Project description
Donor T cell receptors in the treatment of metastases
Recent successes in cancer immunotherapy did not result in significant progress towards a cure for patients with metastatic cancers, which often lack homogeneous highly expressed molecules to serve as targets for efficient T cell responses. The project partners recently demonstrated that donor blood is a rich source of T cell receptors (TCRs) that react to peptides from tissue-restricted proteins when presented on mismatched, foreign human leukocyte antigens. The homogeneous expression of tissue-specific antigens is usually maintained on primary tumours and metastases. The EU-funded OUTSOURCE project will explore patient T cells genetically equipped with donor TCRs (dTCR T cells) to target (reject) cancer-affected organs, including metastases. dTCR T cell therapy could treat malignancies in non-essential for survival organs, such as the prostate, or those that can be replaced by a transplant, such as bone marrow.
Objective
Despite recent advances in cancer immunotherapy, most patients with metastatic cancer are not cured. Major reasons are lack of homogeneously and highly expressed molecules that can be safely targeted and evoke efficient T-cell responses. I propose that the strong T-cell responses leading to rejection of transplanted organs can be exploited to “reject” cancer by specific recognition of tissue-restricted targets. To this end, I recently demonstrated that healthy donor blood provides a rich source of T cells expressing TCRs that specifically and strongly react to peptides from tissue-restricted self-proteins, when presented on mismatched, foreign Human Leukocyte Antigens (HLA). I propose that patient T cells genetically equipped with such donor TCRs (dTCR T cell therapy) may “reject” cancer-affected organs, including metastases. A high and homogeneous expression of tissue-specific antigens is often maintained on both primary tumor and metastatic cancer cells. Here, I will identify peptides from tissue-restricted proteins as novel candidate TCR targets. Next, I will identify donor T cells that recognize such self-peptides in complex with foreign HLA by use of my patented method, and sequence reactive TCRs. Finally, I will establish a preclinical pipeline to characterize safety and efficacy of TCRs in vitro and in vivo in innovative mouse models. Outsourcing cancer immunity to dTCR T cells may bypass major limitations in current immunotherapies, including checkpoint inhibition and T cells gene-modified with chimeric antigen receptors (CARs). Thus, dTCRs can recognize i) intracellular targets and thus manifold more targets than CARs, ii) tumor-associated self-antigens with high affinity in contrast to patient-derived TCRs, and iii) self-antigens, which are more homogeneously expressed than mutations. dTCR T cell therapy could treat malignancies in organs that are non-essential for survival, such as prostate, or that can be replaced by a transplant, such as bone marrow.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- medical and health sciencesmedical biotechnologycells technologies
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
0313 Oslo
Norway