Donor T-cell receptors targeting cells that propagate cancer

Recent advances in cancer immunotherapy have dramatically improved life expectancy of patients with widespread cancer. Still, the large majority of these patients are not cured. Major reasons for therapeutic failure are lack of therapeutic targets that are highly expressed on cancer cells and that are safe to target, and in addition can stimulate efficient immune responses. Our research team recently demonstrated that the strong immune responses leading to rejection of transplanted organs due to a mismatch in tissue type can be exploited to mediate focused attacks on defined targets. Healthy donor blood provides a rich source of immune cells, including so-called T cells, that are equipped with molecules that can be compared with heat-seaking missiles (T-cell receptors). Using technology developed in our group we can identify T cells expressing T-cell receptors that can recognize foreign tissue type molecules combined with protein fragments derived from cancer cells. Patient T cells genetically equipped with such T-cell receptors can efficiently ?reject? cells from cancer-affected organs, including metastases, by ?single cell surgery?. Moreover, our group recently demonstrated that T-cell receptors from healthy donors can recognize more than 5-fold as many peptides encoded by mutations (neoantigens) as tumor-infiltrating immune cells from the patient (Stronen et al, Science 2016 and Ali et al, Nature Protocols, 2019). Patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have a large unmet medical need. Quiescent, non-dividing, cancer stem cells are frequently resistant to chemotherapy and propagate these malignancies. Here, we aim to target quiescent cancer stem cells in MDS and AML by use of novel T-cell receptors derived from healthy donors that are identified by our patented technology, combined with novel strategies to enhance the susceptibility of cancer stem cells to T-cell mediated attack. In 2021, we have screened a large number of AML and MDS patient samples from our biobanks in cell culture assays to identify the most suitable samples for establishment of patient-derived xenograft models. From these, we have selected 10 that are currently tested in vivo for engraftment potential. We have also demonstrated that we can engraft normal hematopoietic stem cells in vivo, and are following these models to study how long the hematopoiesis can be sustained. We have moreover completed the establishment of a pipeline for mapping of TCR safety in vitro, and have generated safety data for several TCRs.

Recent advances in cancer immunotherapy have dramatically improved life expectancy of patients with widespread cancer. Still, the large majority of these patients are not cured. Major reasons for therapeutic failure are lack of molecules that are highly and homogeneously expressed that can be safely targeted, and to which efficient T cell responses can be raised. My team recently demonstrated that the strong but broadly targeted T-cell responses leading to rejection of transplanted organs due to a mismatch in tissue type/Human Leukocyte Antigen (HLA) can be exploited to mediate focused attacks on defined targets. Healthy donor blood provides a rich source of T cells expressing T-cell receptors (TCRs) that specifically and strongly react to peptides from tissue-restricted self-proteins, when presented on mismatched, foreign HLA. Patient T cells genetically equipped with such donor TCRs may specifically and efficiently “reject” cells from cancer-affected organs, including metastases, by “single cell surgery”. Moreover, my team recently demonstrated that TCRs from healthy donors can recognize more than 5-fold as many peptides encoded by mutations (neoantigens) as tumor-infiltrating T cells from the patient (Stronen et al, Science 2016 and Ali et al, Nature Protocols, 2019). Patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have a large unmet medical need. Quiescent cancer stem cells (CSC) are frequently resistant to chemotherapy and propagate these malignancies. Here, we aim to target quiescent cancer stem cells (CSC) in MDS and AML by use of novel donor-derived TCRs (dTCRs) generated by our patented technology, that are reactive to shared self-antigens and shared neoantigens combined with novel strategies to enhance the susceptibility of CSC to T-cell mediated attack.