T-cell receptor-engineered T cells for cancer treatment: current status and future directions

Abstract

T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR-engineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCR-engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1). These successes demonstrate the potential of this approach to treat cancer. In this review, we provide a perspective on the current and future applications of TCR-engineered T cells for the treatment of cancer. Our summary focuses on TCR activation and both pre-clinical and clinical applications of TCR-engineered T cells. We also discuss how to enhance the function of TCR-engineered T cells and prolong their longevity in the tumor microenvironment.

Keywords: T-cell receptor; TCR-engineered T cells; neoantigen; tumor antigen; tumor microenvironment.

Figure 1

Process of TCR-engineered T cells therapy. T cells are isolated from patient blood or tumor tissue. TCR α and β chains are then isolated from single T-cell clones and inserted into a lentivirus or retrovirus vector. T cells isolated from the peripheral blood of the patient can be modified with the lentivirus or retrovirus vector to encode the desired TCRαβ sequences. These modified T cells are then expanded in vitro to obtain sufficient numbers for treatment and re-infusion back into the patient

Figure 2

Schematic demonstration of TCR signaling. T cells recognize pMHC complexes through the TCR-CD3 cluster. Several classes of proteins are then recruited to the plasma membrane by the activated receptors and participate in signal propagation. Phospholipase C-γ1 (PLC-γ1) cleaves molecules of the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). The interaction of IP3 with its receptors in the endoplasmic reticulum up-regulates the level of Ca²⁺ in the cytosol, further activating the Ca²⁺-binding protein calmodulin. NFAT, as a nuclear factor of activated T cells, is regulated by the calcium pathway. DAG is primarily involved in the activation of the Ras/Erk pathway. T cells are activated though these signaling pathways, releasing IFN-γ, Granzyme B, IL-2, and so on

Figure 3

Three typical procedures to obtain TCR sequence. Antigen responsive T cells are isolated, specific TCR genes are identified by single clone derived-cDNA sequencing (I), single cell sequencing (II) or paired sequencing of bulk DNA (III)