{
  "abstract": "Background CLDN18.2 is a tight-junction protein overexpressed in pancreatic, gastric and esophageal cancers but is largely confined to the gastric mucosa in normal tissues. Importantly, this normal expression pattern is maintained in murine models, and off-tumor toxicity in the gastric mucosa can be modeled using murine-reactive CAR-T. 1 While CLDN18.2-directed CAR-T show clinical promise in a late line setting,2 overcoming the immunosuppressive tumor microenvironment (TME) remains a challenge. Immunocompetent, syngeneic mouse models are essential for evaluating CAR-T strategies, yet surrogate murine CAR-Ts (mCAR-T) often elicit variable anti-tumor responses. We sought to explore whether these variable responses were partly due to generation of anti-drug/anti-CAR antibodies (ADA), limiting the overall response.Methods We evaluated two preconditioning regimens in fully immunocompetent, CLDN18.2 tumor bearing mice: whole body irradiation versus B cell depletion using an anti-CD20 antibody (aCD20). Anti-tumor efficacy and ADA development were monitored, and an ELISA was validated to quantify anti-CAR antibodies (ACA) in serial serum samples.Results In WBI-preconditioned mice, adding aCD20 did not further reduce tumor growth or ADA levels. In non-irradiated mice, aCD20 significantly enhanced mCAR-T-mediated tumor regression and markedly suppressed ADA development across multiple timepoints.Conclusions B cell depletion via aCD20 alone achieves tumor control comparable to WBI preconditioning and sustains low ACA levels, eliminating the need for lymphodepletion. Although murine ACA responses may not predict human immunogenicity, this refined syngeneic model enables rigorous evaluation of CAR-T combinations with immuno-oncology checkpoint surrogates in an intact murine setting.References Barrett AM, Britton ZT, Carrasco RA, Breen S, Broggi, MAS, Hatke AL, et al. Preclinical evaluation of AZD6422, an armored chimeric antigen receptor T cell targeting CLDN18.2 in gastric, pancreatic, and esophageal cancers. Clin Cancer Res. 2024;30(23):5413-29.Qi C, Liu C, Peng Z, Zhang Y, Wei J, et al. Claudin-18 isoform 2-specific CAR T-cell therapy (satri-cel) versus treatment of physician’s choice for previously treated advanced gastric or gastro-oesophageal junction cancer (CT041-ST-01): a randomised, open-label, phase 2 trial. Lancet. 2025;405(10494):2049-60.",
  "authors": [
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Alana R Sherker"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Lorenzo Ortiz"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Allison M Barrett"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Shannon Breen"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Brianna Janocha"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Peter Zanvit"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Spencer Park"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Jessica Revolorio"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Lori Clarke"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Diana Moffat"
    },
    {
      "affiliations": [
        "AstraZeneca, Biologics Engineering, Gaithersburg, MD, USA"
      ],
      "name": "Ryan Gilbreth"
    },
    {
      "affiliations": [
        "AstraZeneca, Waltham, MA, USA"
      ],
      "name": "Mark Cobbold"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Emily E Bosco"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Gordon Moody"
    }
  ],
  "title": "260 Evaluation of anti-drug antibody development in syngeneic mouse models used to study chimeric antigen receptor T (CAR-T) cells",
  "uid": "9ca71eaf-3b46-52f7-b57e-3e9aeb9598e9"
}