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.
Mres Eirini Giannakopoulou at Institute of Clinical Medicine will be defending the thesis “Unleashing the power of T cell receptors for adoptive immunotherapy” for the degree of PhD (Philosophiae Doctor).
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Cornelis J.M. Melief, Leiden University Medical Centre
- Second opponent: Professor Bjørn Tore Gjertsen, University of Bergen
- Third member and chair of the evaluation committee: Professor emerita Inger Sandlie, University of Oslo
Chair of the Defence
Professor Emeritus Frode Vartdal, University of Oslo
Principal Supervisor
Adjunct Professor Johanna Olweus, University of Oslo
Summary
Cytotoxic CD8pos T lymphocytes can kill cancer cells by recognizing altered peptides presented on Major Histocompatibility Complex I molecules via their T-cell receptor (TCR). However, in patients with metastatic cancer, the patient´s own immune cells eventually fail to recognize and kill the cancer cells in most cases. Cancer immunotherapy based on infusion of patient cytotoxic T cells that are genetically equipped with cancer-targeted therapeutic TCRs in the laboratory, has therefore emerged as a promising therapeutic option. Two major challenges are, however, 1) identification of safe targets that are present at high levels on cancer cells 2) identification of T-cell receptors that efficiently recognize the targets. Both challenges were addressed in the current thesis.
We first developed a technology to identify mutation-specific T cells from healthy donors with high sensitivity and throughput. Using this technology, we successfully identified and characterized a TCR targeting a point mutation in FLT3 that is shared among patients with acute myeloid leukemia (AML). The TCR mediated efficient killing of patient leukemia cells harboring the mutation both in cell culture and transplanted into mice, while leaving normal cells unaffected. The TCR also mediated elimination of leukemic cells responsible for propagation of disease in mice. In summary, our data indicate that targeting of a single shared mutation with T cells equipped with a therapeutic TCR can provide efficient immunotherapy in patients with AML.
Next, we exploited the technology to identify TCRs recognizing a novel target in acute lymphoblastic leukemia (ALL). Terminal deoxynocleotidyl transferase (TdT) is a DNA polymerase that is overexpressed in most cases of acute lymphoblastic lymphoma (ALL), while it is not expressed in hematopoietic stem cells, myeloid cells and naïve and mature B- and T cells. We identified two TCRs that recognize TdT that mediated efficient killing of leukemia cells from patients transplanted into mice, while sparing all normal cells. Our data suggest that patient T cells equipped with TdT-targeting TCRs can be a promising therapeutic option for ALL patients and pave the way for targeting of other intracellular cell-type-specific antigens that are transiently expressed during differentiation.
Additional information
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