Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities

Abstract

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

Keywords: T cells; chimeric antigen receptors; engineered immune cells; immunotherapy; synthetic Notch; synthetic biology.

Figure 1

The immune system as a platform for interfacing with disease. Different modes of intervention to direct immune responses to disease are shown in orange. (a) Immune cells are an exquisite sensing and response system that monitors and responds to disease and loss of homeostasis. (b) Our endogenous immune system can be manipulated with biologics, but now immune cells can be directly, genetically reengineered to target and treat disease.

Figure 2

Therapeutic cells versus traditional therapeutic modalities. (a) Future therapeutic cells need multiple sensors, intrinsic information processing, decision-making logic, and controlled output programs for more effective and safe treatment of disease. (b) The pros and cons of cell therapies versus biologics and small-molecule therapeutics.

Figure 3

Engineering different immune cell types. (a) Immune cell types amenable to engineering for cell therapies. Here we focus on the use of T cells for targeting cancer (yellow box). (b) Engineered T cells, as well as naturally occurring, cancer-specific tumor-infiltrating lymphocytes, are of particular interest given the recent unprecedented clinical results.

Figure 4

Basic T cell–sensing modules. (a) T cells can be engineered with T cell receptors (TCRs) and chimeric antigen receptors (CARs) to redirect them to cancer or other diseases. These receptors activate the entirety of the immune response. (b) T cells require multiple signals to activate. Synthetic costimulatory and coinhibitory receptors have been engineered that help to initiate or shut down an immune response. (c) synNotch receptors are a new class of receptors that detect environmental cues and directly regulate customized transcriptional circuits. Cells engineered with synNotch receptors can link environmental sensing to a variety of custom effector programs.

Figure 5

Synthetic combinatorial control therapeutic T cell circuits. (a) Split caspases have been engineered that allow for small-molecule control over therapeutic cell death. (b) ON-switch chimeric antigen receptors (CARs) have been engineered such that the ligand-binding domain and signaling chain are split. Receptor activity is regulated by antigen detection and a small-molecule heterodimerizer (AND logic), allowing for control over cellular activity after administration to the patient. (c) iCARs are inhibitory receptors that can overcome the positive activity of stimulatory receptors. These receptors can be utilized to sense bystander tissue and prevent the T cell from causing toxicity (AND-NOT logic). (d) synNotch receptors can be used to control the expression of CARs. synNotch → circuits allow for combinatorial antigen sensing and could help to confine CAR expression and T cell activation to the tumor (temporal AND logic).

Figure 6

Overcoming the challenges of solid tumors. (a) T cell therapies can cause life-threatening damage due to ➊ cross-reaction with off-target tissue and ➋ excessive inflammation. On the other hand, tumor environments can be suppressive, ➌ preventing a curative immune response. (b) To overcome these pitfalls, the T cells can be engineered ➊ to sense combinatorial antigens, ➋ to be regulated with small molecules, and ➌ to produce therapeutic agents that prime the tumor environment for more effective treatment. Abbreviation: CAR, chimeric antigen receptor.

Figure 7

Engineering nonnatural functionalities of T cells. T cells can be engineered to sense disease microenvironments such as tumors and locally perform both natural and synthetic effector programs. T cells can produce cytotoxic agents, cytokines, commercial biologics such as antibodies, and factors involved in regeneration of tissues in a context-dependent manner.