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BIOTEK2021-Bioteknologi for verdiskaping

Optimalisering: Treating lymphoma with novel immunotherapy

Alternative title: Behandling av lymfekreft med ny immunterapi

Awarded: NOK 8.0 mill.

A substantial proportion of patients suffering from B-cell malignancies will not be cured by standard therapies available today. Immunotherapy has in recent years emerged as a new pillar in cancer treatment. One of the most successful approaches involves blood transfusion to the patient of own immune cells that are genetically modified to express artificial immune receptors named CARs ?chimeric antigen receptors? that target cancer cells. Although CAR19 therapy was recently approved by the medicinal authorities in USA (FDA), the majority of patients are still not cured. We have developed an alternative immune receptor for recognition of a protein that is uniquely found in lymphocytes, which is the cell type giving rise to acute leukemia. This immune receptor is a so-called T-cell receptor (TCR). A TCR can recognize lower levels of target than a CAR, and can also recognize targets on the inside of the cancer cell. This provides access to many more therapeutic targets, as >80% of proteins are inside the cell. It could moreover prevent tumor escape, and increase efficacy of therapy. TCR signalling is also more physiological, and this might possibly lead to a lesser degree of the so-called cytokine-release syndrome, representing the most serious side effect of CAR therapy. We have now completed the preclinical development of a TCR targeting B cell malignancies, partly funded by the BIOTEK2021 project. We have demonstrated that our TCR is very efficacious in three different mouse models of leukemia, and in addition shown that it does not harm normal hematopoiesis in a novel mouse model of safety. The results have been accepted for publication in Nature Biotechnology, one of the most prestigious journals in the world. Key Opinion Leader (KOL) analysis of unmet medical need has been completed. We have moreover partly financed production of clinical grade virus for gene transfer to patient immune cells in a clinical trial, through the project. The production started primo 2021 and will be finished medio 2022. Development of a protocol for production of genetically modified T cells is on-going in collaboration with the ACT center at Oslo University Hospital. This center aims to be a national center for production of genetically engineered cells for use in patient treatment, and was established in May 2021 thanks to a generous donation from a private consortium of donors, including the Norwegian Cancer Society. We established the commercialization strategy and development plan for the product. The patent that protects our method for generation of TCRs was granted August 2018. A patent application protecting the TCR sequence was submitted.

The project has contributed to the acquisition of competence in GMP manufacturing protocol development for genetically modified T cells, lacking in Norway. The competence forms basis for the service that will be offered in the new national ACT center, which opened at Oslo University Hospital in 2021 thanks to a private donation. Such a service is essential to translate novel concepts for gene therapy into clinical trials in Norway. The ACT center will also benefit from our experience with GMP production of clinical grade retrovirus (construct design and choice of envelope) through a trusted commercial European CMO. The project has finally facilitated the early development of infrastucture to facilitate clinical trials in gene therapy in Norway, which is currently lacking and essential to bring this field forward.

A substantial proportion of patients who are diagnosed with B-cell malignancies will not be cured by standard therapies available today. Immunotherapy has in recent years emerged as a new pillar in cancer treatment. One of the most successful approaches involves treatment of B-cell leukemia and lymphoma with T cells that are genetically modified to express artificial immune receptors named CARs – chimeric antigen receptors – that target cancer cells. Although CAR19 T cell therapy was recently approved by FDA, the majority of patients are still not cured. We have developed an alternative immune receptor for recognition of a B-cell specific protein – a so-called T-cell receptor (TCR). TCRs have the advantage that they can recognize lower levels of target than CARs, and that they also can recognize intracellular targets. This could prevent tumor escape and increase efficacy of therapy. TCR signalling is more physiological and this might lead to a lesser degree of cytokine-release syndrome, representing the most serious side effect of CAR therapy. The goal of the project is to complete the preclinical development of a TCR targeting B-cell malignancies and integrate an industrial partner, such that at the end of the project we have secured regulatory approval, established the commercialization strategy and development plan for the product, and secured funding for an industry-partnered clinical trial. Key challenges are; establish a process for GMP virus production; analysis of unmet medical need / competitor landscape; file a patent protecting the TCR; refinement of commercialization strategy and integrating an industrial partner; and finalizing design and obtaining regulatory approval and funding for the first-in-man clinical trial.

Funding scheme:

BIOTEK2021-Bioteknologi for verdiskaping