HLA-A*01:01 Restricted Human T Cell Receptor Recognizing the NRAS Q61K Hotspot Mutation

Mutation of amino acid 61of the neuroblastoma rat sarcoma viral oncogene homologue (NRAS) is a known driver of oncogenesis in melanoma. Glutamine (Q) to lysine (K) mutation at this position of NRAS is prevalent in approximately 10% of all melanoma cases and associated with aggressive tumors and low patient survival. Therefore, Q61K mutated NRAS is an important candidate for targeted therapies, including cellular immunotherapy. 

National Cancer Institute scientists developed a T-cell receptor (TCR) specific for NRAS Q61K for use in adoptive cell transfer (ACT) T-cell immunotherapy against melanoma. T cells reactive to NRAS Q61K were screened and isolated from tumor infiltrating lymphocytes of a melanoma patient with this mutation and the human leukocyte antigen (HLA) phenotype of A*01:01. TCR alpha and beta chains from the isolated T cells were then cloned to construct the NRAS Q61K-specific TCR. This TCR can be used to develop T-cell therapies against melanoma. Due to the similarities between different RAS isoforms (NRAS, KRAS, HRAS), the TCR could also be used to target other cancers exhibiting RAS Q61K mutations, such as colorectal, prostate, pancreatic and thyroid cancers in patients with the HLA-A*01:01 phenotype.

The NCI is seeking research co-development and/or licensees for the HLA-A*01:01 restricted human T-cell receptor recognizing the NRAS Q61K hotspot mutation.

Competitive Advantages:

• Potential for lower toxicity as NRAS Q61K is not present in healthy individuals
• Highly expressed target antigen for melanoma indication
• HLA-A*01:01 occurs in high frequency in Caucasian populations, therefore the TCR may benefit many patients 
• Intracellular proteins TCRs target can be tumor-specific
• Redirects the immune system against tumors
• TCRs potentially target more antigens than Chimeric Antigen Receptors (CARs) since both surface and intracellular proteins can be presented as peptides on MHC molecules

Commercial Applications:

• Use in adoptive cell transfer T-cell therapy against melanoma and other cancers
• Solid tumors without target antigens as surface proteins
• Diagnostic tool for NRAS Q61K tumors