Despite recent success of cancer immunotherapy, most patients with metastatic cancer are not cured. One of the most important reasons is lack of homogeneously and highly expressed molecules that can be safely targeted. CAR T cell therapies are now approved in acute B-cell leukemia and lymphoma, and have dramatically improved the outcome for patients with these cancers. These CAR T cells target B cell-specific surface antigens, such as CD19, expressed on normal as well as malignant B cells. The treatment is well tolerated, as we can live without normal B cells for years. We can, however, not live without normal T cells, myeloid cells and liver cells etc, which is why CAR T-cell therapies have not yet been approved for non-B-cell malignancies. CARs – Chimeric Antigen Receptors – are artificial immune receptors binding targets via an antibody domain. Thus CARs can only bind cell-surface molecules on cancer cells. In contrast, T-cell receptors (TCRs) can in principle recognize peptides derived from proteins with any subcellular location when presented in context of class I tissue type molecules – in humans called HLA class I. This dramatically increases the number of potential immunotherapy targets, as >80% of cellular proteins are inside the cell. A major challenge to identify TCRs that can strongly recognize self-antigens is, however, that our T-cells are educated during development to not recognize our own proteins, protecting us from autoimmunity. In OUTSOURCE, I am using technologies developed by my group whereby the mechanism of transplant rejection is exploited to identify TCRs from healthy donors that can strongly react to peptides derived from cell-type specific proteins when presented on foreign (allogeneic) HLA-molecules, in several cancer types. The immune response is “outsourced” to a healthy donor. The overall objective of the project is to demonstrate that T cells genetically equipped with such donor TCRs (dTCR T cell therapy) can efficiently “reject” primary cancer cells. Another important aim is to establish a preclinical pipeline for safety testing, and in vivo models for assessment of efficacy.
