{
  "abstract": "Background Immune checkpoint inhibitors (ICIs) can cause a broad range of autoimmune toxicities or immune-related adverse events (irAEs), which can be debilitating and sometimes fatal. High-dose corticosteroids are standard first-line treatment; however, some patients are steroid-refractory or relapse during tapering. Prolonged steroid use increases the risk of AEs—including weight gain, osteoporosis, bowel ulceration/perforation, infection risk, and possibly reduced immunotherapy efficacy. 1 Mechanistically, irAEs often resemble autoimmune diseases. We conducted a prospective trial evaluating rituximab (anti-CD20) or tocilizumab (anti-IL-6) treatment for steroid-refractory or steroid-dependent irAEs phenotypically resembling diseases for which they are already used in clinical practice.Methods This open-label, multi-center phase II study assessed rituximab (375 mg/m 2 weekly × 4) or tocilizumab (4 mg/kg × 2, 28 days apart) in patients with histologically confirmed solid tumors who developed steroid-dependent (inability to wean to <10mg of prednisone/equivalent within 6 weeks) or refractory (lack of systemic steroid efficacy after 7 days) irAEs from ICIs. Patients were enrolled based on published data supporting use of rituximab or tocilizumab. Each arm aimed to enroll 15 patients. Primary endpoints were the proportion able to discontinue steroids within 4 weeks post-treatment and irAE grade improvement per Common Terminology Criteria for Adverse Events v5. T cell phenotyping used 42-parameter spectral flow cytometry. CD4+ αβ T cells were analyzed using unsupervised Phenograph clustering and dimension reduction with Uniform Manifold Approximation and Projection (UMAP).Results Six patients enrolled; all received tocilizumab. The trial closed early due to slow accrual and COVID-related site closures. Primary irAEs were arthritis (n=4) and bullous pemphigoid-type dermatitis (n=2). All had grade 2 irAEs; mean prednisone dose at screening was 14.2 mg (range 0–50). All patients reduced steroid use or remained off during the trial. One patient with steroid-dependent arthritis had complete symptom resolution and tapered prednisone from 50 to 5 mg without relapse. One month post-treatment, 2 arthritis patients (33%) were steroid-free. All showed stable or reduced irAE grade with lowest mean prednisone dose of 5 mg (range 0–20). Tocilizumab was well tolerated; no unexpected adverse events occurred. Patient 2 showed marked improvement with abundant baseline Th17 cells and a reduction in Th17/ex-Th17 cells post-treatment, while Th17/ex-Th17 levels stayed stable in patients with unchanged irAE grade ( figure 1).Conclusions Tocilizumab appears to be a safe, effective steroid-sparing option for managing steroid-refractory/dependent irAEs—specifically arthritis and bullous pemphigoid. Th17 cell enrichment in irAE arthritis may predict treatment response, supporting further study of this population as a biomarker to guide future therapy.Trial Registration Clinicaltrials.gov registry number: NCT04375228.Reference Maslov DV, Tawagi K, Madhav KC, Simenson V, Yuan H, Parent C, et al. Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer. J Immunother Cancer 2021;9(7):e002261.Ethics Approval The study was approved by Columbia University Institutional Review Board (IRB # AAAS9173). The study was also approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board (IRB protocol number: 21-519).Abstract 516 Figure 1Tocilizumab decreases the abundance of pathogenic Th17 cells mediating irAE-arthritis. A) Study design B) UMAP of CD4+ αβ-T cells with 34 Phenograph clusters; Th17 (pgraph-2) & ex-Th17 (pgraph-11) in black oval C) Th17/ex-Th17 decrease 6-/5-fold post-tocilizumab D) UMAPs pre/post in pts 2 & 3 E) Th17: CD161+CD183−; ex-Th17: CD161+CD183+F) Histograms: CD161, CD183, CD196, CD95, CD27",
  "authors": [
    {
      "affiliations": [
        "Columbia University, New York, NY, USA"
      ],
      "name": "Sunil Bhatt"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Brian Henick"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Matthieu Paiola"
    },
    {
      "affiliations": [
        "Johns Hopkins University, Baltimore, MD, USA"
      ],
      "name": "Aliyah Pabani"
    },
    {
      "affiliations": [
        "Boca Raton Regional Hospital, Boca Raton, FL, USA"
      ],
      "name": "Matthen Mathew"
    },
    {
      "affiliations": [
        "Genentech, Pearland, TX, USA"
      ],
      "name": "Sanjay Bansal"
    },
    {
      "affiliations": [
        "Genentech, San Francisco, CA, USA"
      ],
      "name": "Laura Tang"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Claire Coleman"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Adam Mor"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Edward Bentlyewski"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Moury Minhaz"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Zoe Bertone"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Naomi Sender"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Sarah StaAna Sedycias"
    },
    {
      "affiliations": [
        "F. Hoffmann-La Roche Ltd, Basel, Switzerland"
      ],
      "name": "Rajat Mohindra"
    },
    {
      "affiliations": [
        "Genentech/Roche, Basel, Switzerland"
      ],
      "name": "G Scott Chandler"
    },
    {
      "affiliations": [
        "Synthekine, Inc., Menlo Park, CA, USA"
      ],
      "name": "Naiyer A Rizvi"
    },
    {
      "affiliations": [
        "Columbia University Medical Center, New York, NY, USA"
      ],
      "name": "Stephanie Gallitano"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA",
        "New York University, New York, NY, USA"
      ],
      "name": "Mario E Lacouture"
    }
  ],
  "title": "516 An open-label, phase II multicenter study of rituximab or tocilizumab for steroid-dependent or steroid-refractory immune-related adverse events due to immune checkpoint inhibitors",
  "uid": "ac1e8981-c2da-5c64-aeb1-dbf80f25fb0d"
}