Two studies created gene circuits that improve cancer immunotherapies by enabling the functions of anticancer cells to be activated on demand.
In two separate studies, researchers demonstrate how synthetic biology can be used to address a difficult problem in cancer immunotherapy: how immunotherapy approaches focused on short-term killing of cancer cells can fail to eradicate tumors , because their growth takes place over a longer period of time. In the new study, two research groups present strategies that allow to better control the timing of immunotherapy by using synthetic gene circuits that allow to activate the functions of anticancer cells on demand , or only when CAR T cells (genetically modified lymphocytes used for the treatment of blood cancers) are in direct contact with the cancer cells. “Instead of being limited by ‘natural’ immunology (using leukocytes, antibodies and cytokines), these studies broaden the scope of immune responses elicited by CAR T cells against disease tissues,” write Emmanuel Salazar-Cavazos and Grégoire Altan- Bonnet in a related publication. Among cancer immunotherapy treatments, chimeric antigen receptor (CAR) therapies involve engineering a patient’s cancer killer T cells to make CAR cells that can recognizespecific molecules on the tumor surface. These are then injected into patients to elicit an immune response against the cancer cells. However, CAR T-cell therapies are typically optimized to achieve short-term cellular responses (e.g., tumor cell killing) and may not achieve long-term systemic tumor eradication . To enable precise control of CAR T cell function over time, Greg Allen and colleagues exploited the recently developed synthetic Notch receptors , which served to design CAR T cells enhanced with a second receptor . The second receptor can: 1)recognize a tumor antigen and 2) subsequently, induce T cells to release the cytokine interleukin-2 (dedicated to stimulating white blood cells to recognize and fight certain types of tumor cells), but only when the CAR T cells are in direct contact with the neoplastic cells.
In trials in mice, the approach allowed infiltration of CAR T cells into pancreatic and melanoma tumors, resulting in substantial tumor eradication . According to the authors, these tumor-targeted interleukin-2 delivery loops offer a potential way to target tumors locally while minimizing the toxicity issues that interleukin brings.
In their study, Hui-Shan Li and colleagues developed a kit of 11 programmable synthetic transcription factors that can be activated on demand with timed administration of small molecular inducers approved by the Food and Drug Administration. of the regulation of food and pharmaceutical products. Using these tools, the authors engineered human immune cells that activate specific cellular programs, such as proliferation and anticancer activity, upon request. This allows for gradual and controlled therapeutic responses over time. “The combination of the two technological advances presented by Li et al. and Allen et al. will enable 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.” .
