T Cell Receptors Targeting CDKN2A Mutations for Cancer Immunotherapy

Cyclin-dependent kinase inhibitor 2A gene, also known as CDKN2A, is a tumor suppressor gene and is commonly inactivated through somatic mutations in many human cancers. For example, inactivation of CDKN2A is highly prevalent in melanoma, gastrointestinal and pancreatic cancers. Through germline mutations, CDKN2A is associated with predisposition for a variety of cancers, including melanoma and pancreatic cancers. Despite the high frequency of CDKN2A mutations in cancer, there have been no successful therapies targeting these mutations to date. Adoptive cell therapy, a promising form of immunotherapy, offers a potential form of targeted therapy for cancers with CDKN2A mutations.

Researchers at the National Cancer Institute (NCI) have developed seven novel human T cell receptors (TCRs) targeting CDKN2A. These TCRs may be used in adoptive cell therapy to treat cancers driven by CDKN2A mutations by targeting neoantigens expressed only by cancer cells. More specifically, the TCRs target neoantigens driven by frameshifts and those driven by nonsynonymous mutations that result in a proline to leucine in position 114 in the CDKN2A gene. Together, these account for 53% of CDKN2A mutations. The TCRs are restricted by some of the most common HLA alleles including HLA A*03:01, HLA A*11:01 and HLA A*02:01, which have an approximate frequency of 8%, 7%, and 40% respectively within the United States population. Thus, these TCRs allow for engineering TCR-based therapies resulting in specific elimination of tumor cells with the indicated CDKN2A mutations present in a diverse group of cancer patients.

The NCI seeks parties interested in research co-development and/or licensing this library of TCRs targeting CDKN2A mutations.

Competitive Advantages:

• No approved therapies targeting CDKN2A
• Targeted therapy against CDKN2A mutations with therapeutic potential for a wide variety of cancers
• Targets neoantigens presented by common HLA alleles making the therapy potentially effective for a broad cancer patient population
• CDKN2A mutations not present in healthy cells

Commercial Applications:

• Autologous TCR-engineered T cell therapy for cancer patients with CDKN2A mutations
• Off-the-shelf, allogeneic TCR-engineered T cell therapy for cancer patients with CDKN2A mutations
• Combination immunotherapies using TCR-engineered T cells alongside other immunotherapies targeting common driver mutations or patient specific mutations