Engineering Therapeutic T Cells: From Synthetic Biology to Clinical Trials

Abstract

Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field.

Keywords: T cells; cellular engineering; cellular therapy; immunotherapy; synthetic biology.

Figure 1

Overview of T cell engineering and a chimeric antigen receptor (CAR) structure. (a) T cell engineering currently involves harvest of T cells from a patient or allogeneic donor, modification of the T cells through genetic engineering via viral infection or other specialized culture conditions, expansion, testing, and reinfusion (1). (b) Diagram of a third-generation CAR. Currently, it is difficult to predict the function of a particular CAR component when combined with others, so each CAR must be optimized individually. This lack of modularity is an impediment to the rapid production of CARs with unique desired properties (1, 2).

Figure 2

Diagram of control modules for therapeutic T cells. (a) Logic gates control T cell activation when two antigens are encountered at the same time. Examples include synthetic notch (synNotch) receptors to one antigen that drive chimeric antigen receptor (CAR) expression for a second antigen, CAR T cells in which signal 1 (CD3ς) and signal 2 (costimulation) are triggered by different CARs, and inhibitory CARs where the presence of an antigen blocks activation. (b) Small molecules have been used to control T cell function. Examples include orthogonal chemotaxis using RASSLs (receptors activated solely by a synthetic ligand), RNA aptamers that require small-molecule binding to stabilize specific RNA transcripts (such as IL-15), and small-molecule gated split CARs where both the small molecule and the target antigen are required for T cell activation (also an example of a logic gate). (c) Docking systems allow a single CAR with a common binding domain to use several different adapters with different antigen specificities. The adapters have defined pharmacokinetics, whereas the modified T cells do not. Abbreviations: CD3ς, a component of the T cell receptor; costim, costimulation; Gal4, a yeast transcription factor; PD-1, an inhibitory receptor expressed on T cells.