A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

Kim, Julius W.; Miska, Jason; Young, Jacob S; Rashidi, Aida; Kane, Jason M.; Panek, Wojciech K.; Kanojia, Deepak; Han, Yu; Balyasnikova, Irina V.; Lesniak, Maciej S.

doi:10.1016/j.omto.2017.05.001

Cited by 14 publications

(12 citation statements)

References 36 publications

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“…Following this method, tumor cell injection has a 100% engraftment rate in C57/Bl6 mice. GL-261 lines overexpressing OVA were generated previously ( 70 ) and cultured in G-418 (200 μg/ml; Sigma-Aldrich) to maintain selection pressure.…”

Section: Methodsmentioning

confidence: 99%

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma

et al. 2021

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Glioblastoma is characterized by the robust infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs). It is not fully understood how TAMCs survive in the acidic tumor microenvironment to cause immunosuppression in glioblastoma. Metabolic and RNA-seq analysis of TAMCs revealed that the arginine-ornithine-polyamine axis is up-regulated in glioblastoma TAMCs but not in tumor-infiltrating CD8+ T cells. Active de novo synthesis of highly basic polyamines within TAMCs efficiently buffered low intracellular pH to support the survival of these immunosuppressive cells in the harsh acidic environment of solid tumors. Administration of difluoromethylornithine (DFMO), a clinically approved inhibitor of polyamine generation, enhanced animal survival in immunocompetent mice by causing a tumor-specific reduction of polyamines and decreased intracellular pH in TAMCs. DFMO combination with immunotherapy or radiotherapy further enhanced animal survival. These findings indicate that polyamines are used by glioblastoma TAMCs to maintain normal intracellular pH and cell survival and thus promote immunosuppression during tumor evolution.

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Section: Methodsmentioning

confidence: 99%

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma

et al. 2021

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“…The DNX-2401 trial validated prior preclinical research that injection of CRAd elicits the recruitment of immune cells, particularly T cells, to the tumor site. This is an indication that immunocompetent mouse model of HGG39,46,47,49,57,61,86 was useful to predict, at least, some biological changes evoked in patients by CRAd therapy. However, all current CRAds are based on human adenovirus that replicates poorly in mouse cells 87.…”

Section: Discussion – Challenges and Future Directionsmentioning

confidence: 93%

<p>Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma</p>

Kiyokawa

Wakimoto

2019

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Replication conditional oncolytic human adenovirus has long been considered a promising biological therapeutic to target high-grade gliomas (HGG), a group of essentially lethal primary brain cancer. The last decade has witnessed initiation and some completion of a number of Phase I and II clinical investigations of oncolytic adenovirus for HGG in the US and Europe. Results of these trials in patients are pivotal for not only federal approval but also filling an existing knowledge gap that primarily derives from the stark differences in permissivity to human adenovirus between humans and preclinical mouse models. DNX-2401 (Delta-24-RGD), the current mainstream oncolytic adenovirus with modifications in E1A and the fiber, has been shown to induce impressive objective response and long-term survival (>3 years) in a fraction of patients with recurrent HGG. Responders exhibited initial enlargement of the treated lesions for a few months post treatment, followed by shrinkage and near complete resolution. In accord with preclinical research, post-treatment specimens revealed virus-mediated alteration of the immune tumor microenvironment as evidenced by infiltration of CD8+ T cells and M1-polarized macrophages. These findings are encouraging and together with further information from ongoing studies have a potential to make oncolytic adenovirus a viable option for clinical management of HGG. This review deals with this timely topic; we will describe both preclinical and clinical development of oncolytic adenovirus therapy for HGG, summarize updated knowledge on clinical trials and discuss challenges that the field currently faces.

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“…All adenovirus-based vectors are derived from the human adenovirus serotype 5, which makes these viruses unable to produce progeny in murine cells [ 23 , 24 ]. Nevertheless, human adenoviruses in murine cells can produce the necessary viral proteins by regulating the transcription-translation machinery of infected cells, even though OAds are not able to produce their progeny efficiently [ 25 ]. This was demonstrated by the ability of OAds to direct the expression of the SP/SA/E7/4-1BBL protein in tumor and normal murine cells.…”

Section: Discussionmentioning

confidence: 99%

An Oncolytic Adenovirus Encoding SA-4-1BBL Adjuvant Fused to HPV-16 E7 Antigen Produces a Specific Antitumor Effect in a Cancer Mouse Model

et al. 2021

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Human papillomaviruses (HPVs) are responsible for about 25% of cancer cases worldwide. HPV-16 E7 antigen is a tumor-associated antigen (TAA) commonly expressed in HPV-induced tumors; however, it has low immunogenicity. The interaction of 4-1BBL with its receptor induces pleiotropic effects on innate, adaptive, and regulatory immunity and, if fused to TAAs in DNA vaccines, can improve the antitumor response; however, there is low transfection and antitumor efficiency. Oncolytic virotherapy is promising for antitumor gene therapy as it can be selectively replicated in tumor cells, inducing cell lysis, and furthermore, tumor cell debris can be taken in by immune cells to potentiate antitumor responses. In this study, we expressed the immunomodulatory molecule SA-4-1BBL fused to E7 on an oncolytic adenovirus (OAd) system. In vitro infection of TC-1 tumor cells and NIH-3T3 non-tumor cells with SA/E7/4-1BBL OAd demonstrated that only tumor cells are selectively destroyed. Moreover, protein expression is targeted to the endoplasmic reticulum in both cell lines when a signal peptide (SP) is added. Finally, in an HPV-induced cancer murine model, the therapeutic oncolytic activity of OAd can be detected, and this can be improved when fused to E7 and SP.

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A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

Cited by 14 publications

References 36 publications

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma

<p>Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma</p>

An Oncolytic Adenovirus Encoding SA-4-1BBL Adjuvant Fused to HPV-16 E7 Antigen Produces a Specific Antitumor Effect in a Cancer Mouse Model

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