Bioengineered synthetic gene circuitry enhances cancer immunotherapy

In two separate studies, researchers have shown how synthetic biology can be used to solve a conundrum in cancer immunotherapy: Immunotherapy-related approaches focused on killing tumor cells in a way that kills tumor cells in a short period of time may not eradicate tumors because tumor growth occurs on
longer timescales.
Here, the two research groups propose strategies to better control the timing of immunotherapy using synthetic gene circuits, in which the function of anti-tumor cells can be activated as needed, or only when
CAR-T cells are in direct contact with tumor cells 。 Emmanuel Salazar-Cavazos and Grégoire Altan-Bonnet write in a related view: "These studies are not limited by 'natural' immunology (using white blood cells, antibodies, and cytokines), but expand the range of
immune responses caused by CAR-T cells to disease tissues.
"

In the arsenal of cancer immunotherapies, chimeric antigen receptor (CAR) T therapies involve in vitro engineering of a patient's anti-cancer T cells to express CAR
capable of recognizing specific molecules on the surface of tumors.
These drugs are then injected back into the patient to trigger an immune response
against the cancer cells.
However, CAR-T cell therapies are often optimized for short-term cellular responses (e.
g.
, killing tumor cells) and may not achieve long-term systemic tumor eradication
.
To precisely control the function of CAR-T cells over a period of time, Greg Allen and colleagues designed enhanced CAR-T cells
with a second receptor using the recently developed synthetic Notch receptor.
The second receptor can recognize tumor antigens and subsequently cause T cells to release the cytokine interleukin-2, but only when
CAR-T cells are in direct contact with tumor cells.
In mouse models, this method allows CAR-T infiltration into solid pancreas and melanoma, leading to substantial eradication
of tumors.
Importantly, the authors say, these tumor-targeted IL-2 delivery circuits offer a potential way to target tumors locally while minimizing the long-standing toxicity problem
of IL-2.

In their study, Hui-Shan Li and colleagues developed a toolkit containing 11 programmable synthetic transcription factors that can be activated
on demand through timed management of FDA-approved small molecule inducers.
Using these tools, the authors designed human immune cells to activate specific cellular programs such as proliferation and antitumor activity
on demand.
This makes it possible
to gradually and time-controlled treatment responses.
Salazar-Cavazos and Altan-Bonnet write: "The combination of the two technological advances proposed by Li et al.
and Allen et al.
will allow for an unprecedented ability to precisely control the state of the therapeutic cell population not only at the time of injection, but also as the immune response unfolds in the patient
.
"