{"id":{"repo_id":"tu-berlin","oai_identifier":"oai:depositonce.tu-berlin.de:11303/27307"},"canonical_url":"https://search.dev.ndltd.org/etd/tu-berlin/oai:depositonce.tu-berlin.de:11303/27307","repository":{"repo_id":"tu-berlin","name":"Technische Universität Berlin","base_url":"https://api-depositonce.tu-berlin.de/server/oai/request"},"display":{"title":"T-cell-directed bioorthogonal catalysis for localised prodrug activation in cancer therapy","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Fiedler, Linus Andreas"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Rappsilber, Juri"],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026","date_published":"2026","updated_at":"2026-07-27T21:28:29Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":["https://creativecommons.org/licenses/by-nc/4.0/"],"identifier_entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://doi.org/10.14279/depositonce-26143"],"render_values":[{"text":"https://doi.org/10.14279/depositonce-26143","href":"https://doi.org/10.14279/depositonce-26143","code":true}]}]},"links":{"outbound_url":"https://depositonce.tu-berlin.de/handle/11303/27307","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Rappsilber, Juri"]},{"key":"dc:creator","label":"Author","values":["Fiedler, Linus Andreas"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-07-15T07:10:21Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-07-15T07:10:21Z"]},{"key":"dc:date.issued","label":"Date","values":["2026"]},{"key":"dc:type","label":"Dc Type","values":["Doctoral Thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights.uri","label":"Rights URI","values":["https://creativecommons.org/licenses/by-nc/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://depositonce.tu-berlin.de/handle/11303/27307","https://doi.org/10.14279/depositonce-26143"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.","Krebs zählt zu den schwerwiegendsten Erkrankungen weltweit und ist für nahezu 10 Millionen Todesfälle pro Jahr verantwortlich. Obwohl moderne Krebstherapien die Behandlungsergebnisse bei vielen Tumorarten verbessert haben, stellen solide Tumoren, Metastasen und Krankheitsrezidive nach wie vor erhebliche Herausforderungen dar. Die Wirksamkeit bestehender Therapien ist häufig durch Tumorheterogenität, Immunresistenz-mechanismen, sowie dosislimitierende Nebenwirkungen eingeschränkt. Immuntherapien eröffnen neue Möglichkeiten für gezielte Behandlungsansätze, welche besonders die Spezifität der Therapien erhöhen, jedoch sind Strategien zur selektiven Aktivierung von Chemotherapeutika in Tumornähe bislang nur begrenzt verfügbar. Daher besteht weiterhin ein Bedarf an Ansätzen, die die therapeutische Wirksamkeit verbessern und gleichzeitig systemische Nebenwirkungen minimieren. Diese Doktorarbeit untersucht den Einsatz bioorthogonaler Katalyse in Kombination mit gentechnisch modifizierten T-Zellen zur lokalen Aktivierung von Krebsmedikamenten. Diese Katalyse-verstärkte T-Zell-Therapie stellt eine neuartige Plattformtechnologie dar, bei der T-Zellen so modifiziert werden, dass sie nach Erkennung von Tumorzellen ein Oberflächenprotein exprimieren. Dieses fungiert als induzierbares Antigen, um Antikörper-Katalysator-Konjugate zu rekrutieren, die die Aktivierung von Wirkstoffen in unmittelbarer Nähe des Tumors ermöglichen. Zur Demonstration dieses Konzepts wurde ein bioorthogonaler Katalysator mit einem Antikörper kombiniert und dessen katalytische Aktivität nachgewiesen. Zudem wurde eine von T-Zellen abgeleitete Zelllinie gentechnisch so verändert, dass sie induzierbar ein Oberflächenantigen exprimiert, und entsprechend validiert. Darüber hinaus konnte die gezielte Rekrutierung des Antikörper-Katalysators an aktivierte T-Zellen gezeigt werden. Funktionelle Untersuchungen zeigen, dass dieses System die katalytische Aktivierung von Pro-Medikamenten in vitro ermöglicht und zu einer erhöhten anti-tumoralen Wirkung in Zielzellen führt. Zusammenfassend liefern diese Ergebnisse einen Proof-of-Concept für eine potenzielle, vielseitige Plattformtherapie, die zentrale Limitationen bestehender Behandlungsansätze adressieren und eine verbesserte Wirksamkeit bei gleichzeitig reduzierten Nebenwirkungen ermöglichen könnte."]