Current advances in T-cell-based cancer immunotherapy

Abstract

Cancer is a leading cause of death worldwide; due to the lack of ideal cancer biomarkers for early detection or diagnosis, most patients present with late-stage disease at the time of diagnosis, thus limiting the potential for successful treatment. Traditional cancer treatments, including surgery, chemotherapy and radiation therapy, have demonstrated very limited efficacy for patients with late-stage disease. Therefore, innovative and effective cancer treatments are urgently needed for cancer patients with late-stage and refractory disease. Cancer immunotherapy, particularly adoptive cell transfer, has shown great promise in the treatment of patients with late-stage disease, including those who are refractory to standard therapies. In this review, we will highlight recent advances and discuss future directions in adoptive cell transfer based cancer immunotherapy.

Keywords: adoptive cell transfer; cancer antigen-specific T cells; cancer immunotherapy; genetically modified T cells.

Figure 1

The key points in cancer immunotherapy are ‘one activation and two inhibitions’ where cancer-reactive T-cell activation by cancer antigen represents the one activation and blockade of coinhibitory molecules on T cells and reversal of Treg cell-mediated immunosuppression represent the two inhibitions. DC: Dendritic cell.

Figure 2. Four generations of chimeric antigen receptor structures

First-generation chimeric antigen receptor (CAR) consists of a single signaling domain derived from the CD3ζ chain. Extracellular domain scFv is an antigen-binding site, which is derived from monoclonal antibodies. The CAR is tethered to the plasma membrane via a transmembrane domain; second-generation CAR is added with an additional intracellular signaling domain to the basic first-generation receptor configuration that provides a costimulatory signal (e.g., CD28 or 4-1BB); third-generation CAR is added with two costimulatory domains in series (e.g., CD28 and 4-1BB) to the T-cell activatory signaling domain. Fourth-generation CAR employs a vector encoding a CAR and a CAR-responsive promoter that responds upon successful signaling of the CAR by the transgenic production of cytokines. Either a first-, second- or third-generation CAR may be used in this configuration. scFv: Single-chain variable fragment; TM: Transmembrane.