04.2020 | THE SCIENTIST 33WIKIMEDIA COMMONS, NIAID
itive and negative feedback motifs to modulate dynamic cel-
lular functions, acting as toggle switches, oscillators, counters,
biosensors, and recorders—tools that researchers have used to
design cancer-fighting microbes.
One example of genetic control over cancer-fighting bacteria
is the synchronized lysis circuit developed in 2016 by Jeff Hasty’s
group at the University of California, San Diego, in collaboration
with Sangeeta Bhatia’s laboratory at MIT, where both of us did our
postgraduate training. (T.D. was a coauthor on this 2016 study.) In
this circuit, bacteria localize to tumors and grow to a critical den-
sity, then synchronously rupture to release therapeutic compounds
that the microbes had been producing. This approach, which takes
advantage of natural bacterial quorum sensing, improves upon sev-
eral features of previously developed bacterial therapies, most of
which constitutively produce drugs, meaning they might make and
release the therapeutics in unintended areas of the body. Because
bacteria only reach critical density within tumors, they will only
self-destruct and release their therapeutic payload there. This leads
to pruning of the microbial population, preventing uncontrolled
growth of bacteria in the tumor or elsewhere. In a colorectal liver
metastasis mouse model, this system resulted in a twofold increase
in survival when paired with chemotherapy, as compared with
chemotherapy or bacteria alone.^3
Several groups have further developed this approach. In 2019,
for example, one of us (T.D.), along with Columbia University micro-
biologist and immunologist Nicholas Arpaia and colleagues, created
bacteria that produced molecules known to block immune check-
points, such as CD47 or PD-L1, which ordinarily put the brakes on
immune cells and thereby decrease anti-tumor activity.4,5 As a result
of blocking these pathways in tumors, bacteria were able to prime Tcells and to facilitate the clearance of cancer in a lymphoma mouse
model. Most surprisingly, untreated tumors within treated animals
also shrank, suggesting that local priming could trigger distant and
durable antitumor immunity.
The approach of using bacteria as a cancer therapy is starting
to attract the attention of the biotech industry. One company,
BioMed Valley Discoveries, has been testing injections of the
spores of Clostridium novyi-NT, an obligate anaerobe that can
only grow in hypoxic conditions and is genetically attenuated so
that a lethal toxin is not produced, in several clinical trials. In rats,
dogs, and the first human patient, the treatment showed “precise,
robust, and reproducible antitumor responses,” according
to a 2014 report.^6
Another company, Synlogic, is developing intratumorally injected
bacteria designed to produce a STING (STImulator of INterferon
Genes) agonist and act as an innate immune activator. The bacteria
are sensed and engulfed by antigen-presenting cells that have infil-
trated the tumor, and within those immune cells they activate the
STING pathway, resulting in interferon release and tumor-specific
T cell responses. A Phase 1 clinical trial is underway to evaluate this
therapy for the treatment of refractory solid tumors, and trials for use
in combination with a checkpoint inhibitor are planned.
The results of these and other trials will serve to guide fur-
ther innovations in safety and efficacy for engineered bacterial
cancer therapies. For instance, these studies will shed light not
only on therapeutic efficacy, but on bacterial colonization lev-
els and distribution in patient tumors, shedding or off-target
colonization, and stability of genetic modifications over time—
factors that have only been studied at a detailed level in mouse
models. Once a proof-of-principle is established in humans,Salmonella typhimurium