T Cell Receptors Targeting BRAF V600E Mutation for Cancer Immunotherapy

BRAF is an oncogene that encodinges a serine-threonine kinase (B-Raf kinase) important in regulating cell growth and differentiation. Spontaneous mutations in the BRAF gene allow cells to continuously divide, leading to the development of cancer. A substitution of glutamic acid for valine at amino acid number 600 (designated V600E) accounts for 90% of BRAF mutations and is a driver of many cancers. The V600E mutation is present in ~3% of all cancer cases, representing a patient population of 540,000 patients per year. Though While the V600E mutation is found in a wide variety of cancers, it ishas a particularly high prevalentce in metastatic melanoma, colorectal cancer, thyroid cancer, and lung cancer. Many of these cancers are aggressive and the V600E mutation is commonly recognized as a poor prognostic factor. Therapies for these cancers are often nonspecific or limited by acquired resistance, necessitating novel therapeutic approaches specifically targeting the BRAF V600E mutation. 

Researchers at the National Cancer Institute (NCI) have identified two T cell receptors (TCRs) that target the BRAF V600E mutation. These TCRs specifically recognize tumor cells expressing the BRAF V600E mutation when presented by HLA-A*0301 molecules. The TCRs were identified by first using mass spectrometric analysis to isolate a short peptide derived from the BRAF V600E mutated protein that binds to HLA-A*0301. Transgenic mice harboring the HLA-A*0301 allele were then immunized with the peptide to obtain T cells recognizing the BRAF V600E mutation. The two TCRs were isolated from these T cells and tested in vitro for efficacy. Genetically engineered human T cells transduced with the TCRs were specifically reactive against multiple human tumor cell lines harboring the BRAF V600E mutation. These encouraging preclinical results suggest the potential for the TCRs to be used in a therapeutic approach such as T-cell therapy against cancers with the BRAF V600E mutation. Given the broad distribution of the V600E mutation across cancers, the TCRs are also an attractive candidate for allogeneic T-cell therapy among cancer patients with the HLA-A*0301 allele.

The NCI seeks parties interested in research co-development and/or licensing of these HLA-A*0301 restricted TCRs that target the BRAF V600E mutation.

Competitive Advantages:

• Potential for therapeutic efficacy against many cancers, given the high prevalence and broad distribution of the BRAF V600E mutation among cancer patients
• Therapies for BRAF V600E mutation-relevant cancers are often nonspecific or limited by acquired resistance
• T cells engineered with the TCRs are cytotoxic to tumor cells as the BRAF V600E mutation is not present in healthy tissues
• Efficacy against solid tumors

Commercial Applications:

• Adoptive cell therapy for cancers expressing the BRAF V600E mutation
• “Off-the-shelf” allogenic cell therapy for BRAF V600E mutated cancers