Characterization of the immune response in patients with cancer of the oral cavity after neoadjuvant immunotherapy with the IRX-2 regimen

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Abstract

Objective: IRX-2 is a homologous cell-derived multi-cytokine biologic with multifaceted immune modulatory effects that has been shown to induce increased lymphocyte infiltration into primary tumors in oral cavity carcinoma. Our objective was to characterize tumor immune gene expression and epigenomic changes after neoadjuvant IRX-2 immunotherapy in patients with squamous cell carcinoma of the oral cavity. Methods: A randomized phase II trial was conducted of the IRX regimen 3 weeks prior to surgery for previously untreated patients with Stage II-IV oral cavity carcinoma. The treatment regimen consisted of low dose (300 mg/m2) cyclophosphamide (day 1) followed by 10 days of regional perilymphatic IRX-2 cytokine injections and daily oral indomethacin, zinc and omeprazole (Regimen 1) compared to the identical regimen without the IRX-2 cytokines (Regimen 2). The NanoString immune panel (730 genes) and Infinium MethylationEPIC BeadChip were performed to assess the gene expression and DNA methylation signatures, respectively, in pre- and post-immunotherapy tumor samples. Results: A total of 51 and 79 immune-related genes were found upregulated and downregulated, respectively, in the samples from Regimen 1 patients after treatment, while 51 and 56 were found upregulated and downregulated in the samples for Regimen 2. When comparing the changes between the two regimens, we identified 9 genes significantly different, including DMBT1, a potential tumor suppressor, functioning in tumor invasion of head and neck cancer. The exploration of DNA methylation showed slight overall hypermethylation after treatment in both regimens, especially for Regimen 1 immune responders, and methylation-based cell type deconvolution demonstrated high concordance with tumor infiltrating T lymphocyte cell counts. Conclusion: While a consistent patient response after treatment was observed, most changes were similar between regimens, indicating a subtle, targeted, or patient-specific effect of IRX-2 cytokines. Change in DMBT1 expression was a unique finding that will require further study to better understand its significance.

Original languageEnglish
Article number105587
JournalOral Oncology
Volume123
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Wolf was a recipient of grant funding from the clinical trial sponsor, Brooklyn ImmunoTherapeutics, for central laboratory tissue collection and correlative immune studies. Dr. Wolf also serves on the Scientific Advisory Board for Brooklyn ImmunoTherapeutics, Inc.

Funding Information:
Research reported in this publication was supported in part by grant funding from Brooklyn ImmunoTherapeutics, Inc., Brooklyn, New York and the National Cancer Institute of the National Institutes of Health under Award Number P30CA046592 by the use of the following Cancer Center Shared Resource(s): Tissue and Molecular Pathology. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Clinical trial was sponsored by Brooklyn ImmunoTherapeutics, Inc. and the Rogel Cancer Center at University of Michigan.

Publisher Copyright:
© 2021 Elsevier Ltd

Keywords

  • Cytokine
  • Immunotherapy
  • NanoString
  • Neoadjuvant
  • Oral cavity carcinoma
  • Tumor infiltrating lymphocytes

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research

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