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)
Période du rapport: 2017-06-01 au 2019-05-31
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.
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.
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.
- 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.
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.
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.