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Review
. 2020 Jul 10;8(7):204.
doi: 10.3390/biomedicines8070204.

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

Zong Sheng Guo  1   2 , Michael T Lotze  1   2   3 , Zhi Zhu  1   2 , Walter J Storkus  1   3   4 , Xiao-Tong Song  5
Affiliations
Review

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy

Zong Sheng Guo et al. Biomedicines. .

Abstract

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.

Keywords: adenovirus; bispecific T cell engager; bispecific antibody; measles virus; oncolytic virus; trispecific T cell engager; trispecific antibody; tumor antigen-specific T cells; vaccinia virus.

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Conflict of interest statement

X.-T.S. is the founder and CEO of Icell Kealex Therapeutics, a biotech company developing armed oncolytic viruses for cancer therapy. No other authors declare conflict of interest.

Figures

Figure 1
Figure 1
The design of a bispecific T cell engager antibody (BiTE). (A). Schematic representation of the derivation and structure of a BiTE molecule generated from two different antibodies, one with specificity for a T cell activation molecule and another one specific for a tumor-associated antigen (TAA). (B). Schema of a BiTE-coding gene used to produce the recombinant BiTE protein. Linkers were inserted between VH and VL domains of the single-chain fragment variable (scFv) and between the two scFvs. The linker between the two scFv is short (~5 aa) while the other linker within scFv is usually longer (~15 aa). (C). A BiTE creates an immunologic synapse by binding simultaneously to a tumor cell, via TAA, and a T cell, via CD3. This figure is modified from the Figure 1 in Slaney CY et al., Cancer Discovery, 2018 [49]. The drawings were created using BioRender (https://app.biorender.com).
Figure 2
Figure 2
The design of a triple specific T cell engager (TriTE) antibody and how it links the T cells to the targeted cancer cells. This trispecific antibody binds three targets: the CD38 protein on a myeloma cell, and the protein CD28 and the CD3 protein complex on a T cell (the antibody’s target-binding domains are shown in red, blue and yellow, respectively). CD3 is a component of the T cell receptor (TCR). The binding of CD3 by the antibody drives T cell activation without requiring antigen recognition by the TCR, which leads to the killing of the myeloma cell and the production and release of toxic cytokine molecules. This image is modified from that in Garfall AL and June C, Nature, 2019 [53], and it was made using BioRender.
Figure 3
Figure 3
Working mechanisms of a BiTE-armed oncolytic virus (OV). The efficacy of a “pure” OV is often limited by suboptimal spread of the OV throughout the tumor tissue and induction of tumor antigen-specific T cells. BiTE-armed OV may overcome these limitations as the armed OV produces and secrete these BiTEs that diffuse within the tumor tissue, activating and directing endogenous T cells to recognize and kill the tumor cells or/and stromal cells effectively (even if not directly infected by the OV), resulting in improved antitumor efficacy. This is a modified version of a figure originally published by Song XT, Discovery Med, 2013 [71].
See this image and copyright information in PMC

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