{
  "abstract": "Background Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer, representing less than 1% of all cases of thyroid cancer and accounting for more than half of the related deaths. There is currently only one clinical trial using CAR-T cell therapy to treat this disease and it targets ICAM-1, a protein with broad normal tissue expression. There is a need for systematic surface antigen identification to identify best possible targeting strategies.Methods We integrated publicly available single-cell RNA sequencing datasets from multiple human atlas studies of adult healthy organs into a Cross Organ Tissue Atlas (COTA) as well as thyroid cell data from healthy patients, patients with papillary thyroid carcinoma, and patients with ATC. We performed differential expression analysis between malignant ATC cells and the COTA. We confirmed the abundance of potential novel CAR target antigens in 40 tissue samples from patients with ATC by immunohistochemistry (IHC) and in a panel of thyroid cancer cell lines by flow cytometry. Using an IL13 E13Y mutein, we engineered CAR T cells that target IL13Rα2 (CAR13).Results We found that two well-known immunotherapy targets in other contexts, IL13Rα2 and CD70, were among the top hits for genes more highly expressed in ATC versus the COTA. In an orthogonal cohort analyzed by IHC, we found that IL13Rα2 was expressed in 38 of 40 and CD70 was expressed in 18 of 40 cases of ATC. CAR13 T cells demonstrated target antigen-dependent tumor cell cytolysis, proliferation, and cytokine production. In a xenograft NSG mouse model of poorly differentiated thyroid cancer, CAR13 T cells exhibited tumor infiltration and anti-tumor potency, with additional in vivo studies in progress.Conclusions A cell atlas-resolved scRNAseq-to-IHC pipeline identified IL13Rα2 and CD70 as top CAR targets in ATC. CAR T cells targeting the dominant ATC-associated antigen, IL13Rα2, demonstrated in vitro and in vivo anti-tumor activity versus dedifferentiated thyroid cancer cells.",
  "authors": [
    {
      "affiliations": [
        "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA"
      ],
      "name": "Aonkon Dey"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA"
      ],
      "name": "Manuella Talla Takoukam"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA",
        "Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Emily M Schneider"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Bayan A Alzumaili"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA"
      ],
      "name": "Angelique Pham"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA"
      ],
      "name": "Ditsa Sarkar"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Harvard University, Boston, MA, USA"
      ],
      "name": "Noor Radde"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Leland G Richardson"
    },
    {
      "affiliations": [
        "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Michelle Rengarajan"
    },
    {
      "affiliations": [
        "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA",
        "Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Rachelly Normand"
    },
    {
      "affiliations": [
        "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Mark B Leick"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA"
      ],
      "name": "Amanda A Bouffard"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Mohsen Mazloomrezaei"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA",
        "Broad Institute, Cambridge, MA, USA"
      ],
      "name": "Neal P Smith"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Gilbert H Daniels"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Lori Wirth"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Valentina Nardi"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Sareh Parangi"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA",
        "Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Christopher J Ott"
    },
    {
      "affiliations": [
        "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Charlestown, MA, USA"
      ],
      "name": "Marcela V Maus"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Bryan D Choi"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Peter M Sadow"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA",
        "Massachusetts General Hospital, Boston, MA, USA",
        "Broad Institute, Cambridge, MA, USA"
      ],
      "name": "Alexandra-Chloe Villani"
    },
    {
      "affiliations": [
        "Broad Institute of MIT and Harvard, Cambridge, MA, USA",
        "Massachusetts General Hospital Cancer Center, Boston, MA, USA",
        "Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Max Jan"
    }
  ],
  "title": "280 Cell atlas-resolved discovery and targeting of novel CAR antigens in anaplastic thyroid carcinoma",
  "uid": "1f713785-1297-5db9-b32e-44103ba7230a"
}