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T Cell Receptors (TCRs) Specific for Mutant p53

Summary
National Cancer Institute (NCI) researchers have isolated T cell receptors (TCRs) reactive to the highly prevalent p53-R175H mutant in the context of the human leukocyte antigen (HLA) class II allele, HLA-DRB1*13:01. These TCRs can be used for a variety of therapeutic, diagnostic, and research applications. NCI seeks licensing and/or co-development research collaborations for TCRs that recognize the p53-R175H mutation and the associated HLA allele, and methods for identifying p53 mutation-reactive T cell receptors.
NIH Reference Number
E-135-2019
Product Type
Keywords
  • p53, R175H, Human Leukocyte Antigen, HLA-DRB1*13:01, T Cell receptors, TCR, Adoptive Cell Transfer, ACT, Epithelial, Deniger
Collaboration Opportunity
This invention is available for licensing and co-development.
Contact
Description of Technology

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.

Potential Commercial Applications
  • Cellular immunotherapy against cancer
  • Treatment of various cancers expressing the p53-R175H mutant
  • Companion diagnostics based on detection of the p53-R175H mutation
Competitive Advantages
  • 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
Inventor(s)

Drew C Deniger Ph.D. (NCI), Parisa Malekzadeh M.D. (NCI), Steven A Rosenberg M.D., Ph.D. (NCI)

Development Stage
Publications

Malekzadeh P, et al. Neoantigen screening identified broad TP53 mutant immunogenicity in patients with epithelial cancers.  [PMID: 30714987]

Deniger DC, et al. T-cell responses to TP53 “hotspot” mutations and unique neoantigens expressed by human ovarian cancers.  [PMID: 29853601]

Patent Status
  • U.S. Provisional: U.S. Provisional Patent Application Number 62/867,619 , Filed 27 Jun 2019
Therapeutic Area
Updated
Tuesday, September 17, 2019