Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies

Abstract

Bispecific T cell engagers (BiTEs) are an innovative class of immunotherapeutics that redirect T cells to tumor surface antigens. While efficacious against certain hematological malignancies, limited bioavailability and severe toxicities have so far hampered broader clinical application, especially against solid tumors. Another emerging cancer immunotherapy are oncolytic viruses (OVs) which selectively infect and replicate in malignant cells, thereby mediating tumor vaccination effects. These oncotropic viruses can serve as vectors for tumor-targeted immunomodulation and synergize with other immunotherapies. In this article, we discuss the use of OVs to overcome challenges in BiTE therapy. We review the current state of the field, covering published preclinical studies as well as ongoing clinical investigations. We systematically introduce OV-BiTE vector design and characteristics as well as evidence for immune-stimulating and anti-tumor effects. Moreover, we address additional combination regimens, including CAR T cells and immune checkpoint inhibitors, and further strategies to modulate the tumor microenvironment using OV-BiTEs. The inherent complexity of these novel therapeutics highlights the importance of translational research including correlative studies in early-phase clinical trials. More broadly, OV-BiTEs can serve as a blueprint for diverse OV-based cancer immunotherapies.

Viro-antibody therapy: engineering oncolytic viruses for genetic delivery of diverse antibody-based biotherapeutics

“…Viro-antibody therapy is a promising strategy to overcome some of the drawbacks of conventional BiTE therapy by intratumoral and extended BiTE expression ( viro-BiTE therapy ). 123 , 124 This mode of delivery facilitates enhanced accumulation and penetration of BiTEs in the tumor and minimizes systemic BiTE distribution to reduce off-tumor activities and adverse effects. Moreover, OVs induce inflammation, thereby triggering infiltration of T cells including potentially powerful antiviral T cells that can be redirected to tumor targets by the BiTEs.…”

Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies

“…Moreover, in patient-derived xenograft models, the combination of MeV BiTE and adoptive immune cell transfer significantly prolonged survival compared to monotherapies. This was the first study to demonstrate efficacy of an OV encoding a tumor-targeting BiTE in both, syngeneic and patient-derived xenograft models, highlighting the potential of this combination [ 93 ]. To further improve effector T cell function, Engeland and colleagues had previously demonstrated strong anti-tumor efficacy of an oMeV encoding IL-12, achieving 90% complete tumor remissions in the MC38cea model, a colorectal cancer model in fully immunocompetent C57BL/6 mice [ 65 ].…”

Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells

“…combination therapy (e.g., with Blinatumomab, a bispecific T cell engager [BiTE]) or by developing OVs that encode these bispecific molecules [91]. The use of BiTEs with OV has only recently been explored in preclinical studies [91,92].…”

“…Typically, one of the scFvs specifically binds to a tumour antigen on cancer cells, while the other binds to an immune activator on the target immune cells. These novel molecules could be incorporated with OV therapies as combination therapy (e.g., with Blinatumomab, a bispecific T cell engager [BiTE]) or by developing OVs that encode these bispecific molecules [ 91 ]. The use of BiTEs with OV has only recently been explored in preclinical studies [ 91 , 92 ].…”

“…These novel molecules could be incorporated with OV therapies as combination therapy (e.g., with Blinatumomab, a bispecific T cell engager [BiTE]) or by developing OVs that encode these bispecific molecules [ 91 ]. The use of BiTEs with OV has only recently been explored in preclinical studies [ 91 , 92 ]. With the development of multifunctional NK cell engagers (NKCEs) [ 93 ], it is plausible that these could be also used to augment OV efficacy.…”