Engineering an 'invisible cloak' for bacteria to deliver drugs to tumors
Date:
March 17, 2022
Source:
Columbia University School of Engineering and Applied Science
Summary:
Researchers have genetically engineered a microbial encapsulation
system for therapeutic bacteria that can hide them from immune
systems, enabling them to reach tumors more effectively and kill
cancer cells in mice.
FULL STORY ========================================================================== Columbia Engineering researchers report that they have developed a
"cloaking" system that temporarily hides therapeutic bacteria from
immune systems, enabling them to more effectively deliver drugs to
tumors and kill cancer cells in mice. By manipulating the microbes'
DNA, they programmed gene circuits that control the bacteria surface,
building a molecular "cloak'' that encapsulates the bacteria.
========================================================================== "What's really exciting about this work is that we are able to dynamically control the system," said Tal Danino, associate professor of biomedical engineering, who co-led the study in collaboration with Kam Leong,
Samuel H.
Sheng Professor of Biomedical Engineering. "We can regulate the time that bacteria survive in human blood, and increase the maximum tolerable dose
of bacteria. We also showed our system opens up a new bacteria delivery strategy in which we can inject bacteria to one accessible tumor, and have
them controllably migrate to distal tumors such as metastases, cancer
cells that spread to other parts of the body." For the study published
today by Nature Biotechnology, the researchers focused on capsular polysaccharides (CAP), sugar polymers that coat bacterial surfaces.
In nature, CAP helps many bacteria to protect themselves from attacks
including immune systems. "We hijacked the CAP system of a probiotic
E. colistrain Nissle 1917," said Tetsuhiro Harimoto, a PhD student
in Danino's lab who is the study's co-lead author. "With CAP, these
bacteria can temporarily evade immune attack; without CAP, they lose
their encapsulation protection and can be cleared out in the body. So
we decided to try to build an effective on/off switch." An Effective
On/Off Switch To do this, the researchers engineered a new CAP system,
which they call inducible CAP, or iCAP. They control the iCAP system
by giving it an external cue -- a small molecule called IPTG -- that
allows for programmable and dynamic alteration of the E. colicell
surface. Because iCAP alters bacterial interactions with immune systems
(such as blood clearance and phagocytosis) in a directed manner, the team
found that they could control the time to which bacteria can survive in
human blood, by tuning how much IPTG they give to the iCAP E. coli.
Using Bacteria For Therapy While using bacteria for therapy is a new, alternative approach to treating a broad array of cancers, there are
a number of challenges, in particular, their toxicity. Unlike many
traditional drugs, these bacteria are alive and can proliferate within the body. They are also detected by the body's immune systems as foreign and dangerous, causing high inflammatory response -- too much bacteria means
high toxicity due to over-inflammation -- or rapid bacteria elimination --
too little bacteria means no therapeutic efficacy.
========================================================================== Jaeseung Hahn, a postdoctoral research scientist in Danino and
Leong's labs who co-led the project, noted, "In clinical trials,
these toxicities have been shown to be the critical problem, limiting
the amount we can dose bacteria and compromising efficacy. Some trials
had to be terminated due to severe toxicity." The Ideal Bacteria The
ideal bacteria should be able to evade the immune system upon entry
to the body, and efficiently get to the tumor. And once they are in
the tumor, they need to be eliminated in other parts of the body to
minimize toxicity. The team used mouse tumor models to demonstrate that, through iCAP, they could increase the maximum tolerable dose of bacteria
10 times. They encapsulated the E. coli strain to enable it to evade the
immune system and get to the tumor. Because they did not give IPTG in the
body, the E. coli iCAP lost its encapsulation over time, and was easier
to be eliminated in other parts of the body, thus minimizing toxicity.
To test efficacy, the researchers then engineered E. coli iCAP to produce
an antitumor toxin and were able to shrink tumor growth in colorectal
and breast cancer mouse models more so than in the control group without
the iCAP system.
The team also demonstrated controllable bacterial migration within
the body.
Past studies have shown that low levels of bacteria leak out from tumors
upon tumor growth. For this new study, the Columbia team used iCAP to show
that they can control bacterial leakage from a tumor, as well as their translocation to other tumors. They injected E. coli iCAP into one tumor,
fed the mice with water containing IPTG, activated iCAP within a tumor,
and saw E. coli iCAP leak out and migrate to uninjected tumors.
==========================================================================
Next Steps The group is exploring a range of research areas. There are
more than 80 different types of CAP that exist just for E. coli and even
more for other bacteria species that could be engineered using similar approaches. In addition, CAP is not the only molecule that bacteria have
on their surface, and other surface molecules could be controlled in a
similar fashion. Additionally, while iCAP is controlled by an externally provided IPTG in this example, other control systems such as biosensors
could be used to autonomously control surface properties of therapeutic bacteria.
The team, also affiliated with Columbia's Herbert Irving Comprehensive
Cancer Center and Data Science Institute, notes that clinical translation
is the next major challenge they would like to tackle. "While there
is a good deal of laboratory research showing various ways to engineer microbes, it is very difficult to apply these powerful therapies to a
complex animal or human body.
We've shown proof of concept in mouse models, but given that humans are
250 times more sensitive to bacterial endotoxins than mice, we expect our results may have an even bigger effect on human patients than on mice,"
said Harimoto.
Leong added, "Bacterial cancer therapy holds unique advantages over conventional drug therapy, such as efficient targeting of the tumor tissue
and programmable drug release. Potential toxicity has been limiting
its full potential. The cloaking approach presented in this study may
address this critical issue."
========================================================================== Story Source: Materials provided by Columbia_University_School_of_Engineering_and_Applied Science. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Tetsuhiro Harimoto, Jaeseung Hahn, Yu-Yu Chen, Jongwon Im,
Joanna Zhang,
Nicholas Hou, Fangda Li, Courtney Coker, Kelsey Gray, Nicole Harr,
Sreyan Chowdhury, Kelly Pu, Clare Nimura, Nicholas Arpaia, Kam
W. Leong, Tal Danino. A programmable encapsulation system improves
delivery of therapeutic bacteria in mice. Nature Biotechnology,
2022; DOI: 10.1038/ s41587-022-01244-y ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220317120348.htm
--- up 2 weeks, 3 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)