Synthetic immunity by remote control

Abstract

Cell-based immunotherapies, such as T cells engineered with chimeric antigen receptors (CARs), have the potential to cure patients of disease otherwise refractory to conventional treatments. Early-on-treatment and long-term durability of patient responses depend critically on the ability to control the potency of adoptively transferred T cells, as overactivation can lead to complications like cytokine release syndrome, and immunosuppression can result in ineffective responses to therapy. Drugs or biologics (e.g., cytokines) that modulate immune activity are limited by mass transport barriers that reduce the local effective drug concentration, and lack site or target cell specificity that results in toxicity. Emerging technologies that enable site-targeted, remote control of key T cell functions - including proliferation, antigen-sensing, and target-cell killing - have the potential to increase treatment precision and safety profile. These technologies are broadly applicable to other immune cells to expand immune cell therapies across many cancers and diseases. In this review, we highlight the opportunities, challenges and the current state-of-the-art for remote control of synthetic immunity.

Keywords: engineered cells; gene switches; immunotherapy; remote control; synthetic immunity.

Figure 1

Remote control of immune cell activity. (Top) The isolation of autologous T cells enables ex vivo reprogramming and expansion of antitumor T cells for adoptive cell therapy. The magnitude of the immune response (i.e. output) can be titrated by varying the location, duration, and intensity of the remote-controlled trigger input. (Bottom) Remote triggers initiate the activation of a synthetic gene circuit to modulate programmed functions.

Figure 2

An effective antitumor response requires unique interactions of T cells in different immunological sites. Produced in the bone marrow, T cells move to the thymus where they mature and differentiate into various subtypes before trafficking to secondary lymphoid organs for priming by DCs. T cells subsequently enter circulation and transport to diseased sites expressing cognate antigens, where they must overcome immunosuppressive signals to effectively clear malignant cells.

Figure 3

Mechanisms of action for small molecule triggers. (Top Left) Ion channel activity may be gated by small molecules to regulate signaling pathways (Top Right) Small molecules can also be engineered as dimerizers to control the functional state of proteins (Bottom) Small molecules can effectively sequester transcription factors through a steric hindrance mechanism to regulate transcriptional activity.

Figure 4

Heat responsive molecular components for thermal regulation of engineered gene expression. (Top Left) RNA thermometers protect ribosome binding site until heat-triggered conformational change allow translation of mRNA. (Top Right) Temperature-gated ion channels open in response to thermal change. (Bottom Left) Transcriptional regulators with thermal sensitivity allow for DNA activation or repression upon heat stimulation. (Bottom Right) Heat shock induces trimerization of HSF1 monomer allowing for its translocation into the nucleus where they bind to HSEs to initiate transcription of heat shock proteins.

Figure 5

Environmental cues for autonomous systems. The tumor microenvironment harbors a myriad of biological molecules that engineered circuits can exploit for autonomous activation.