Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Satu Mustjoki, University of Helsinki
- Second opponent: Professor Bjørn Tore Gjertsen, University of Bergen
- Third member and chair of the evaluation committee: Professor II Guttorm Haraldsen, University of Oslo
Chair of the Defence
Professor II Anne Simonsen, University of Oslo
Principal Supervisor
Professor II Johanna Olweus, University of Oslo
Summary
This thesis is within the fields of cancer immunotherapy and hematology, and focuses on developing new T-cell–based treatments for acute lymphoblastic leukemia (ALL). The research aimed to answer two main questions: how tumor-reactive T-cell receptors (TCRs) can be identified from healthy donors, and whether a leukemia-specific protein called terminal deoxynucleotidyl transferase (TdT) can be safely targeted in ALL.
First, a standardized method was developed to identify rare T cells that recognize cancer-specific targets. Dendritic cells from healthy donors were engineered to present selected tumor antigens to naïve CD8⁺ T cells. Antigen-reactive T cells were then identified and isolated for the subsequent analysis of their TCRs for anti-tumor reactivity. This method allowed efficient discovery of tumor-reactive TCRs.
The second part of the thesis focused on TdT, a protein found in most B- and T-cell ALL cases but absent from mature B and T cells, and blood stem cells. Because the immune system is normally tolerant to TdT, the method was modified to allow discovery of TdT-reactive T cells. By using this approach, two TdT-specific TCRs were identified from healthy donor repertoires and introduced into human T cells. Laboratory experiments showed that these engineered T cells efficiently killed TdT-positive leukemia cells while sparing healthy stem cells and their mature counterparts. Additional safety studies found no clinically relevant off-target activity. In mouse models, the treatment showed strong anti-leukemic effects without significantly affecting normal hematopoiesis.
Overall, this thesis establishes a robust platform for identifying therapeutic TCRs and demonstrates that TdT is a promising target for TCR-based immunotherapy in ALL. The findings directly supported the initiation of a first-in-human clinical trial (InsighT-1) for patients with relapsed or refractory lymphoblastic malignancies.
Additional information
Contact the research support staff.