{
  "abstract": "Background Public neoantigens derived from recurrent mutations in genes like KRAS, TP53, and PIK3CA are shared across diverse tumor types and represent promising targets for cancer immunotherapy. Clinical trials targeting these neoantigens have shown encouraging outcomes, including tumor regression and prolonged relapse-free survival. Here, we evaluated the biophysical properties of T-cell epitopes from these public neoantigens to identify optimal targets for the development of T-cell receptor (TCR)-based therapeutics.Methods We assessed the binding affinity and stability of public neoantigen peptides to various HLA class I molecules. Using naive T-cell repertoires, we screened for and isolated neoantigen-specific TCRs. The functionality of these TCR clones was characterized using engineered TCR-Jurkat and primary T-cells. TCR specificity was further interrogated using an HLA-transgenic cell panel and the X-scan peptide library assay. Finally, the in vivo anti-tumor efficacy of lead TCR-T cells was evaluated in multiple solid tumor xenograft models.Results Our analysis revealed that the KRAS G12V epitope presented by HLA-A*11:01 (KRAS G12V/HLA-A*11:01) demonstrated the highest HLA binding stability among the tested pairs. We identified four TCR clones specific for the 9-mer KRAS G12V peptide (KRAS G12V[9]). Notably, all newly identified and previously reported KRAS G12V[9]-specific TCRs exhibited cross-reactivity with an exogenous RAB7B-derived self-peptide. However, one TCR clone, KT18, displayed superior functional avidity, effectively recognizing and eliminating KRAS G12V-mutant tumor cells while critically showing no off-target activity against endogenously expressed RAB7B or related peptides. In preclinical validation, KT18 TCR-T cells mediated potent and significant tumor regression in multiple xenograft models.Conclusions Our findings highlight the significant variability in binding stability across public neoantigen-HLA complexes. Cross-reactivity with the RAB7B self-antigen represents a critical safety consideration for the development of HLA-A*11:01-restricted KRAS G12V[9]-specific TCRs. The KT18 TCR is highly potent, lacks this off-target reactivity, and thus represents a promising candidate for clinical development against KRAS G12V-driven solid tumors.",
  "authors": [
    {
      "affiliations": [
        "Chongqing Medical University, Chongqing, China"
      ],
      "name": "Xiaojian Han"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"
      ],
      "name": "Meiying Shen"
    },
    {
      "affiliations": [
        "Chongqing Medical University, Chongqing, China"
      ],
      "name": "Aishun Jin"
    }
  ],
  "title": "326 Therapeutic potential of T cell receptor targeting KRASG12V neoantigen without cross-recognition of the self-antigen RAB7B",
  "uid": "45e3b70d-7c83-5794-964f-424d1c6ad573"
}