2. Academic Validation
  3. Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting

Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting

  • PLoS One. 2021 Aug 12;16(8):e0255798. doi: 10.1371/journal.pone.0255798.
Kara Magee 1,  Ian R Marsh 2,  Michelle M Turek 3,  Joseph Grudzinski 2,  Eduardo Aluicio-Sarduy 2,  Jonathan W Engle 2,  Ilene D Kurzman 1,  Cindy L Zuleger 4 5,  Elizabeth A Oseid 6,  Christine Jaskowiak 7,  Mark R Albertini 4 5 8,  Karla Esbona 9,  Bryan Bednarz 2 7,  Paul M Sondel 5 10 11,  Jamey P Weichert 5 7,  Zachary S Morris 5 9,  Reinier Hernandez 2 5 7,  David M Vail 1 5
Affiliations

Affiliations

  • 1 Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
  • 2 Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
  • 3 Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
  • 4 Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
  • 5 Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
  • 6 Office of Environment, Health and Safety, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
  • 7 Department of Radiology, School of Medicine and Public Health, Madison, Wisconsin, United States of America.
  • 8 The Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, United States of America.
  • 9 Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, Madison, Wisconsin, United States of America.
  • 10 Department of Human Oncology, School of Medicine and Public Health, Madison, Wisconsin, United States of America.
  • 11 Department of Pediatrics, School of Medicine and Public Health, Madison, Wisconsin, United States of America.
PMID: 34383787 DOI: 10.1371/journal.pone.0255798
Abstract

Rationale: Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced Cancer.

Methods: The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage Cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed.

Results: The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT.

Conclusions: The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.

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