A novel single-chain antibody redirects adenovirus to IL13Rα2-expressing brain tumors

Kim, Julius W.; Young, Jacob S; Solomaha, Elena; Kanojia, Deepak; Lesniak, Maciej S.; Balyasnikova, Irina V.

doi:10.1038/srep18133

Cited by 15 publications

(18 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RNA sequencing analysis detected CDH2 (encoding N-Cadherin) expressed at significantly higher levels in iSOX11 cells grown in 2D and as spheroids, whilst other EMT markers, including CDH1 (encoding E-cadherin) and VIM were not significantly changed compared to control cells ( Supplementary file 1 ). Other notable downstream targets of SOX11 included MEX3A , which encodes an RNA-binding protein, that marks slowly proliferating multipotent stem cells in mouse intestine ( Barriga et al, 2017 ) and totipotent cells in C. elegans ( Pereira et al, 2013 ); MMP11, ST6GALNAC5, and TUBB3, which are highly expressed in breast cancers that metastasize to brain ( Bos et al, 2009 ; Kim et al, 2015 ; Lee et al, 2016 ). We confirmed that a number of putative SOX11 targets of interest ( Figure 3C and Figure 3—figure supplement 1 , Supplementary file 2 ), including MEX3A and TUBB3 were upregulated in iSOX11 cells when measured by qPCR ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells

Oliemuller

Newman

Tsang

et al. 2020

eLife

View full text Add to dashboard Cite

SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.

show abstract

Section: Resultsmentioning

confidence: 99%

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells

Oliemuller

Newman

Tsang

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…7,8 To selectively target IL13Rα2, we previously had generated a monoclonal antibody (MAb) and scFv that specifically recognized IL13Rα2 (clone 47; scFv47) with a high affinity and no cross-reactivity to IL13Rα1. 23,24 Here, we report the development of IL13Rα2-specific CARs with a scFv47-based antigenbinding domain (IL13Rα2-CARs). We show that IL13Rα2-CARs require a short spacer region for optimal functionality, and that IL13Rα2-CAR T cells are able to recognize and kill only IL13Rα2positive and not IL13Rα1-positive target cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma

et al. 2016

View full text Add to dashboard Cite

Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies.

show abstract

“…For intracranial glioma xenograft implantation, GL261-OVA (4 × 10 5 cells) murine glioma cells were implanted via cranial guide screws as described previously. 36 Mice were cared for in accordance with a study-specific animal protocol approved by Northwestern University Institutional Animal Care and Use Committee. Five days after tumor implantation, mice were randomly separated into three groups and were then injected with either 2.5 μL PBS or 10 9 VPs.…”

Section: Methodsmentioning

confidence: 99%

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

Kim

Miska

Young

et al. 2017

Molecular Therapy - Oncolytics

Self Cite

View full text Add to dashboard Cite

Oncolytic virotherapy is a treatment approach with increasing clinical relevance, as indicated by the marked survival benefit seen in animal models and its current exploration in human patients with cancer. The use of an adenovirus vector for this therapeutic modality is common, has significant clinical benefit in animals, and its efficacy has recently been linked to an anti-tumor immune response that occurs following tumor antigen presentation. Here, we analyzed the adaptive immune system’s response following viral infection by comparing replication-incompetent and replication-competent adenoviral vectors. Our findings suggest that cell death caused by replication-competent adenoviral vectors is required to induce a significant anti-tumor immune response and survival benefits in immunocompetent mice bearing intracranial glioma. We observed significant changes in the repertoire of immune cells in the brain and draining lymph nodes and significant recruitment of CD103+ dendritic cells (DCs) in response to oncolytic adenoviral therapy, suggesting the active role of the immune system in anti-tumor response. Our data suggest that the response to oncolytic virotherapy is accompanied by local and systemic immune responses and should be taken in consideration in the future design of the clinical studies evaluating oncolytic virotherapy in patients with glioblastoma multiforme (GBM).

show abstract

A novel single-chain antibody redirects adenovirus to IL13Rα2-expressing brain tumors

Cited by 15 publications

References 45 publications

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells

SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma

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

Contact Info

Product

Resources

About