Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles

Kakiuchi, Yoshihiko; Kuroda, Shigetoshi; Kanaya, Nobuhiko; Kumon, Kento; Tsumura, Tomoko; Hashimoto, Masashi; Yagi, Chiaki; Sugimoto, Ryujiro; Hamada, Yuki; Kikuchi, Shinichi; Nishizaki, Masahiko; Kagawa, Shunsuke; Tazawa, Hiroshi; Urata, Yasuo; Fujiwara, Toshiyoshi

doi:10.1016/j.ymthe.2021.05.015

Cited by 16 publications

(15 citation statements)

References 40 publications

(43 reference statements)

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“…Notably, the induction of ICD was not exclusive for OAV injected tumors, but was also present in the contralateral tumors, mimicking infiltratively growing GM cells ( Figure 3 , Supplementary Figure S5 ). In colon cancer, OAVs can be transferred to metastases located far away from virus injected tumors via tumor-derived exosomes, in this way inducing abscopal effects due to the oncolysis of metastatic cells by OAVs transported by these exosomes [ 40 ]. However, at least in the late stages (day 35), we did not observe any virus replication in the contralateral gliomas ( Figure 4 ) indicating that, at least for brain tumors, the growth reduction we saw for contralateral tumors did not seem to be a result of oncolysis, but might be explained by a kind of “secondary ICD burst“ induced by CD8 + cytotoxic TILs [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

Klawitter

El-Ayoubi

Buch

et al. 2022

IJMS

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Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary preclinical data, the YB-1 dependent oncolytic adenovirus (OAV) XVir-N-31 represents a promising therapeutic agent to treat, in particular, therapy resistant GBM. Preclinical studies have shown that XVir-N-31 prolonged the survival of GBM bearing mice. Now using an immunohumanized mouse model, we examined the immunostimulatory effects of XVir-N-31 in comparison to the wildtype adenovirus (Ad-WT). Additionally, we combined OVT with the inhibition of immune checkpoint proteins by using XVir-N-31 in combination with nivolumab, or by using a derivate of XVir-N-31 that expresses a PD-L1 neutralizing antibody. Although in vitro cell killing was higher for Ad-WT, XVir-N-31 induced a much stronger immunogenic cell death that was further elevated by blocking PD-1 or PD-L1. In vivo, an intratumoral injection of XVir-N-31 increased tumor infiltrating lymphocytes (TILs) and NK cells significantly more than Ad-WT not only in the virus-injected tumors, but also in the untreated tumors growing in the contralateral hemisphere. This suggests that for an effective treatment of GBM, immune activating properties by OAVs seem to be of greater importance than their oncolytic capacity. Furthermore, the addition of immune checkpoint inhibition (ICI) to OVT further induced lymphocyte infiltration. Consequently, a significant reduction in contralateral non-virus-injected tumors was only visible if OVT was combined with ICI. This strongly indicates that for an effective eradication of GBM cells that cannot be directly targeted by an intratumoral OV injection, additional ICI therapy is required.

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Section: Discussionmentioning

confidence: 99%

The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

Klawitter

El-Ayoubi

Buch

et al. 2022

IJMS

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“…Exosomes separated from HCT116 human colon carcinoma cells treated with OBP-301 demonstrated an increased programmed cell death and autophagy comparable to OBP-301. In different cancer experimental models, an intra-tumoral dispensation of OBP-301 provoked decisive anticancer actions on tumors that were not directly treated with OBP-301, implicating straight intervention by cancer-originated exosomes enclosing OBP-301 [ 225 ].…”

Section: Discussionmentioning

confidence: 99%

Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies

Allegra

Petrarca

Gioacchino

et al. 2022

Cells

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Exosomes are small membrane vesicles of endocytic origin containing cytokines, RNAs, growth factors, proteins, lipids, and metabolites. They have been identified as fundamental intercellular communication controllers in several diseases and an enormous volume of data confirmed that exosomes could either sustain or inhibit tumor onset and diffusion in diverse solid and hematological malignancies by paracrine signaling. Thus, exosomes might constitute a promising cell-free tumor treatment alternative. This review focuses on the effects of exosomes in the treatment of tumors, by discussing the most recent and promising data from in vitro and experimental in vivo studies and the few existing clinical trials. Exosomes are extremely promising as transporters of drugs, antagomir, genes, and other therapeutic substances that can be integrated into their core via different procedures. Moreover, exosomes can augment or inhibit non-coding RNAs, change the metabolism of cancer cells, and modify the function of immunologic effectors thus modifying the tumor microenvironment transforming it from pro-tumor to antitumor milieu. Here, we report the development of currently realized exosome modifiers that offer indications for the forthcoming elaboration of other more effective methods capable of enhancing the activity of the exosomes.

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“…Human immortalised stem cells expressing E1A/B effectively produced a non-replicating virus that was released and infected the murine TRAMPC PCa tumours in vivo. Other strategies for the systemic delivery of virus include the transduction of extracellular vesicles from bone marrow mesenchymal stem cells [ 46 ] or the isolation of vesicles from infected cultured cancer cells (HCT116) [ 10 ]. There are no reports of any toxicity in association with using cell carrier or extracellular vesicle systems in vivo or in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…For example, when OAds were combined with immune checkpoint inhibitors (e.g., anti-PD-1) or cytokines, the activation of the host immune system resulted in the elimination of non-treated tumours and long-term immunity [ 8 , 9 ]. Another example of the abscopal effect is the spread of OAds from the tumour site to distant tumours via extracellular vesicles [ 10 ]. Various engineered OAd mutants have been evaluated in clinical trials including both PCa and PDAC patients [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models

Man

Aguirre-Hernández

Fernández

et al. 2022

IJMS

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Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24–72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.

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Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles

Cited by 16 publications

References 40 publications

The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis, Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

Exosome-Mediated Therapeutic Strategies for Management of Solid and Hematological Malignancies

Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models

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