Using synthetic gene cir­cuits to better control the timing of immunotherapy

In two separate studies, researchers demonstrate how synthetic biology can be used to tackle a difficult issue in cancer immunotherapy: the way immunotherapy-related approaches focused on short-term killing of tumor cells may fail to eradicate tumors because growth of tumors happens on longer timescales. Here, two research groups present strategies to allow better control over the timing of immunotherapy using synthetic gene cir­cuits whereby anti-tumor cell functions can 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," write Emmanuel Salazar-Cavazos and Grégoire Altan-Bonnet in a related Perspective.

Among the arsenal of cancer immunotherapy treatments, chimeric antigen receptor (CAR) T therapies involve ex vivo engineering of a patient's cancer-killing T cells to express CARs that recognize specific molecules on a tumor's surface. These are then injected back into patients to elicit an immune response against cancer cells. However, CAR T cell therapies are typically optimized for short-term cellular responses (e.g., killing of tumor cells) and may not achieve long-term systemic tumor eradication. To allow precise control of CAR T cell function over time, Greg Allen and colleagues leveraged recently developed synthetic Notch receptors to design enhanced CAR T cells with a second receptor. The second receptor can recognize a tumor antigen and subsequently cause the T cell to release cytokine interleukin-2, but only when the CAR T cells are in direct contact with tumor cells. In a mouse model, the approach allowed CAR T infiltration into solid pancreatic and melanoma tumors, resulting in substantial tumor eradication. Critically, say the authors, these tumor-targeted IL-2 delivery circuits offer a potential way to target tumors locally while minimizing longstanding toxicity issues with IL-2.

In their study, Hui-Shan Li and colleagues developed a toolkit of 11 programmable synthetic transcription factors that could be activated on demand with the timed administration of FDA-approved small molecule inducers. Using these tools, the authors engineered human immune cells that activate specific cellular programs – such as proliferation and antitumor activity – on demand. This enables stepwise and time-controlled therapeutic responses. "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," write Salazar-Cavazos and Altan-Bonnet, "but also while the immune response is unfolding within the patient."