Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects

Water, Jeroen A. J. M. van de; Bagcı-Önder, Tugba; Agarwal, Aneesh; Wakimoto, Hiroaki; Roovers, Rob C.; Zhu, Yu; Kasmieh, Randa; Bhere, Deepak; Henegouwen, Paul M.P. van Bergen en; Shah, Khalid

doi:10.1073/pnas.1202832109

Cited by 76 publications

(79 citation statements)

References 32 publications

(39 reference statements)

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“…by interacting with the binding of ligands to the extracellular domain of the EGFR were established. [13][14][15][16][17] Unfortunately, these therapeutic approaches are frequently compromised by the development of refractory disease, e.g., by increased signaling via a non-targeted member of the ErbB network, receptor transactivation or increased production/release of ligands. [18][19][20][21][22][23][24][25][26] One idea to overcome such a therapeutic resistance is to go for a direct cytolytic approach 27 e.g., T or NK cells genetically modified with chimeric antigen receptors (CARs) directed against EGFR that can destroy EGFR-overexpressing tumor cells.…”

Section: Introductionmentioning

confidence: 99%

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

et al. 2017

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Recent treatments of leukemias with chimeric antigen receptor (CAR) expressing T cells underline their impressive therapeutic potential. However, once adoptively transferred into patients, there is little scope left to shut them down after elimination of tumor cells or in case adverse side effects occur. This becomes of special relevance if they are directed against commonly expressed tumor associated antigens (TAAs) such as receptors of the ErbB family. To overcome this limitation, we recently established a modular CAR platform technology termed UniCAR. UniCARs are not directed against TAAs but instead against a unique peptide epitope on engineered recombinant targeting modules (TMs), which guide them to the target. In the absence of a TM UniCAR T cells are inactive. Thus an interruption of any UniCAR activity requires an elimination of unbound TM and the TM complexed with UniCAR T cells. Elimination of the latter one requires a disassembly of the UniCAR-TM complexes. Here, we describe a first nanobody (nb)-based TM directed against EGFR. The novel TM efficiently retargets UniCAR T cells to EGFR positive tumors and mediates highly efficient target-specific and target-dependent tumor cell lysis both in vitro and in vivo. After radiolabeling of the novel TM with 64 Cu and 68 Ga, we analyzed its biodistribution and clearance as well as the stability of the UniCAR-TM complexes. As expected unbound TM is rapidly eliminated while the elimination of the TM complexed with UniCAR T cells is delayed. Nonetheless, we show that UniCAR-TM complexes dissociate in vitro and in vivo in a concentration-dependent manner in line with the concept of a repeated stop and go retargeting of tumor cells via the UniCAR technology.

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Section: Introductionmentioning

confidence: 99%

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

et al. 2017

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“…Xenografted mice survived for 51 days upon treatment with control NSC-ENb2 and 80% of mice survived for 80 days after treatment with NSC-ENb2-TRAIL. These findings indicated that tumoritropic NSC-releasing ENb2 inhibited growth of glioblastoma and effectiveness of ENb2-based therapy was markedly improved by NSC-releasing ENb2-TRAIL [28].…”

Section: Proliferative and Antiproliferative Pathways And Their Rolesmentioning

confidence: 65%

Critical Molecular and Genetic Markers in Primary Brain Tumors with Their Clinical Importance

Yaylım¹,

Azam²,

Farooqı³

et al. 2016

Neurooncology - Newer Developments

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Classification of primary brain tumors is based mainly on histopathological characteristics. Due to the peculiarity of the central nervous system (CNS), the location of the tumor is also used in the naming of the CNS tumors. These features, histopathology, and location determine the main prognostic factors in these tumors. Updated molecular and genetic findings in the last two decades accumulated vast amount of knowledge about the biological behavior, response to the treatment, and consequently the prognosis of CNS tumors. After the clinical use of these data, a recent classification is proposed by the International Society of Neuropathology named as "integrated diagnosis."This classification considers the histopathological classification, World Health Organization (WHO) grade along with the molecular information. The emerging molecular-genetic data about the CNS tumors will allow the translational researchers to deliberately understand the oncogenic mechanisms involved in the evolution of these tumors and judge the optional treatment strategies.Evaluating the check points of cell cycle and apoptosis provides valuable information about the tumor biology (tumorigenesis). These mechanisms (pathways) also play an exclusive role in CNS tumors. Knowledge concerning the gene repressors and gene activators or some epigenetic changes in proliferative and antiproliferative pathways that regarded gliomas may yield new individualized treatment options.In this chapter, we will review the basic and translational research molecular-genetic data of gliomas with special interest on proliferative and antiproliferative pathways. Further emerging treatment options and treatment responses in gliomas will be © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.critically evaluated with regard to their histopathology, anatomical location, and molecular-genetic fingerprints.

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“…For example, NSCs expressing variants of EGFR-specific nanobodies reduced glioma growth and invasiveness [14]. NSCs secreting an anti-HER2 antibody inhibited breast cancer growth in vitro and although an anti-tumor effect wasn't shown, migrated successfully to in vivo to breast cancer xenografts [15].…”

Section: Neural Stem Cellsmentioning

confidence: 99%

Cells As Delivery Vehicles for Cancer Therapeutics

Basel

Shrestha

Bossmann

et al. 2014

Therapeutic Delivery

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Cell-based therapeutics have advanced significantly over the past decade and are poised to become a major pillar of modern medicine. Three cell types in particular have been studied in detail for their ability to home to tumors and to deliver a variety of different payloads. Neural stem cells, mesenchymal stem cells and monocytes have each been shown to have great potential as future delivery systems for cancer therapy. A variety of other cell types have also been studied. These results demonstrate that the field of cell-based therapeutics will only continue to grow.

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Therapeutic stem cells expressing variants of EGFR-specific nanobodies have antitumor effects

Cited by 76 publications

References 32 publications

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

Critical Molecular and Genetic Markers in Primary Brain Tumors with Their Clinical Importance

Cells As Delivery Vehicles for Cancer Therapeutics

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