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Table 2 Preclinical studies investigating oncolytic viruses encoding bispecific T cell engagers

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

Study (1) Oncolytic virus (2) Immune effects (3) Anti-tumor effects
Vector platform BiTE targets Highlights
Yu et al. (2014) Oncolytic Vaccinia virus (VV), derived from Western Reserve vaccine strain EphA2 First OV-BiTE agent described in the literature In vitro: T cell effector cytokine production and cytotoxicity
In vivo: T cell effector cytokine production
T cell proliferation requires exogenous IL-2
SCID mice with A549 xenografts
s.c. tumors pre-mixed with PBMCs, virus i.p.: no tumor engraftment
i.v. lung colonization model, PBMC and virus mix i.v.: delayed tumor progression and prolonged survival
Fajardo et al. (2017) Oncolytic adenovirus (AdV), derived from ICOVIR-15 K EGFR   In vitro: T cell activation, proliferation, cytotoxicity, effector, and proinflammatory cytokine production
In vivo: transient increase in intratumoral T cell abundance (HCT116 model)
no T cell-mediated depletion of virus
SCID/beige mice with s.c. xenografts
A549 tumors, virus i.t., PBMCs i.v.: delayed tumor progression
HCT116 tumors, virus i.v., pre-activated T cells i.v., IL-2 i.p.: reduced tumor growth
Barlabé et al. (2019) AdV (Fajardo et al. 2017) EGFR OV delivery via menstrual blood-derived mesenchymal stem cells (MenSCs) In vitro: T cell cytotoxicity
In vivo: reduced viral load vs. unmodified virus
NSG mice with s.c. A549 xenografts
i.v. PBMCs, i.p. virus/virus-infected MenSCs: delayed tumor growth vs. OV-BiTE application without MenSCs/MenSCs carrying unmodified virus
Freedman et al. (2017) AdV, derived from enadenotucirev (EnAd) EpCAM, FHA (control) First OV-BiTE study to include efficacy studies in primary, patient-derived model systems In vitro: CD4+ and CD8+ T cell activation, proliferation, effector and inflammatory cytokine production, degranulation, cytotoxicity (recombinant BiTE from transfected cells); T cell activation and cytotoxicity via apoptosis induction (OV-BiTE)
Ex vivo: T cell activation, proliferation, degranulation, cytotoxicity
Tumor cell depletion in ex vivo malignant peritoneal ascites and pleural effusions containing tumor cells, immune cells, stromal cells, and soluble immunosuppressive factors
Speck et al. (2018) Oncolytic measles viruses, derived from Edmonston B vaccine strain CEA, CD20 BiTEs engineered to target human and murine CD3ε, respectively, for use in complementary mouse models and as controls; first study to show superiority of OV-BiTE to purified BiTE In vitro: T cell cytotoxicity, effector and inflammatory cytokine production
In vivo: no negative selection of BiTE target antigen, no BiTE detected in serum following i.t. injection (PDX model); increased intratumoral mT cell levels and effector-to-regulatory T cell ratio; increased expression of T cell activation, differentiation, proliferation, and exhaustion markers (B16 model)
NSG mice with s.c. patient-derived xenografts, PBMCs i.t., virus i.t.: delayed tumor progression and prolonged survival
C57BL/6J mice with s.c. MC38/B16 tumors expressing human antigens, endogenous mT cells, virus i.t.: Delayed tumor progression, prolonged survival, long-term remissions with immune protection; efficacious also in MV-immune animals; no significant difference in efficacy compared to UV-inactivated, i.e., non-replicative, virus
Wing et al. (2018) AdV (Fajardo et al. 2017) EGFR First study describing combination of OV-BiTE with CAR T cells In vitro: CAR T cell cytotoxicity toward BiTE-targeted tumor cells, T cell activation, effector cytokine production and proliferation
In vivo: increased intratumoral abundance of CAR T cells, CAR T cell activation and proliferation (Panc-1 model)
NSG mice with s.c. xenografts, virus i.t., FRα-CAR T cells i.v
HCT116 (CAR target high) tumors: delayed tumor growth, prolonged survival
Panc-1 (CAR target low): delayed tumor growth
Porter et al. (2020) AdV plus helper-dependent adenovirus encoding immunomodulators CD44v6, CD19 (control) Additional transgenes IL-12p70, PD-L1 inhibitor In vitro: T cell activation, differentiation (TH1), exhaustion
In vivo: CAR T cell activation, lower CAR levels at the tumor site
NSG mice with xenografts
FaDu/CAPAN-1 tumors s.c., virus i.t., HER2-/PSCA-CAR T cells i.v.: Similar efficacy for immunomodulatory vectors with and without BiTE transgene
Orthotopic FaDu/FaDu-HER2−/− xenografts, virus i.t., HER2-CAR T cells: Trends toward reduced tumor load and prolonged survival
Yu et al. (2017) VV FAP BiTE targeting CAFs instead of tumor cells; first study describing TME targeting via BiTE-encoding OV In vitro: T cell effector cytokine production, cytotoxicity
In vivo: Increased intratumoral T cell infiltration, effector cytokine production, B16-specific T cell responses (ELISpot)
C57BL/6J mice with B16 tumors
s.c. model with virus i.t. and uninjected contralateral tumors: Correlation of FAP+ cell depletion with increased viral load in injected tumors; delayed tumor progression
i.v. B16F10 lung colonization model with virus i.v.: Reduced number of tumor nodules
Freedman et al. (2018) EnAd AdV FAP CAF-targeting BiTE In vitro: CD4+ and CD8+ T cell activation, degranulation and cytotoxicity, T cell proliferation, effector cytokine production (recombinant BiTE from transfected cells), T cell activation and cytotoxicity via induction of apoptosis (OV-BiTE)
Ex vivo: T cell activation, effector cytokine production, proliferation, cytotoxicity, reduction in TGF-β levels, differential gene expression—upregulation of T cell-associated genes and chemokines and antigen-presenting machinery, downregulation of fibroblast-associated genes and chemokines, and shift from M2 to M1 macrophage markers (malignant exudates), T cell activation, effector cytokine production, cytotoxicity via induction of apoptosis (prostate tumor biopsies)
Ex vivo malignant peritoneal ascites and pleural effusions: Reduction in FAP+ cells
Ex vivo thin tissue slices from prostate cancer samples: Stromal degradation
Sostoa et al. (2019) ICOVIR-15K AdV FAP CAF-targeting BiTE; recognizes both human and mouse FAP In vitro: CD4+ and CD8+ T cell proliferation, T cell activation, effector cytokine production, cytotoxicity
In vivo: Increased intratumoral T cell accumulation (A549 model)
NSG mice with s.c. A549/HPAC xenografts, virus i.t., T cells i.v.: FAP depletion, delayed tumor progression, prolonged survival
Scott et al. (2019) EnAd AdV FRβ, FHA (control) BiTE targeting TAMs instead of tumor cells; comparison of different scFv orders; study also reports on trispecific T cell engagers In vitro: T cell activation and cytotoxicity, also in presence of ascites fluid (recombinant BiTE from transfected cells)
Ex vivo: CD4+ and CD8+ T cell activation and proliferation, T cell effector cytokine production and cytotoxicity (for both recombinant BiTE from transfected cells and OV-BiTE)
CD11b+ CD64+ target cell reduction in ex vivo malignant peritoneal ascites and pleural effusions containing tumor cells, immune cells, stromal cells, and soluble immunosuppressive factors
  1. FHA, filamentous hemagglutinin adhesin (B. pertussis)