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 the short-term killing of tumour cells may fail to eradicate tumours because the growth of tumours 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-tumour cell functions can be activated on demand, or only when CAR T cells are in direct con­tact with tumour 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 recognise specific molecules on a tumour’s surface.

These are then injected back into patients to elicit an immune response against cancer cells. However, CAR T cell therapies are typically optimised for short-term cellular responses (e.g., killing of tumour cells) and may not achieve long-term systemic tumour 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 recognise a tumour antigen and subsequently cause the T cell to release cytokine interleukin-2, but only when the CAR T cells are in direct contact with tumour cells.

In a mouse model, the approach allowed CAR T infiltration into solid pancreatic and melanoma tumours, resulting in substantial tumour eradication. Critically, say the authors, these tumour-targeted IL-2 delivery circuits offer a potential way to target tumours locally while minimising 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 programmes – such as proliferation and antitumour 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.”

Source: American Association for the Advancement of Science/AAAS