued to co-write grants and have recently won awards from Columbia’s Irving Institute for Clinical and Translational Research and the Bonnie J. Addario Lung Cancer Foundation. 

While true for many research fields, investigating a complex problem like cancer requires expertise from multiple disciplines. Says Arpaia, “In order to have a successful multidisciplinary collaboration, you have to have trainees who are committed to doing research in a truly interdisciplinary fashion.” 

Trust plays a big role. 

“I don’t know everything Tal knows about synthetic biology, and I’m not going to. And Tal isn’t going to know everything I know about immunology,” says Arpaia. “Our collaboration is us agreeably trusting each other for our own expertise. And, we’re jointly making sure that we have our bases covered but also explaining to each other the cool parts about our fields.”

Arpaia and Danino meet one to two times a week, shuttling to and from the Morningside and CUIMC campus. The team is currently working on optimizing their bacteria-based cancer immunotherapy to eventually test in patients, and have had conversations about therapeutic dosing and toxicity with Gary Schwartz, MD, deputy director of the HICCC, an oncologist, and visionary in targeted cancer therapy, especially in the treatment of sarcoma and melanoma. At the end of the day, adds Arpaia, “We are all equally committed to doing impactful science the best way we can.” 

“I’m so happy that Nick and Tal are writing and winning multiple grants together and involving more members of both labs on collaborative projects,” says Chowdhury. “They’re actually pretty close friends now, and I’m happy to have been the catalyst.” 

-Melanie A. Farmer

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Video: Programmed Bacteria for Cancer Immunotherapy