Investigating the recognition of a novel ligand by gamma-delta T cells and the translation of this interaction into molecules for future cancer immunotherapy

Projektinformationen

gdTCR-Ligand

ID Finanzhilfevereinbarung: 749010

DOI

10.3030/749010

Projekt abgeschlossen

EK-Unterschriftsdatum 10 Mai 2017

Startdatum 1 Juni 2017

Enddatum 31 Mai 2019

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 177 598,80

EU-Beitrag

€ 177 598,80

Koordiniert durch

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands

Periodic Reporting for period 1 - gdTCR-Ligand (Investigating the recognition of a novel ligand by gamma-delta T cells and the translation of this interaction into molecules for future cancer immunotherapy)

Berichtszeitraum: 2017-06-01 bis 2019-05-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Gamma-delta (gd-)T cells are a fast acting subset of T cells that recognize a wide variety of ligands. In contrast to alpha-beta T cells they are not restricted to classical peptide-MHC (pMHC) antigens and the consensus in the field is that they do not interact with pMHC at all. Our preliminary data on a gd-T cell clone shows selective recognition of HLA-A*24:02 positive tumour cells in a pMHC restricted manner, whereas healthy HLA-A*24:02 cells are not recognized.

The objectives of this action are; 1) elucidating the molecular mechanism of the gd-T cell receptor (TCR) recognizing pMHC on cancer cells and 2) generating soluble gamma-delta TCR based molecules as therapeutic agents to target cancer cells.

Understanding the molecular mechanism of the interaction of gd-TCR with its ligand on the tumor cell surface might open new therapeutic opportunities that haven't been explored thus far. One of these novel opportunities might be the soluble gamma-delta TCR based molecules for immune therapy against cancer.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The work on objective 1, the molecular mechanism of the gdTCR ligand interaction, two unforseen conclusions:
- the gdTCR of interest does not require a specific peptide antigen to recognize HLA-A*24:02 on the surface of tumour cells, this is in contrast to alpha-beta TCRs, which are highly peptide specific.
- the gdTCR senses membrane mobility of HLA-A*24:02 which differs between healthy cells and malignant cells

These results are included in a manuscript, which is currently in an advanced state of the peer review process.


The work on objective 2, did not lead to any promising soluble therapeutic formats for the intended gdTCR clone. However, work on other gdTCR clones showed more promising results, these agents potently target a diverse range of tumor cell lines as well as primary acute myeloid leukemic blasts.
The results on the latter ones were used for a patent application.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

During the project we explored several options to improve and create gdTCR based immunotherapies. One of these concepts entail soluble gd-TCR therapeutic agents, these could have the potential to become an off-the-shelf therapeutic agents for certain malignancies, and
will overcome many biological limitations and economic barriers associated with gdT cell and TEG based therapies. Currently, we are looking, together with Utrecht Holdings, for the best way to further develop this concept.

gdTCR-ligand