Manipulating the T-Cell Receptor Yields Promising Immunotherapies

Jane de Lartigue, PhD
Published: Tuesday, May 01, 2018
Components of the T-cell receptor (TCR) complex, which links antigen recognition with T-cell activity and effector function, are being exploited for several types of cancer immunotherapy. Although these strategies have not received the same level of attention as blockbuster immunotherapies such as checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies, they have made steady progress over the past few years, and many novel agents are undergoing clinical testing.

Broadly speaking, investigational therapies that target the TCR are being developed in 3 categories: TCR-engineered T cells, bispecific antibodies, and immune-mobilizing monoclonal T-cell receptors (ImmTACs).

TCR-engineered T cells are an alternative form of adoptive cell therapy (ACT). These therapies redirect the specificity of the TCR against tumor-associated antigens (TAAs) to target intracellular antigens, where CAR T cells are only just beginning to venture. Stateof- the-art genetic engineering techniques such as CRISPR have the potential to fine-tune these therapies more precisely.

Bispecific antibodies target both tumor cells and T cells via the CD3 component of the TCR complex. Clinical development has yielded FDA approval of the first-in-class drug blinatumomab (Blincyto) for the treatment of patients with acute lymphoblastic leukemia (ALL). Recent expansion of its approved indications offers a new option for patient populations with few therapeutic avenues.

Researchers also are working on ImmTACs, a new class of bispecific drugs that combines the advantageous properties of targeting intracellular antigens and the benefits of a soluble drug format without the time-consuming and labor-intensive manufacturing requirements of cell-based therapies.

Immune Therapies Exploit T Cells

As our understanding of the dual role of the immune system in both restraining and promoting cancer has evolved, so too has our ability to harness its components to yield groundbreaking therapies that augment the antitumor immune response and offer the promise of long-lasting tumor regression.

The focus of cancer immunotherapy has been on mobilizing cytotoxic T cells, the central mediators of cell-mediated adaptive immunity. T cells are activated by protein fragments derived from pathogens that are displayed on the surface of antigen-presenting cells (APCs), such as macrophages, bound to major histocompatibility complex (MHC) molecules.

Although cancers are derived from the body’s own cells gone awry and, in theory, should not stimulate an immune response, the accumulated genetic alterations that often drive cancer can generate unique proteins that T cells recognize and by which they are activated. Tumor antigen–specific T cells, known as tumor-infiltrating lymphocytes (TILs), can be identified in most tumor types.

In response, cancer cells have evolved a multitude of mechanisms to suppress TIL activity and tip the balance of power to the tumor. The idea of immunotherapy is, therefore, to restimulate the antitumor immune response and wrestle back that control. Two major strategies for manipulating T cells have proved particularly effective: immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway and CTLA-4 and genetically engineered CAR T cells.1

TCR-Mediated T-Cell Activation

T-cell activation is dependent on the TCR upon its surface, which engages the antigen-MHC complex on APCs, triggering a cascade of signaling molecules within the cell that ultimately promotes the proliferation of T cells and the acquisition of the properties that enable their effector functions.

This downstream signaling is a highly complex branched network of events that is still not fully understood but maintains a precisely set threshold of activation, ensuring that T cells are switched on only at the appropriate time and for only as long as necessary.

The TCR is a member of the immunoglobulin superfamily and consists of a heterodimer of 2 highly variable protein chains (Figure 1). In most cases, those protein chains are encoded by the TRA and TRB genes. In 5% of cases, the TCR instead is composed of TCRδ and γ chains, although these percentages can change in certain circumstances, such as during T-cell development. Each TCR possesses unique antigen specificity thanks to their random assembly of different gene segments.

 

Figure 1. Basic Structure of the TCR

  The constituent protein chains are made up of a variable and constant region that protrudes from the cell, a portion that spans the membrane, and a short tail inside the cell. Unlike most transmembrane receptors, the tail of the TCR has no inherent signaling activity. Instead, the TCR forms a complex with the CD3 protein family consisting of CD3δ, γ, ε, and ζ, which link the antigen recognition abilities of the TCR with the activation of downstream signaling pathways.


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