Abstract
Immunotherapeutic approaches based on the redirection of T cell activity toward tumor cells are actively being investigated. The impressive clinical success of the continuously intravenously infused T cell-redirecting bispecific antibody (T-bsAb) blinatumomab (anti-CD19 x anti-CD3), and of engineered T cells expressing anti-CD19 chimeric antigen receptors (CAR-T cells) in hematological malignancies, has led to renewed interest in a novel cancer immunotherapy strategy that combines features of antibody- and cell-based therapies. This emerging approach is based on the endogenous secretion of T-bsAbs by engineered T cells (STAb-T cells). Adoptive transfer of genetically modified STAb-T cells has demonstrated potent anti-tumor activity in both solid tumor and hematologic preclinical xenograft models. We review here the potential benefits of the STAb-T strategy over similar approaches currently being used in clinic, and we discuss the potential combination of this promising strategy with the well-established CAR-T cell approach.
Highlights
The immune system plays an important role in shaping the immunogenicity of tumors [1]
T cell-redirecting bispecific antibody (T-bispecific antibodies (bsAbs))-mediated activation has been shown to induce an increase in transgene expression [41], which may favor the secretion of the T-bsAbs primarily at the tumor site and, reducing systemic toxicity
Recent studies have shown that the expression of 4-1BB and CD80 ligands on the surface of engineered T cells secreting and anti-CD19 bispecific T cell-engagers (BiTEs) significantly increased the antileukemia activity in vivo [60]
Summary
The immune system plays an important role in shaping the immunogenicity of tumors [1]. The T cell receptor (TCR)-mediated recognition of processed tumor-associated antigens (TAAs) drives the elimination or sculpting of developing cancer cells, which can generate immune-resistant cell variants [1, 2]. Due to this selective immune pressure, these variant cells display a multitude of evasion mechanisms from immune recognition and destruction, such as abnormalities in the antigen presentation machinery [2], and the generation of an immunosuppressive environment that promotes tumor growth [3]. The ectodomain is usually a single-chain fragment variable (scFv) antibody, that allows the synthetic receptor to recognize a user-defined cell surface TAA in an major histocompatibility complex (MHC)independent manner, and is tethered to the transmembrane domain through the spacer or hinge region [8] (Figure 1). Third-generation CARs further expanded on the second-generation by adding an additional co-stimulatory domain [14, 15]
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