TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma

Hutzen, Brian; Chen, Chun-Yu; Wang, Pin-Yi; Sprague, Les; Swain, Hayley M.; Love, Julia; Conner, Joe; Boon, Louis; Cripe, Timothy P.

doi:10.1016/j.omto.2017.09.001

Cited by 34 publications

(35 citation statements)

References 36 publications

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“…With respect to growth in cancer cell lines, R-593 replicated in PC3-PIP-PSMA, a cell line derived from a human prostate adenocarcinoma made transgenic for PSMA, to a titer similar to that attained in J-PSMA ( Figure 2 E). Replication in the murine prostate cancer TRAMP-PSMA was about two orders of magnitude lower ( Figure 2 E), a result in agreement with the scarce infection of murine cells, in particular cells derived from C57BL/6 mice, which are among the most highly resistant to HSV [ 63 , 64 , 65 ]. The cytotoxic activity of R-593 was specific for PSMA expressing cells, and was undetectable in J-nectin1 cells ( Figure 2 F).…”

Section: Resultssupporting

confidence: 79%

HSV as A Platform for the Generation of Retargeted, Armed, and Reporter-Expressing Oncolytic Viruses

Menotti

Avitabile

Gatta

et al. 2018

Viruses

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Previously, we engineered oncolytic herpes simplex viruses (o-HSVs) retargeted to the HER2 (epidermal growth factor receptor 2) tumor cell specific receptor by the insertion of a single chain antibody (scFv) to HER2 in gD, gH, or gB. Here, the insertion of scFvs to three additional cancer targets—EGFR (epidermal growth factor receptor), EGFRvIII, and PSMA (prostate specific membrane antigen)—in gD Δ6–38 enabled the generation of specifically retargeted o-HSVs. Viable recombinants resulted from the insertion of an scFv in place of aa 6–38, but not in place of aa 61–218. Hence, only the gD N-terminus accepted all tested scFv inserts. Additionally, the insertion of mIL12 in the US1-US2 intergenic region of the HER2- or EGFRvIII-retargeted o-HSVs, and the further insertion of Gaussia Luciferase, gave rise to viable recombinants capable of secreting the cytokine and the reporter. Lastly, we engineered two known mutations in gB; they increased the ability of an HER2-retargeted recombinant to spread among murine cells. Altogether, current data show that the o-HSV carrying the aa 6–38 deletion in gD serves as a platform for the specific retargeting of o-HSV tropism to a number of human cancer targets, and the retargeted o-HSVs serve as simultaneous vectors for two molecules.

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Section: Resultssupporting

confidence: 79%

HSV as A Platform for the Generation of Retargeted, Armed, and Reporter-Expressing Oncolytic Viruses

Menotti

Avitabile

Gatta

et al. 2018

Viruses

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“…Pre-clinical evidence also supports the rationale of combining TGF-β and vascular-endothelial growth factor (VEGF) blockade to synergistically enhance anti-tumor immunity [ 182 ]. Likewise, the combination of TGF-β with oncolytic viruses can potently increase immune-based tumor control [ 183 ]. In addition, the inhibition of TGF-β in combination with vaccination has also shown great promise in pre-clinical settings [ 184 , 185 , 186 , 187 , 188 ] but has not provided a clear indication of clinical efficacy to this date [ 15 ].…”

Section: Tgf-β: Architect Of the Immune Tumor Microenvironment Andmentioning

confidence: 99%

TGF-β in T Cell Biology: Implications for Cancer Immunotherapy

Dahmani

Delisle

2018

Cancers

154

106

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Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy.

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“…The R-87 recombinant was selected to evaluate the antitumor efficacy in vivo , in an immunocompetent mouse model. In general, the murine cancer cells are not as permissive to HSV as the human cancer cells; hence, this model underestimates the antitumor efficacy, a property shared with the vast majority of murine cancer models for oncolytic HSVs ( 46 , 47 ). Here, the important result was that the antitumor efficacy of R-87 could not be differentiated from that of R-LM113 and of the gB recombinant R-317, described in the companion paper ( 45 ).…”

Section: Discussionmentioning

confidence: 98%

Simultaneous Insertion of Two Ligands in gD for Cultivation of Oncolytic Herpes Simplex Viruses in Noncancer Cells and Retargeting to Cancer Receptors

Leoni

Petrovic

Gianni

et al. 2018

J Virol

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Insertion of a single-chain variable-fragment antibody (scFv) to HER2 (human epidermal growth factor receptor 2) in gD, gH, or gB gives rise to herpes simplex viruses (HSVs) specifically retargeted to HER2-positive cancer cells, hence to highly specific nonattenuated oncolytic agents. Clinical-grade virus production cannot rely on cancer cells. Recently, we developed a double-retargeting strategy whereby gH carries the GCN4 peptide for retargeting to the noncancer producer Vero-GCN4R cell line and gD carries the scFv to HER2 for cancer retargeting. Here, we engineered double-retargeted recombinants, which carry both the GCN4 peptide and the scFv to HER2 in gD. Novel, more-advantageous detargeting strategies were devised so as to optimize the cultivation of the double-retargeted recombinants. Nectin1 detargeting was achieved by deletion of amino acids (aa) 35 to 39, 214 to 223, or 219 to 223 and replacement of the deleted sequences with one of the two ligands. The last two deletions were not attempted before. All recombinants exhibited the double retargeting to HER2 and to the Vero-GCN4R cells, as well as detargeting from the natural receptors HVEM and nectin1. Of note, some recombinants grew to higher yields than others. The best-performing recombinants carried a gD deletion as small as 5 amino acids and grew to titers similar to those exhibited by the singly retargeted R-LM113 and by the nonretargeted R-LM5. This study shows that double retargeting through insertion of two ligands in gD is feasible and, when combined with appropriate detargeting modifications, can result in recombinants highly effective in vitro and in vivo.IMPORTANCE There is increasing interest in oncolytic viruses following the FDA and European Medicines Agency (EMA) approval of the oncolytic HSV OncovexGM-CSF and, mainly, because they greatly boost the immune response to the tumor and can be combined with immunotherapeutic agents, particularly immune checkpoint inhibitors. A strategy to gain high cancer specificity and avoid virus attenuation is to retarget the virus tropism to cancer-specific receptors of choice. However, cultivation of retargeted oncolytics in cells expressing the cancer receptor may not be approvable by regulatory agencies. We devised a strategy for their cultivation in noncancer cells. Here, we describe a double-retargeting strategy, based on the simultaneous insertion of two ligands in gD, one for retargeting to a producer, universal Vero cell derivative and one for retargeting to the HER2 cancer receptor. These insertions were combined with novel, minimally disadvantageous detargeting modifications. The current and accompanying studies indicate how to best achieve the clinical-grade cultivation of retargeted oncolytics.

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TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma

Cited by 34 publications

References 36 publications

HSV as A Platform for the Generation of Retargeted, Armed, and Reporter-Expressing Oncolytic Viruses

HSV as A Platform for the Generation of Retargeted, Armed, and Reporter-Expressing Oncolytic Viruses

TGF-β in T Cell Biology: Implications for Cancer Immunotherapy

Simultaneous Insertion of Two Ligands in gD for Cultivation of Oncolytic Herpes Simplex Viruses in Noncancer Cells and Retargeting to Cancer Receptors

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