Mutations in tumor protein p53 are expressed in a variety of human cancers such as colon, pancreatic, breast, and non-small cell lung cancer. P53 acts as a tumor suppressor by regulating cell division and DNA repair. Mutations of p53 reduce or eliminate its regulatory functions, contributing to cancer formation and progression. Novel therapeutics are needed that specifically target p53 mutations, as small molecule inhibitors lack sequence specificity.
T cell receptors (TCRs) are proteins expressed on the surface of T lymphocytes that can recognize peptide antigens from infected and malignant cells in the context of human leukocyte antigen (HLA) molecules with exquisite specificity. Subsequent T cell activation leads to an immune response which aims to eliminate abnormal cells. TCRs may be further engineered to recognize specific tumor antigens. Adoptive transfer of these tumor antigen-specific TCR-engineered T cells into patients has been demonstrated as a promising cancer treatment strategy.
Researchers at the National Cancer Institute (NCI) identified T-cell receptors (TCRs) targeting a specific mutation in the p53 tumor suppressor, R175H, in the context of HLA-DRB1*13:01. The p53-R175H “hotspot” mutation occurs in ~4.5% of all cancers, and as such, is an attractive target for adoptive T cell immunotherapy. Normal tissue does not express the mutated p53 protein. Therefore, these TCRs are expected to specifically eliminate human cancer cells that express both the appropriate p53 mutant and HLA molecules upon adoptive transfer into patients. NCI researchers have shown that T cells with these TCRs can be purified and enriched from the peripheral blood leukocytes of cancer patients and respond to stimulation by p53-R175H synthetic peptides.
The Surgery Branch is seeking statements of capability or interest from parties interested in collaborating to further develop and/or license these TCRs targeting mutant p53 and the associated HLA molecule.
- Cellular immunotherapy against cancer
- Treatment of various cancers expressing the p53-R175H mutant
- Companion diagnostics based on detection of the p53-R175H mutation
- p53-R175H is expressed in ~4.5% of all cancers and targeting this mutation has immense therapeutic potential
- T cells targeting mutated p53 may be isolated from a patients’ own peripheral blood leukocyte pool and enriched or engineered for adoptive cell therapy
Drew C Deniger Ph.D. (NCI), Parisa Malekzadeh M.D. (NCI), Steven A Rosenberg M.D., Ph.D. (NCI)
- U.S. Provisional: U.S. Provisional Patent Application Number 62/867,619 , Filed 27 Jun 2019
- PCT: PCT Application Number PCT/US2020/039785 , Filed 26 Jun 2020