Oncolytic Virus Combination Therapies-with Bispecific T-Cell Engagers (BiTEs)
Immunotherapy with bispecific T cell cement has achieved amazing success in combating hematological malignancies, but its efficacy in solid tumors is limited. Effective immunotherapy of stromal-rich tumors requires immunosuppressive components that target both cancer cells and the microenvironment. By modifying the oncolytic virus (OV), bispecific T cell engagers (BiTE) targeting the matrix can be expressed. For example, a BiTE binds to fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ε on T cells, resulting in effective T cell activation and fibroblast death. The significance of this combination therapy is that the genetically engineered oncolytic virus encoding a bispecific antibody combines direct viral lysis with endogenous T cell activation, attacks stromal fibroblasts, and provides a multimodal treatment strategy within a single therapeutic agent.
Fig.1 MV-BiTE-infected tumor cells express and secrete BiTE antibodies. (Speck, 2018)
Limitation of Bispecific T cell Immunotherapy
BiTEs are a promising method to enhance the anti-tumor immunity of cells. They are composed of tandem single-chain variable fragments (scFv) targeting CD3 and tumor-associated antigens on T cells. Therefore, regardless of T cell receptor specificity, antigen presentation and co-stimulation, T cells can be recruited to the tumor area. BiTE-mediated T cell-tumor cell interaction triggers the formation of immune synapses, which ultimately leads to tumor-specific cell lysis and the release of TH1 effector cytokines. However, due to its short half-life and dose-limiting side effects, BiTE usually requires continuous infusion, but systemic administration may still cause serious, and in some cases even fatal toxicity. This is why there have been no reports of successful BiTE treatment of solid tumors.
BiTEs Combination Therapies with OVs
OVs can selectively infect and replicate tumor cells, thereby inducing the death of immunogenic lysed cells. The expression of BiTEs targeting the tumor with OV vector can improve the BiTE treatment of solid tumors. This approach can allow tumor-restricted BiTE expression, thereby increasing local concentration and reducing systemic exposure, resulting in a higher therapeutic index. In addition, the oncolytic effect induces the release of tumor antigens in the case of immunostimulation, thereby enabling in situ inoculation of tumors. This indicates that the inherent immunomodulatory effect of OV combined with local BiTE-mediated T cell recruitment may induce sustained anti-tumor immune responses.
In an in vitro mouse model experiment, the oncolytic measles virus of the Edmonston B vaccine strain encoding the bispecific T cell cement (MV-BiTE) showed the expected effect. The survival period of the administered mice was significantly prolonged, and the tumor growth rate was inhibited. The levels of MV-N mRNA and BiTE mRNA in the tumor showed viral gene expression until 48 hours after treatment. The potential of this technology is that as long as the appropriate binding moiety is available, OV-BiTE combination therapy can target almost any tumor surface antigen. This enables the application to other tumor entities with the concomitant targeting of several tumor antigens to prevent potential antigen escape.
Reference
- Speck, T.; et al. Targeted bite expression by an oncolytic vector augments therapeutic efficacy against solid tumors. Clinical Cancer Research. 2018, 24.9: 2128-2137.