Programmable bacteria clear tumors in mouse models, and also treat distant tumors that were not injected; this novel method could be used to locally prime tumors and stimulate the immune system to seek out difficult-to-treat tumors
The emerging field of synthetic biology--designing new biological components and systems--is revolutionizing medicine. Through the genetic programming of living cells, researchers are creating engineered systems that intelligently sense and respond to diverse environments, leading to more specific and effective solutions in comparison to current molecular-based therapeutics.
At the same time, cancer immunotherapy--using the body's immune defenses to fight cancer--has transformed cancer treatment over the past decade, but only a handful of solid tumors have responded, and systemic therapy often results in significant side effects.
Designing therapies that can induce a potent, anti-tumor immune response within a solid tumor without triggering systemic toxicity has posed a significant challenge.
Researchers at Columbia Engineering and Columbia University Irving Medical Center (CUIMC) announced today that they are addressing this challenge by engineering a strain of non-pathogenic bacteria that can colonize solid tumors in mice and safely deliver potent immunotherapies, acting as a Trojan Horse that treats tumors from within.
The therapy led not only to complete tumor regression in a mouse model of lymphoma, but also significant control of distant, uninjected tumor lesions. Their findings are published today in Nature Medicine.
"Seeing untreated tumors respond alongside treatment of primary lesions was an unexpected discovery. It is the first demonstration following a bacterial cancer therapy of what is termed an 'abscopal' effect," says Tal Danino, assistant professor of biomedical engineering. "This means that we'll be able to engineer bacteria to prime tumors locally, and then stimulate the immune system to seek out tumors and metastases that are too small to be detected with imaging or other approaches."
The study was led in collaboration with Nicholas Arpaia, assistant professor of microbiology & immunology at CUIMC, and co-senior author on the publication. The team combined their expertise in synthetic biology and immunology to engineer a strain of bacteria able to grow and multiply in the necrotic core of tumors. When bacteria numbers reach a critical threshold, the non-pathogenic E. coli are then programmed to self-destruct, allowing for effective release of therapeutics and preventing them from wreaking havoc elsewhere in the body.
Subsequently, a small fraction of bacteria survive lysis and reseed the population, allowing for repeated rounds of drug delivery inside treated tumors. The proof of concept in programming the bacteria in this way was originally developed a few years ago (Din & Danino et al. Nature 2016). In the current study, the authors chose to release a nanobody that targets a protein called CD47.
CD47, a "don't-eat-me" signal, protects cancer cells from being eaten by innate immune cells such as macrophages and dendritic cells. It is found in abundance on a majority of human solid tumors and has recently become a popular therapeutic target.
"But CD47 is present elsewhere in the body, and systemic targeting of CD47 results in significant toxicity as evidenced by recent clinical trials. To solve this issue, we engineered bacteria to target CD47 exclusively within the tumor and avoid systemic side-effects of treatment," adds Sreyan Chowdhury, the paper's lead author and a PhD student co-mentored by Arpaia and Danino.
The combined effect of bacterially induced local inflammation within the tumor and the blockade of CD47 leads to increased ingestion, or phagocytosis of tumor cells and subsequently to enhanced activation and proliferation of T cells within the treated tumors. The team found that treatment with their engineered bacteria not only cleared the treated tumors but also reduced the incidence of tumor metastasis in multiple models.
"Treatment with engineered bacteria led to priming of tumor-specific T cells in the tumor that then migrated systemically to also treat distant tumors," Arpaia says. "Without both live bugs lysing in the tumor and the CD47 nanobody payload, we were not able to observe the therapeutic or abscopal effects."
The team is now performing further proof-of-concept tests, as well as safety and toxicology studies, of their engineered immunotherapeutic bacteria in a range of advanced solid tumor settings in mouse models. Positive results from those tests may lead to a clinical trial in patients. They are also collaborating with Gary Schwartz, CUIMC's chief of hematology/oncology and deputy director of the Herbert Irving Comprehensive Cancer Center, on clinical translation aspects of their work, and have started a company to translate their promising technology to patients.
About the Study
The study is titled "Programmable bacteria induce durable tumor regression and systemic antitumor immunity."
Authors are: Sreyan Chowdhury1,2; Samuel Castro1; Courtney Coker1; Taylor E. Hinchliffe1; Nicholas Arpaia2,3; Tal Danino1,3,4
1Department of Biomedical Engineering, Columbia University
2Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University
3Herbert Irving Comprehensive Cancer Center, Columbia University
4Data Science Institute, Columbia University
This work was supported by the NIH Pathway to Independence Award (R00CA197649-02) (T. Danino), DoD Idea Development Award (LC160314) (T. Danino), DoD Era of Hope Scholar Award (BC160541) (T. Danino), NIH NIGMS (R01GM069811) (T. Danino), NIH K22AI127847 (N. Arpaia), Searle Scholars Program SSP-2017-2179 (N. Arpaia), Bonnie J. Addario Lung Cancer Foundation Young Investigators Team Award (N. Arpaia and T. Danino) and the Roy and Diana Vagelos Precision Medicine Pilot Grant (N. Arpaia and T. Danino).
S. Chowdhury, N.A., and T.D. have filed a provisional patent application with the US Patent and Trademark Office (US Patent Application No. 62/747,826) related to this work. T.D. and N.A. 270 have a financial interest in GenCirq, Inc.
Columbia Engineering, based in New York City, is one of the top engineering schools in the U.S. and one of the oldest in the nation. Also known as The Fu Foundation School of Engineering and Applied Science, the School expands knowledge and advances technology through the pioneering research of its more than 220 faculty, while educating undergraduate and graduate students in a collaborative environment to become leaders informed by a firm foundation in engineering. The School's faculty are at the center of the University's cross-disciplinary research, contributing to the Data Science Institute, Earth Institute, Zuckerman Mind Brain Behavior Institute, Precision Medicine Initiative, and the Columbia Nano Initiative. Guided by its strategic vision, "Columbia Engineering for Humanity," the School aims to translate ideas into innovations that foster a sustainable, healthy, secure, connected, and creative humanity.
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