T Cell Receptors Targeting the KRAS G13D Mutation in the Context of HLA-A11:01 for Research Use

Summary:

The National Cancer Institute (NCI) has identified HLA-A11:01-restricted T Cell Receptors (TCRs) targeting the KRAS G13D mutation. The NCI seeks licensees for the use of these TCRs in research.

Description of Technology:

Tumor-specific mutated proteins can create immunogenic, mutation-containing “neoepitopes” which are attractive targets for adoptive T-cell therapies. There has been major interest in the field in targeting common shared mutations in driver genes, such as KRAS, using off-the-shelf T-cell receptors (TCRs) engineered into autologous lymphocytes. However, identifying the neoepitopes to pursue as therapeutics is a complex and challenging process. One method to demonstrate whether an epitope is presented at the cell surface is to elute peptides bound to a specific human leukocyte antigen (HLA) allele and analyze them by mass spectrometry (MS). These MS data can then be prospectively applied to isolate TCRs specific to the neoepitope.

Using this MS methodology, investigators at the Surgery Branch have identified TCRs that can recognize the G13D substitution mutation of KRAS in the context of HLA-A11:01. Importantly, the G13D mutation of KRAS is an attractive target for adoptive cell therapy as it is highly mutated in cancers (e.g., KRAS is found to be mutated in 45% of all colorectal carcinoma patients, and about 16% of these patients have the G13D mutation). Furthermore, approximately 15% of the US population has the HLA-A11:01 allele.

This is the first known report of HLA-A11:01-restricted TCRs that can recognize KRAS G13D. The identified TCRs have high specificity and immunogenicity for the G13D mutation and can recognize processed and presented antigen on the surface of cells. While these TCRs are not effective as therapeutics, they would be useful for identification of other KRAS G13D reactive TCRs in patient and animal models.

The National Cancer Institute (NCI) seeks licensees for T Cell Receptors (TCRs) targeting the KRAS G13D mutation for potential use in research.

Potential Commercial Applications 

• Research use
• Diagnostic use
• Use as positive controls to identify other HLA-A11:01 KRAS G13D reactive T cells from different patient and/or animal models
• Use as negative controls in other research applications

Competitive Advantages

• The KRAS G13D TCRs are highly specific and immunogenic
•  G13D is a common mutation of the KRAS driver gene in cancers, making it an attractive target for immunotherapy
• The HLA-A11:01 allele is present in about 15% of the US population and up to 60% of the Asian and Oceanian populations
• The results indicate that Mass Spectrometry is an effective and accurate way to detect antigens on specific HLA complexes