Evidence map›Paper›PMID 27650544›Full record

ArticleOncotarget2016

Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker.

Joerg U Schmohl, Martin Felices, Deborah Todhunter, Elizabeth Taras, Jeffrey S Miller, Daniel A Vallera

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.

0numbers the graph read from it
0cells of the map it votes in
44citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

44 citing papers in PubMed, 63 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

6 authors at 3 institutions in 2 countries.

Joerg U SchmohlUniversity of Minnesota, Masonic Cancer Center, Section of Molecular Cancer Therapeutics, Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.
Martin FelicesUniversity of Minnesota, Department of Medicine, Division of Hematology, Oncology, and Transplantation, Minneapolis, MN, USA.
Deborah TodhunterUniversity of Minnesota, Masonic Cancer Center, Section of Molecular Cancer Therapeutics, Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.
Elizabeth TarasUniversity of Minnesota, Masonic Cancer Center, Section of Molecular Cancer Therapeutics, Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.
Jeffrey S MillerUniversity of Minnesota, Department of Medicine, Division of Hematology, Oncology, and Transplantation, Minneapolis, MN, USA.
Daniel A ValleraUniversity of Minnesota, Masonic Cancer Center, Section of Molecular Cancer Therapeutics, Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.
University of Minnesota Medical Center · USUniversity of Minnesota · USUniversity of Tübingen · DE

Funding

Trial Design and Biostatistical Support CoreP01CA065493 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Mark J Osborn · 1995 to 2026
$48.2M
Therapeutic Potential of Adaptive NK Cells in Cancer and TransplantationP01CA111412 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI MILLER, JEFFREY S. · 2005 to 2025
$38.2M
Viral priming and targeting NK cells against solid tumor malignanciesR35CA197292 · NCI · UNIVERSITY OF MINNESOTA · PI MILLER, JEFFREY S. · 2015 to 2021
$6.2M
GVL TO REDUCE AML RELAPSE AFTER MURINE ALLOGENEIC BMTR01CA072669 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI BLAZAR, BRUCE R · 1997 to 2017
$4.9M
IMMUNOTOXINS IN HUMAN BONE MARROW TRANSPLANTATIONR01CA036725 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI VALLERA, DANIEL A · 1985 to 2015
$3.3M
NCI NIH HHS P01 CA065493NCI NIH HHS P01 CA111412NCI NIH HHS R01 CA036725NCI NIH HHS R01 CA072669NCI NIH HHS R35 CA197292
6 · The paper itself

Abstract

backgroundThe design of a highly effective anti-cancer immune-engager would include targeting of highly drug refractory cancer stem cells (CSC). The design would promote effective antibody-dependent cell-mediated cytotoxicity (ADCC) and simultaneously promote costimulation to expand and self-sustain the effector NK cell population. Based on our bispecific NK cell engager platform we constructed a tetraspecific killer engager (TetraKE) comprising single-chain variable fragments (scFvs) binding FcγRIII (CD16) on NK cells, EpCAM on carcinoma cells and CD133 on cancer stem cells in order to promote ADCC. Furthermore, an Interleukin (IL)-15-crosslinker enhanced NK cell related proliferation resulting in a highly active drug termed 1615EpCAM133.

resultsProliferation assays showed TetraKE promoted proliferation and enhanced NK cell survival. Drug-target binding, NK cell related degranulation, and IFN-γ production was specific for both tumor related antigens in EpCAM and CD133 bearing cancer cell lines. The TetraKE showed higher killing activity and superior dose dependent degranulation. Cytokine profiling showed a moderately enhanced IFN-γ production, enhanced GM-CSF production, but no evidence of induction of excessive cytokine release.

methodsAssembly and synthesis of hybrid genes encoding the TetraKE were performed using DNA shuffling and ligation. The TetraKE was tested for efficacy, specificity, proliferation, survival, and cytokine production using carcinoma cell lines and functional assays measuring NK cell activity.

conclusion1615EpCAM133 combines improved induction of ADCC with enhanced proliferation, limited cytokine response, and prolonged survival and proliferation of NK cells. By linking scFv-related targeting of carcinoma and CSCs with a sustaining IL-15 signal, our new construct shows great promise to target cancer and CSCs.

Indexed as

Antibody-Dependent Cell CytotoxicityAC133 AntigenBiomarkersCell DegranulationCell Line, TumorCytokinesEpithelial Cell Adhesion MoleculeHumansInterferon-gammaInterleukin-15Killer Cells, NaturalNeoplastic Stem CellsProtein BindingRecombinant Fusion ProteinsSingle-Chain AntibodiesAC133 AntigenBiomarkersCytokinesEpithelial Cell Adhesion MoleculeInterferon-gammaInterleukin-15Recombinant Fusion ProteinsSingle-Chain Antibodiescancer stem cellscarcinomaCD133EpCAMTetraKE

Identifiers

PMID27650544
PMCPMC5342017
OpenAlexW2522051371

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.