Addressing challenges in TCR-based cancer immunotherapy

Cytotoxic CD8 positive T cells are immune cells that can destroy cancer cells by detecting foreign peptides presented on Major Histocompatibility Complex I molecules (MHC I) via their T-cell receptor (TCR). Cancer immunotherapy based on infusion of patient cytotoxic T cells that are genetically modified to express cancer-targeted therapeutic TCRs in the laboratory, is a treatment option for an increasing number of patients. Neoantigens are peptides derived from tumor-specific mutations that can be recognized as foreign by T cells. However, only few patients suffering from metastatic cancer have T cells that effectively can recognize their own cancer cells. In this doctoral thesis we developed a protocol based on a strategy previously established by our group to identify neoantigen-specific T cells from healthy donor blood with higher throughput and sensitivity. We moreover demonstrated that naive CD8 positive T cells are the source of the neoantigen-reactive responses. Clinical trials where cancer patients were treated with TCR-modified T cells have resulted in side effects due to recognition of unintended targets, highlighting the need for a standardized method to map TCR-reactivity. We developed a systematic pipeline to map unintended reactivity among therapeutic TCR-candidates. This platform can contribute to selection of safe TCRs for future clinical use. Myelodysplastic syndrome (MDS) is initiated by mutations in hematopoietic stem cells. The mutated stem cells are otherwise very similar to the healthy HSCs, and are highly treatment resistant. We identified a TCR that recognizes a peptide from a normal protein presented on the surface of healthy and malignant stem cells. Our data suggest that a future treatment strategy using T cells genetically engineered with TCRs directed against the self-proteins combined with stem cell transplantation has potential to treat MDS patients not responding to conventional therapy