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BIOTEK2021-Bioteknologi for verdiskaping

Novel technology for identification of T cell targets and therapeutic T cell receptors for use in cancer immunotherapy

Alternative title: Ny teknologi for identifisering av målpeptider for T-celler og terapeutiske T-cellereseptorer til anvendelse innen immunterapi mot kreft

Awarded: NOK 5.0 mill.

An emerging promising therapeutic concept in cancer is based on immune cells called T cells. T cells can selectively kill certain cell types without damaging neighbouring cells, as their T cell receptor (TCR) can bind protein fragments present only in the target cell. The TCR can thus be likened by a targeting missile. Thanks to recent technological advances the genetic code for the TCR can be isolated and transferred to other T cells. T cells can be harvested from the blood of a cancer patient and equipped with a TCR directed to the cancer. The gene-modified T cells are then injected back into the patient. Clinical studies using such TCR-modified T cells have shown great efficacy in the treatment of malignant melanoma and synovial sarcoma. If the target i s common for all patients with a particular cancer type and tissue type, the same TCR can be used for this patient group, making the treatment widely applicable. However, this therapeutic strategy is currently hampered by difficulties in 1) identifying peptide targets for the TCRs that are selectively expressed in a particular cancer type and capable of evoking an immune reaction, and 2) identifying therapeutically efficient TCRs that show strong binding to the targets. Using novel, patent-protected technology we will solve both of these problems. The first goal for the current project is a validated novel assay for high-throughput identification of TCR peptide targets and efficient TCRs. Furthermore, we will use this technology to select a TCR reactive with target peptides from a novel and promising target protein in myeloid leukemia, identified by the group. The second goal is to demonstrate therapeutic safety and efficacy for the selected TCR, preparing for a follow-up proof-of-concept study. In the project we have optimized and validated the technology for high-throughput T-cell target discovery. Furthermore, we identified a large number of TCRs that react to target proteins in myeloid leukemia. The clones have been characterized for specificity and sensitivity using our new live-cell bar coding assay. We have show that these TCRs are specific for cells expressing the target protein, including patient-derived leukemia cells, and that they do not recognize cells lacking the target protein. We will next validate these TCRs in preparation for potential clinical use. Results achieved during the project were instrumental to get an agreement with one of the leading pharmaceutical companies in the area of immunogene therapy, which was recently signed.

An emerging promising therapeutic concept in cancer is based on immune cells called T cells. T cells can selectively kill certain cell types without damaging neighboring cells, as their T cell receptor (TCR) can bind protein fragments (peptides/epitopes) present only in the target cell. The TCR can thus be likened by a targeting missile. Thanks to recent technological advances the genetic code for the TCR can be isolated and transferred to other T cells. T cells can be harvested from the blood of a cancer patient and equipped with a TCR directed to the cancer. The gene-modified T cells are then injected back into the patient. Clinical studies using such TCR-modified T cells have shown great efficacy in the treatment of malignant melanoma and synovial sarc oma. If the target is common for all patients with a particular cancer type and tissue type, the same TCR can be used for this patient group, making the treatment widely applicable. However, this therapeutic strategy is currently hampered by difficulties in 1) identifying peptide targets (epitopes) for the TCRs that are selectively expressed in a particular cancer type and capable of evoking an immune reaction, and 2) identifying therapeutically efficient TCRs that show strong binding to the targets. Usin g novel, patent-protected technology we will solve both of these problems. The first goal for the current project is a validated novel assay for high-throughput identification of TCR peptide targets and efficient TCRs, with the aim of licencing of the tec hnology to a commercial partner in the epitope discovery market. Furthermore, we will use this technology to select a TCR reactive with target peptides from a novel and promising target protein in myeloid leukemia, identified by the group. The second goal is to demonstrate therapeutic efficacy for the selected TCR in a mouse model of myeloid leukemia, preparing for a follow-up proof-of-concept study within the FORNY programme.

Funding scheme:

BIOTEK2021-Bioteknologi for verdiskaping