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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Researcher Laurie Menger, Gustave Roussy, France
- Second opponent: Professor Sébastien Anguille, University of Antwerp, Belgium
- Third member and chair of the evaluation committee: Associate Professor Asbjørn Otto Christophersen, University of Oslo
Chair of defence
Professor Emeritus Haakon Breien Benestad, University of Oslo
Principal Supervisor
Sébastien Wälchli, Oslo University Hospital
Summary
Immunotherapy aims to help the immune system to recognize and eliminate tumor cells. One approach is to modify T cells with a Chimeric Antigen Receptor (CAR), an artificial protein that redirects T lymphocytes to target antigens on tumor cells. In clinical practice, T cells are collected from the patient, genetically modified, and, after expansion, reinfused into the patient. CAR T-cell therapy has shown success in treating B-cell malignancies, leading to complete remissions in patients with cancers resistant to conventional treatments. However, its effectiveness is limited in solid tumors and non-B cell hematological malignancies due to factors such as a lack of cancer-specific antigens and the tumor microenvironment’s inhibitory effect on CAR T cells, reducing their effectiveness.
The objective of this thesis was to address these therapeutic challenges by identifying safer CAR targets and evaluating a combinatorial strategy to enhance CAR T-cell redirection and tumor control. Using preclinical in vitro and in vivo assays, the efficacy and safety of two novel CARs, OSCAR-1 and OSCAR-3, were demonstrated. These CARs target an Alkaline Phosphatase (ALPL-1), that we newly identified as a common antigen particularly expressed in lung metastases of osteosarcoma (OS). We also identified CD37 as an attractive target for acute myeloid leukemia (AML) and performed a preclinical validation of CD37CAR, extending its known potential beyond B-cell lymphoma treatment. Finally, a novel C-X-C motif chemokine receptor 4 (CXCR4) antagonist, R54, was evaluated in combination with OSCAR T-cell therapy. This antagonist targets the CXCR4/CXC chemokine ligand 12 (CXCL12) axis, which plays a key role in metastasis development.
In conclusion, this thesis highlights the preclinical validation of novel safe therapeutic targets and/or CAR constructs against OS and AML and proposes a CAR/CXCR4-targeted combination therapy as a promising strategy to enhance anti-tumor efficacy.
Additional information
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