Solid Tumor Immunotherapy with T Cell Engager-Armed Oncolytic Viruses.

Oncolytic viruses (OVs) are novel anticancer agents that combine direct cancer cell killing with the stimulation of antitumor immunity. In addition, OVs can be engineered to deliver biological therapeutics directly to tumors, offering unique opportunities to design multimodal anticancer strategies. Here, a case for arming OVs with bispecific T cell engagers (BiTEs) is put forward. BiTEs redirect the cytotoxicity of polyclonal T cells to target cells of choice, and have demonstrated efficacy against a number of hematological cancers. However, the success of BiTEs in the treatment of solid tumors appears more limited, at least in part due to: (i) poor delivery kinetics and penetration into tumors, and (ii) on-target off-tumor activity, leading to dose-limiting toxicities. Linking the production of BiTEs to OV replication provides an exciting means to restrict production to the tumor site, widen their therapeutic window, and synergize with direct oncolysis. This review summarizes progress thus far in the preclinical development of BiTE-armed OVs, and explores the possibility of cotargeting cancer cells and nontransformed stromal cells.

Scott EM ，Duffy MR ，Freedman JD ，Fisher KD ，Seymour LW ... -  《-》

Arming oncolytic viruses with bispecific T cell engagers: The evolution and current status.

Oncolytic viruses (OVs) are emerging as therapeutically relevant anticancer agents as contemporary immunotherapy gains traction. Furthermore, OVs are an ideal platform for genetic modification to express therapeutic transgenes. Bispecific T cell engagers (BiTEs) can redirect T cells to tumor cells, resulting in targeted cytotoxicity. BiTEs have demonstrated success in hematological cancers but are rarely used in solid tumors. The drawbacks of BiTEs, including inadequate delivery and on-target-off-tumor activity have limited their efficacy. Combining OVs with BiTEs is a prospective area to investigate. This combined strategy can benefit from the best qualities of both therapies while overcoming the limitations.

Wang Y ，Cheng P 《-》

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

Heidbuechel JPW ，Engeland CE 《Journal of Hematology & Oncology》

Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors.

Purpose: Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T-cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination.Experimental Design: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers.Results: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T-cell infiltration and induction of protective antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells.Conclusions: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. Clin Cancer Res; 24(9); 2128-37. ©2018 AACR.

Speck T ，Heidbuechel JPW ，Veinalde R ，Jaeger D ，von Kalle C ，Ball CR ，Ungerechts G ，Engeland CE ... -  《-》

Fighting Cancer with Viruses: Oncolytic Virus Therapy in China.

Wei D ，Xu J ，Liu XY ，Chen ZN ，Bian H ... -  《-》