{
  "abstract": "Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by early liver metastases. Chimeric antigen receptor (CAR) modified cells (T and NK) have been largely unsuccessful in PDAC and other solid tumors, despite success in hematologic malignancies. Limitations in homing and engraftment of CAR cells into the solid tumor microenvironment may limit clinical efficacy. Regional CAR cell delivery and liver-directed radiation may improve this therapy against PDAC liver metastases. We investigated the impact of regional delivery and radiation therapy (RT) on B7-H3 CAR T cells.Methods Human PANC-1 cells were treated with radiation in vitro and in vivo using a liver-only metastatic model and assessed for expression of B7-H3 and NKG2D activating ligands MICA/MICB. B7-H3 CAR T cells were generated and assessed by flow cytometry and killing assays against PANC-1 cells treated with or without 4 Gy RT. CD8 T cells were transferred into NSG mice via tail vein (IV) or portal vein (PV) injection and engrafted cells were isolated and assessed by flow cytometry.Results Following exposure to 4 Gy RT, PANC-1 cells in vitro exhibited a significant increase in expression of B7-H3 and MICA/MICB. This was also detected in vivo following 4 Gy liver-directed RT where PANC-1 liver metastases had significantly increased percent expression of B7-H3 (90% ± 1.4% vs. 72% ± 6.6%, P = 0.005) and MFI of MICA/MICB (5479 ± 1680 vs. 1069 ± 691, P = 0.003), compared to non-radiated controls. Cytotoxicity of B7-H3 CAR T cells against PANC-1 cells was further increased when PANC-1 cells were pre-treated with 4 Gy RT in vitro. Human CD8 T cells were isolated from the liver of mice 24 hours after injection by either PV or IV. When administered by PV, CD8 T cells isolated from the liver showed significantly higher expression of tissue resident marker CD69 compared to IV administration (36% ± 3.9 vs. 16% ± 1.5, P < 0.001).Conclusions RT increases expression of both B7-H3 and NKG2D activating ligands MICA/MICB on PANC-1 cells in vitro and this is recapitulated in vivo following liver-directed RT. These RT-induced changes result in greater B7-H3 CAR T cell killing. CD8 T cells administered by portal vein are enriched in the tissue resident marker CD69 within the liver, suggesting route of administration may impact engrafting T cells. Overall, liver-directed RT and regional CAR T administration may be a strategy to target PDAC liver metastases.",
  "authors": [
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Megan C Purl"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Alexandria Shick"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Makan Karimzadeh"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Cyrus Sholevar"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Tasneem Mukarrama"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Natalie Liu"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Marshall L Lammers"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "Jinhwan Kim"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA",
        "UC Davis Comprehensive Cancer Center, Sacramento, CA, USA"
      ],
      "name": "Edward Kim"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA",
        "UC Davis Comprehensive Cancer Center, Sacramento, CA, USA"
      ],
      "name": "Arta Monjazeb"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA"
      ],
      "name": "William J Murphy"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA",
        "UC Davis Comprehensive Cancer Center, Sacramento, CA, USA"
      ],
      "name": "Robert J Canter"
    },
    {
      "affiliations": [
        "University of California, Davis, Sacramento, CA, USA",
        "UC Davis Comprehensive Cancer Center, Sacramento, CA, USA"
      ],
      "name": "Sean J Judge"
    }
  ],
  "title": "268 Regional B7-H3 CAR cell therapy and liver-directed radiation for pancreatic cancer liver metastases",
  "uid": "c449051a-5a31-5a92-8690-0d5e45575afa"
}