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BIOTEK2021-Bioteknologi for verdiskaping

Personalized Immunotherapy: Re-targeting T-cells against cancer

Alternative title: Adoptive T-cell therapy in cancer

Awarded: NOK 9.2 mill.

Adoptive T-cell therapy (ACT) is a type of immunotherapy where tumour-reactive T cells are expanded in the laboratory and then infused back into the patient. To increase the reactivity against the tumour, patient T cells can be modified to express a receptor which can bind to tumour cells and then these modified T cells are re-infused. The tumour-specific receptor can either be an artificial receptor recognizing a protein on the surface of the tumour cells (chimeric antigen receptor, CAR) or a T-cell receptor (TCR) which is isolated from cells in a cancer patient who had a good immune response and clinical response against their cancer. In other words, the anti-cancer reactivity of a good responder is transferred to other patients. The method is well tested in preclinical models and several clinical trials performed in other institutions have shown great potential in the treatment of some hard-to-treat cancers. We have cloned a panel of such TCRs which have been identified in patients that have performed well clinically after having received immunotherapy (cancer vaccines). When these TCRs were transferred to normal T cells we showed that the cells became capable of killing tumour cells. Additionally, we perform safety testing of our receptors to make sure they do not have reactivity against other normal cells in the body such as stem cells from bone marrow. This is particularly important for telomerase which is the main antigen that we target in this project. In a different research programme at the Research Council we have recently tested the first T-cell receptor clinically in patients with colon cancer targeting a mutated protein. We are currently finalizing the clinical protocol for testing the first receptor against telomerase in lung cancer and looking for funding to support the production for the clinical cellular product and the treatment.

We will develop cancer therapy by reprogramming immune cells to target the universal tumour antigen telomerase. Early clinical trials have demonstrated that reprogrammed T cells may effectively eradicate cancer even in patients with disseminated disease. We aim at extending this therapeutic principle to most cancer forms by targeting the universal tumour antigen telomerase. At OUS-Radiumhospitalet we have conducted a series of clinical trials with telomerase-based cancer vaccines demonstrating prolonged survival for patients that developed an immune response. However, only a minority of patients appear able to respond clinically after vaccination partly due to the cancer being too advanced and their immune system suppressed by the tumour. We bypass the tumour's success in escaping the host immune system by equipping the patient's T cells with optimized tumour-targeting TCRs. We have isolated a selection of telomerase-specific TCRs from long term survivors after cancer vaccination. These TCRs have circulated for up to 10 years in the patients, without causing side effects and are associated with clinical responses. In laboratory studies, the TCRs can effectively reprogram otherwise non-responsive T cells into tumour-targeting missiles. We have thus developed tumour-reactive TCRs that can potentially be exploited to fight cancer in a large proportion of patients. To advance this project we need to finalize pre-clinical development and demonstrate proof-of-principle in early clinical trials: 1) Finalize pre-clinical studies of efficacy and safety equipping T cells with telomerase-specific TCRs and 2) Initiate clinical studies in cancer patients where the TCRs are transferred to their T cells and given back to the patient. If successful, this project will demonstrate clinical utility of the TCRs targeting telomerase in cancer therapy. The long term aim is to establish a cancer therapeutics start-up based in Norway or license out these TCRs to an existing company.

Publications from Cristin

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BIOTEK2021-Bioteknologi for verdiskaping