Tumor protein 53 (tp53 or 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. Such mutations in tumor protein p53 are expressed in a variety of human cancers such as colon, pancreatic, breast, and non-small cell lung cancer. 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) have identified TCRs targeting two “hotspot” mutations in the p53 tumor suppressor, Y220C and R273C, estimated to occur in 1.5% to 2.8% of all cancer patients. The TCRs targeting p53 Y220C are restricted by HLA DRB3*02:02, which is found in ~33% of the US Caucasian populations, and the TCRs targeting p53 R273C are restricted by HLA DPB1*04:02, which is found in ~24% of the Caucasian populations and 60~80% of the Hispanic populations in the US. Therefore, such TCRs may be used to treat a diverse group of patients with cancer. These TCRs also have high antigenic specificity against mutated p53. In addition, these TCRs have the potential to be used in an allogeneic manner as an “off-the-shelf” reagent for patients who share the same p53 mutations and HLA genotypes.
The NCI Surgery Branch is seeking statements of capability or interest from parties interested in further developing and licensing these TCRs targeting mutant p53 and the associated HLA molecule.
- Treatment of various cancers expressing the p53-Y220C and p-53 R273C mutants
- Diagnostic test for cancers expressing p53-Y220C and p-53 R273C mutations
- Patients whose cancer cells express TP53 Y220C or R273C mutations and also have HLA DRB3*02:02 or HLA DPB1*04:02, respectively
- Adoptive cellular therapy using the TCRs in an “off-the-shelf” manner
- These TCRs can be used for a broad range of patients with cancer, given the high frequency of p53 Y220C or R273C mutations and HLA DRB3*02:02 and HLA DPB1*04:02
Sanghyun Kim Ph.D. (NCI), Nikolaos Zacharakis Ph.D. (NCI), Steven A Rosenberg M.D., Ph.D. (NCI)
- U.S. Provisional: U.S. Provisional Patent Application Number 63/074,747 , Filed 04 Sep 2020