Synthetic immunology: T-cell engineering and adoptive immunotherapy

Abstract

During the past decades, the rapidly-evolving cancer is hard to be thoroughly eliminated even though the radiotherapy and chemotherapy do exhibit efficacy in some degree. However, a breakthrough appeared when the adoptive cancer therapy [1] was developed, especially T cells armed with chimeric antigen receptors (CARs) showed great potential in tumor clinical trials recently. CAR-T cells successfully elevated the efficiency and specificity of cytotoxicity. In this review, we will talk about the design of CAR and CAR-included combinatory therapeutic applications in the principles of systems and synthetic immunology.

Keywords: Cell therapy; Chimeric antigen receptor (CAR); Immunotherapy; Systems and synthetic biology; Systems and synthetic immunology; T cell signaling; Tumor immunology.

Fig. 1

Three-signal model in T cell activation and the design principle of CAR. Interaction between T cell receptor (TCR)/CD3 complex with tumor antigen peptide fragment presented by major histocompatibility complex (MHC) leads to phosphorylation of TCR/CD3 intracellular domain, which produces signal 1 to activate T cells. Meanwhile, some ligands such as B7H2, 4-1BBL, and OX40L on the antigen-presenting cells can be recognized by costimulatory receptors on T cells, like CD28, 4-1BB and OX40. This recognition helps the activation of T cell as signal 2. Cytokines are a broad category of small proteins secreted by many immune cells. Combination of cytokines and their receptors on T cells called as signal 3 can also enhance the T cells' activation. CARs are recombinant immune receptors that mimic the signal transduction of T cell activation and are independent of MHC.

Fig. 2

Multi-targeting CARs: (A) α-FITC CARs: The extracellular domain of α-FITC CAR is the scFv which recognizes FITC. It can recognize many kinds of TAAs with the help of different antibodies modified with FITC. (B) SUPRA CARs: It's another design of two-component system based on leucine zipper. By changing the type of zipFv, zipCAR can indirectly interact with different TAAs.

Fig. 3

The evolution of CAR designs. The first generation CAR contains a scFv, a hinge region, a transmembrane region and the endodomain of CD3ζ chain. In contrast with the first generation CAR, one intracellular domain of costimulatory receptors, such as CD28 or 4-1BB, is added into the second generation CAR, and the third generation CAR combines two kinds of costimulatory signals like CD28 and 4-1BB.

Fig. 4

Strategies to improve safety of CARs. (A) On-switch CARs: A CAR is split into two parts which form an AND-Gate. Only when adding small molecules, these two parts join together and transform the signal from antigen. (B) SynNotch CARs: Activation of synNotch induces expression of CARs. Only when there are both antigens corresponding to synNotch and CAR, T cells immune response can be activated. (C) Inhibitory CARs (iCARs): T cells cannot be activated when iCARs react with their antigen expressed on normal tissue even though CARs are stimulated at the same time. (D) Drug-induced suicide CARs: A small molecular named AP1903 leads to the dimerization of modified caspase9, and induces CAR-T cells apoptosis.

Fig. 5

Strategies to against tumor inhibitory microenvironment. (A) Armored CARs: Compared with traditional CAR-T cells, armored CAR-T cells are optimized to constitutively or inducibly secrete cytokines such as IL-12 or express costimulatory ligands like 4-1BBL [79], which strengthens the anti-tumor efficiency. (B) Immune checkpoint blockade: Utilizing antibodies to block immune-suppressive signals. (C) Chimeric PD-1: Chimeric PD-1 is a modified PD-1 whose intracellular domain is replaced by that of CD28. This receptor can recognize PD-L1 but induce a costimulatory signal.