T-cell-directed bioorthogonal catalysis for localised prodrug activation in cancer therapy
Cancer is one of the most severe diseases worldwide, accounting for almost 10 million deaths a year. While modern cancer treatments have improved patient outcomes in many cancer types, solid cancers, metastases and relapse still pose immense challenges. Cancer treatments remain limited by poor efficacy due to tumour heterogeneity, immune evasion and acquired resistance or dose-limiting toxicities. Immunotherapy opened up new possibilities of targeted treatments to increase specificity, but strategies that enable selective activation of therapeutics at the tumour site remain scarce. As a result, there is a continued need for strategies that improve therapeutic efficacy, while minimising systemic toxicities. This thesis investigates the use of bioorthogonal catalysis in combination with engineered T-cells to locally activate anticancer drugs. Catalysis-augmented T-cell therapy is a newly developed platform technology, in which T-cells, engineered to express a surface protein upon cancer recognition, are used as an inducible antigen to recruit antibody-catalysts that facilitate drug activation in tumour proximity. To demonstrate this concept, we integrated a bioorthogonal catalyst with a single-domain antibody and demonstrated catalytic properties. A T-cell derived cell line was engineered and validated to inducibly express a surface antigen. Further recruitment of the antibody-catalyst to the activated T-cells was demonstrated. Functional studies showed that this system enabled catalytic activation of anticancer prodrugs in vitro, resulting in enhanced antitumour efficacy in target cells. These findings demonstrate a proof-of-concept to a potential strategy for a versatile platform therapy that could addressed key limitations of current therapies to increase efficacy with reduced off-target effects.
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