{
  "abstract": "Background Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor T-cell therapy (CART) for B-cell acute lymphoblastic leukemia (B-ALL). Lower rates of severe CRS have been reported in patients treated with CD22-directed CART (CART22) compared with those treated with CD19-directed CART (CART19).Methods More than 1,000 serum proteins were measured using a proximity extension assay on 40 patients treated with CART19 or CART22 and cytokines were compared. Single-cell (single-cell RNA-sequencing (scRNAseq)) was used to identify cellular and transcriptional differences between patients treated with CART19 and CART22. CART19-blast and CART22-blast interactions at the immune synapse (IS) were modeled in vitro.Results We identified interleukin-10 (IL-10) as a critical endogenous modulator of CRS and demonstrated that previous treatment with CART is associated with increased serum IL-10 in the setting of subsequent relapse. Mechanistically, IL-10 induced higher interferon gamma expression and SOCS3 upregulation in both CART19 and CART22 cells. IL-10 differentially impacted the CART IS, prolonging the CART19 but shortening the CART22 IS. Using scRNAseq we demonstrated upregulation of SOCS3 in CART22 patient CD4 T-cells, potentially suppressing trans-IL-6 signaling.Conclusions These findings reveal IL-10 as a potent CRS‐mitigating factor and support IL-10 enhancement strategies to improve the safety of CART.",
  "authors": [
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Caroline Diorio"
    },
    {
      "affiliations": [
        "Division of Oncology and Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Rawan Shraim"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Anusha Thadi"
    },
    {
      "affiliations": [
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Anastasia Frank-Kamenetskii"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Lahari Uppuluri"
    },
    {
      "affiliations": [
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Hannah Klinghoffer"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Zachary Martinez"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Apoorva Babu"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Regina M Myers"
    },
    {
      "affiliations": [
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Joseph A Fraietta"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Andrew Hughes"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Jonathan Sussman"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Jason Xu"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Susan E McClory"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Katherine Mueller"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Jessica Perazzelli"
    },
    {
      "affiliations": [
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Laura A Vella"
    },
    {
      "affiliations": [
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Immunology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Sarah E Henrickson"
    },
    {
      "affiliations": [
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Marco Ruella"
    },
    {
      "affiliations": [
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Edward M Behrens"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Amanda M DiNofia"
    },
    {
      "affiliations": [
        "Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Janis K Burkhardt"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Shannon L Maude"
    },
    {
      "affiliations": [
        "Immune Dysregulation Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Scott Canna"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Kai Tan"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Stephan Grupp"
    },
    {
      "affiliations": [
        "Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"
      ],
      "name": "David T Teachey"
    }
  ],
  "title": "Differential cytokine architecture in patients treated with CART19 versus CART22",
  "uid": "0d986d6a-15e2-5113-af5f-43f3d69440d3"
}