Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation

Area of Science:

• Immunology
• Oncology
• Bioinformatics

Background:

• Cancer neoantigens presented by human leukocyte antigen (HLA) molecules are targets for cytotoxic T cells, potentially leading to durable tumor regression.
• Current neoantigen-based immunotherapies have limited patient eligibility due to the rarity of shared immunogenic neoantigen-HLA pairs across individuals.
• The KRAS G12D mutation is a target for neoantigen immunotherapy in patients with HLA-C*08:02, highlighting the need to identify additional presenting HLA alleles.

Purpose of the Study:

• To develop and validate a novel strategy for identifying alternative human leukocyte antigen (HLA) alleles that can present the KRAS G12D neoantigen.
• To expand the patient population eligible for neoantigen-based immunotherapy targeting the KRAS G12D mutation.
• To provide an alternative method for predicting neoantigen-HLA pairs that improves upon in silico binding predictions and maximizes the clinical utility of shared neoantigens.

Main Methods:

• A combinatorial strategy integrating phylogenetic and structural analyses was employed to identify potential HLA alleles capable of presenting the KRAS G12D neoantigen.
• This approach was designed to overcome the limitations of in silico binding predictions, which exhibit variable accuracy across different HLA alleles.
• The study focused on finding HLA alleles that could present the KRAS G12D neoantigen, building upon existing successful immunotherapies in HLA-C*08:02 positive patients.

Main Results:

• The proposed combinatorial strategy successfully identified potential alternative HLA alleles for presenting the KRAS G12D neoantigen.
• This method offers an alternative to traditional in silico binding predictions, providing more reliable identification of neoantigen-HLA pairs.
• The findings suggest an expanded patient population could benefit from immunotherapy targeting the KRAS G12D mutation.

Conclusions:

• The developed combinatorial strategy (phylogenetic and structural analyses) is effective in identifying novel HLA alleles for neoantigen presentation.
• This approach broadens the potential application of KRAS G12D-targeted neoantigen immunotherapy to a larger patient cohort.
• The study presents a valuable alternative method for neoantigen-HLA pair prediction, enhancing the clinical impact of shared neoantigens in cancer immunotherapy.