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

Abstract

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 tumor vaccination. 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 by complementary binding and cytotoxicity assays. efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers. 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. 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. .

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

“…However, pre-existing anti-measles immunity did not affect anti-CHIKV immune responses in human subjects [10]. In the context of oncolytic virotherapy, pre-existing anti-viral immunity may even be conducive to anti-tumor efficacy [21,71,72].…”

“…B16-OVA cells and the immortalized mouse (C57BL/6) dendritic cell line DC2.4 were obtained from H. Weyd (German Cancer Research Center, Heidelberg, Germany). MC38-hCD46 and B16-OVA-hCD46 cells were generated by lentiviral transduction as described previously [21]. The ovalbumin-specific cytotoxic T cell (CTL) line, which recognizes the H-2K b -restricted epitope aa257-264 (SIINFEKL) [33] and the TRP-2-specific CTL line, which recognizes the epitope aa180-188 (SVYDFFVWL) [34], have been described previously [32].…”

“…The advantages of oncolytic measles vaccines include the well documented safety record, genomic stability, and the versatility of the reverse genetics system [2,14,15]. Insertion of immunomodulatory genes encoding cytokines, chemokines or immune checkpoint antibodies into the oncolytic vector can enhance anti-tumor immunity [16][17][18][19][20][21][22][23].…”

An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells

“…An encoded FAP-specific BiTE would be produced and secreted only upon virus infection of tumor cells, allowing it to access tumor-infiltrating lymphocytes (TIL). This approach has been validated using BiTEs to target T-cell cytotoxicity to tumor cell antigens (21,(26)(27)(28). However, a virus-encoded BiTE that activates T cells to kill tumor stromal fibroblasts would provide a "multimodal" therapeutic agent that simultaneously targets two distinct cell types within the tumor.…”

Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

“…2 In addition to their diversity of application, ICR immunotherapies can also vary widely in their composition and mode of delivery. They encompass nanoparticle [9][10][11] , bispecific IgG, 12,13 scFv fusion, 14 and mRNA 15 constructs, as well as vectors based on oncolytic viruses 16 and engineered cells. 17 While a majority of ICR therapies in clinical testing are produced using traditional genetic engineering techniques, one challenge to their discovery and development is the relatively low-throughput manner in which drug candidates can be investigated and the relatively high dependency of drug action on the affinity of individual cell-binding domains.…”