Improving cancer immunotherapies with bioengineered synthetic gene circuits

In two distinct studies, scientists show how synthetic biology can be used to address a challenging problem in cancer immunotherapy: the way immunotherapy-related approaches focused on the short-term killing of tumor cells could fail to eradicate tumors because tumor growth occurs on longer timescales.

Here, two research teams present methods for better timing immunotherapy through the use of artificial gene circuits, which enable anti-tumor cell functions to be activated on demand or only when CAR T cells are in direct contact with tumor cells.

“Rather than being limited by ‘natural’ immunology (using leukocytes, antibodies, and cytokines), these studies expand the scope of immune responses elicited by CAR T cells against disease tissues,” Emmanuel Salazar-Cavazos and Grégoire Altan-Bonnet stated.

Chimeric antigen receptor (CAR) T therapies are a class of cancer immunotherapy drugs that work by ex vivo engineering a patient’s cancer-fighting T cells to express CARs that recognize particular molecules on a tumor's surface. To stimulate an immune response against cancer cells, these are then injected back into patients.

CAR T cell therapies may not, however, achieve long-term systemic tumor eradication because they are typically optimized for short-term cellular responses (such as the killing of tumor cells).

Greg Allen and colleagues used recently created synthetic Notch receptors to design improved CAR T cells with a second receptor, enabling precise control of CAR T cell function over time. The release of the cytokine interleukin-2 can be triggered by the second receptor’s recognition of a tumor antigen, but only when the CAR T cells are in close proximity to the tumor cells.

The method enabled CAR T infiltration into solid pancreatic and melanoma tumors in a mouse model, leading to significant tumors eradication. Critically, the authors claim that these tumor-targeted IL-2 delivery circuits present a potential method to locally target tumors while reducing IL-2’s long-standing toxicity problems.

With the timed administration of FDA-approved small molecule inducers, Hui-Shan Li and colleagues created a toolkit of 11 programmable synthetic transcription factors in their study.

With the aid of these techniques, the authors created human immune cells that can instantly activate particular cellular programs, such as proliferation and antitumor activity. As a result, therapeutic responses can be timed and implemented in steps.

Salazar-Cavazos and Altan-Bonnet further stated, “The combination of the two technological advances presented by Li et al. and Allen et al. will allow for an unprecedented ability to precisely control the state of therapeutic cell populations not only at the time of injection, but also while the immune response is unfolding within the patient.”