{
  "abstract": "Background KRAS is one of the most mutated genes in human cancer, with the G12D mutation having the highest frequency, occurring in 28% and 12% of pancreatic cancer (PDAC) and colorectal cancer (CRC), respectively. KRAS G12D-containing peptides are presented by the common HLA allele HLA-A*11:01, making this cancer neoantigen a highly attractive target for the development of adoptive TCR-T cell therapy. However, the levels of cancer neoantigen presentation are typically low and combined with the immunosuppressive tumor microenvironment this compromises the activation and reactivity of TCR-engineered T cells, posing a major hurdle for these cells to eradicate tumor lesions.Methods To establish a TCR-T cell therapy intended for the treatment of solid cancers, including PDAC and CRC, we developed AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A*11:01. To improve the reactivity of AZD0240 to the KRAS-G12D neoantigen, we developed a novel multi-armoring strategy, involving the combined disruption of a key negative regulator of T cell function and the introduction of a positive enhancement of TCR signaling.Results Employing this multi-armoring strategy, we observed enhanced cytokine production in response to low levels of exogenously loaded KRAS-G12D peptide, as well as to HLA-A*11:01 + tumor cells that express the KRAS-G12D mutation. Moreover, assessment of the in vitro and in vivo proliferative and cytotoxic capacity revealed that the AZD0240 armoring strategy profoundly increased both the clonal expansion and the anti-tumor efficacy of TCR-engineered T cells. Notably, the armored AZD0240 T cells were unable to respond to the KRAS G12 wild-type epitope, and no signs of increased TCR cross- or allo-reactivity, or malignant transformation were detected, derisking the clinical use of this armoring strategy.Conclusions Taken together, AZD0240 is a KRAS-G12D/HLA-A*11:01-targeted TCR-T cell therapy that employs a novel multi-armoring strategy and is currently in preparation for clinical testing, with encouraging signs of pre-clinical efficacy and safety.",
  "authors": [
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Lianne Kok"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Sander Eshuis"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Xiangjun Kong"
    },
    {
      "affiliations": [
        "AstraZeneca, Santa Monica, CA, USA"
      ],
      "name": "Jennifer Ma"
    },
    {
      "affiliations": [
        "AstraZeneca, Santa Monica, CA, USA"
      ],
      "name": "Michelle Mojadidi"
    },
    {
      "affiliations": [
        "AstraZeneca, Santa Monica, CA, USA"
      ],
      "name": "Elizabeth Hall"
    },
    {
      "affiliations": [
        "AstraZeneca, Santa Monica, CA, USA"
      ],
      "name": "Ka Hei Grace Sun"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Paula Kroon"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Vanessa Tubb"
    },
    {
      "affiliations": [
        "Netherlands Cancer Institute, Amsterdam, Netherlands"
      ],
      "name": "Ton Schumacher"
    },
    {
      "affiliations": [
        "AstraZeneca, Santa Monica, CA, USA"
      ],
      "name": "Arianne Perez"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Carsten Linnemann"
    },
    {
      "affiliations": [
        "AstraZeneca, Waltham, MA, USA"
      ],
      "name": "Mark Cobbold"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Jeroen van Heijst"
    },
    {
      "affiliations": [
        "AstraZeneca, Amsterdam, Netherlands"
      ],
      "name": "Gavin Bendle"
    }
  ],
  "title": "346 Pre-clinical characterization of AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A*11:01 that is multi-armored to increase epitope sensitivity",
  "uid": "a2b48d5b-110a-5298-9c1b-01ef0e413339"
}