In the emerging field of synthetic biology, the design of new components and biological systems is revolutionizing medicine. At the same time, immunotherapy against cancer, which uses the body's immune defenses to fight it, has transformed treatment over the past decade, but only a few solid tumors have responded, and systemic therapy often produces significant side effects. The design of therapies that can induce a potent antitumor immune response within a solid tumor without triggering systemic toxicity has posed a significant challenge.
Researchers of School of Engineering and Applied Sciences at Columbia University (CUIMC), as published in the magazine Nature Medicine, are addressing this challenge by designing a strain of nonpathogenic bacteria that can colonize solid tumors and deliver powerful immunotherapies safely, acting like a Trojan horse attacking tumors from within. The therapy led not only to complete tumor regression in a lymphoma model, but also to significant control of distant non-injected tumor lesions.
“Seeing the untreated tumors respond together with the treatment of the primary lesions was an unexpected discovery. It is the first demonstration after a bacterial cancer therapy of what is called an 'abscopal' effect, says Tal Danino, an assistant professor of biomedical engineering. This means that we can design bacteria to prime tumors locally, and then stimulate the immune system to look for tumors and metastases that are too small to be detected with imaging or other methods. “
The team combined its expertise in synthetic biology and immunology to design a strain of bacteria capable of growing and multiplying in the necrotic nucleus of tumors. When the numbers of bacteria reach a critical threshold, the 'E. Non-pathogenic coli are programmed to self-destruct, which allows an effective release of therapy and prevents them from wreaking havoc in other parts of the body.
Subsequently, a small fraction of bacteria survives lysis, allowing repeated rounds of drug administration within the treated tumors. The proof of concept in the programming of the bacteria was originally developed a few years ago. In the current study, the authors decided to launch a nanobody that targets a protein called CD47.
CD47, a “no-eat” signal, protects cancer cells from being ingested by innate immune cells such as macrophages and dendritic cells. It is found in abundance in most solid human tumors and has recently become a popular therapeutic target.
“But CD47 is present in other parts of the body, and the systemic orientation of CD47 produces significant toxicity, as recent clinical trials have shown. To solve this problem, we designed bacteria to attack the CD47 exclusively within the tumor and avoid the systemic side effects of the treatment, “adds Sreyan Chowdhury, the lead author of the article.
The combined effect of local inflammation induced by bacteria within the tumor and blockage of CD47 leads to a greater ingestion or phagocytosis of the tumor cells and, subsequently, to a greater activation and proliferation of the T cells in the treated tumors. The team discovered that the treatment with its designed bacteria not only eliminated the treated tumors, but also reduced the incidence of tumor metastasis in several models.
The team is now conducting additional proof-of-concept tests, as well as safety and toxicology studies, of its immunotherapeutic bacteria designed in a range of advanced configurations of solid tumors.
The positive results of these tests can soon lead to a clinical trial in patients.