},{"key":"dc:title","label":"Title","values":["T-cell-directed bioorthogonal catalysis for localised prodrug activation in cancer therapy"]}]}],"canonical_facts":{"dc:contributor.advisor":["Rappsilber, Juri"],"dc:creator":["Fiedler, Linus Andreas"],"dc:date.accessioned":["2026-07-15T07:10:21Z"],"dc:date.available":["2026-07-15T07:10:21Z"],"dc:date.issued":["2026"],"dc:description.abstract":["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.","Krebs zählt zu den schwerwiegendsten Erkrankungen weltweit und ist für nahezu 10 Millionen Todesfälle pro Jahr verantwortlich. Obwohl moderne Krebstherapien die Behandlungsergebnisse bei vielen Tumorarten verbessert haben, stellen solide Tumoren, Metastasen und Krankheitsrezidive nach wie vor erhebliche Herausforderungen dar. Die Wirksamkeit bestehender Therapien ist häufig durch Tumorheterogenität, Immunresistenz-mechanismen, sowie dosislimitierende Nebenwirkungen eingeschränkt. Immuntherapien eröffnen neue Möglichkeiten für gezielte Behandlungsansätze, welche besonders die Spezifität der Therapien erhöhen, jedoch sind Strategien zur selektiven Aktivierung von Chemotherapeutika in Tumornähe bislang nur begrenzt verfügbar. Daher besteht weiterhin ein Bedarf an Ansätzen, die die therapeutische Wirksamkeit verbessern und gleichzeitig systemische Nebenwirkungen minimieren. Diese Doktorarbeit untersucht den Einsatz bioorthogonaler Katalyse in Kombination mit gentechnisch modifizierten T-Zellen zur lokalen Aktivierung von Krebsmedikamenten. Diese Katalyse-verstärkte T-Zell-Therapie stellt eine neuartige Plattformtechnologie dar, bei der T-Zellen so modifiziert werden, dass sie nach Erkennung von Tumorzellen ein Oberflächenprotein exprimieren. Dieses fungiert als induzierbares Antigen, um Antikörper-Katalysator-Konjugate zu rekrutieren, die die Aktivierung von Wirkstoffen in unmittelbarer Nähe des Tumors ermöglichen. Zur Demonstration dieses Konzepts wurde ein bioorthogonaler Katalysator mit einem Antikörper kombiniert und dessen katalytische Aktivität nachgewiesen. Zudem wurde eine von T-Zellen abgeleitete Zelllinie gentechnisch so verändert, dass sie induzierbar ein Oberflächenantigen exprimiert, und entsprechend validiert. Darüber hinaus konnte die gezielte Rekrutierung des Antikörper-Katalysators an aktivierte T-Zellen gezeigt werden. Funktionelle Untersuchungen zeigen, dass dieses System die katalytische Aktivierung von Pro-Medikamenten in vitro ermöglicht und zu einer erhöhten anti-tumoralen Wirkung in Zielzellen führt. Zusammenfassend liefern diese Ergebnisse einen Proof-of-Concept für eine potenzielle, vielseitige Plattformtherapie, die zentrale Limitationen bestehender Behandlungsansätze adressieren und eine verbesserte Wirksamkeit bei gleichzeitig reduzierten Nebenwirkungen ermöglichen könnte."],"dc:identifier.uri":["https://depositonce.tu-berlin.de/handle/11303/27307","https://doi.org/10.14279/depositonce-26143"],"dc:language.iso":["en"],"dc:rights.uri":["https://creativecommons.org/licenses/by-nc/4.0/"],"dc:title":["T-cell-directed bioorthogonal catalysis for localised prodrug activation in cancer therapy"],"dc:type":["Doctoral Thesis"]},"updated_at":"2026-07-27T21:28:29Z"}