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

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 transla...

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Published in:	PloS one 2021-08, Vol.16 (8), p.e0255798-e0255798
Main Authors:	Magee, Kara, Marsh, Ian R, Turek, Michelle M, Grudzinski, Joseph, Aluicio-Sarduy, Eduardo, Engle, Jonathan W, Kurzman, Ilene D, Zuleger, Cindy L, Oseid, Elizabeth A, Jaskowiak, Christine, Albertini, Mark R, Esbona, Karla, Bednarz, Bryan, Sondel, Paul M, Weichert, Jamey P, Morris, Zachary S, Hernandez, Reinier, Vail, David M
Format:	Article
Language:	eng
Subjects:	Adverse events Animal models Animals Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal - therapeutic use Antitumor activity Biomedical materials Biopsy Bone marrow Bone Marrow - chemistry Bone Marrow - metabolism Bone Marrow - pathology Cancer Cancer therapies Cancer vaccines Care and treatment Combined Modality Therapy Dogs Dosage Dosimeters Dosimetry Drug dosages Feasibility Feasibility Studies Female Funding Gene Expression Health physics Immunization Immunohistochemistry Immunomodulation Immunotherapy Interleukin 2 Interleukin-2 - adverse effects Interleukin-2 - therapeutic use Investigations Laboratories Leukocytes, Mononuclear - cytology Leukocytes, Mononuclear - metabolism Lymphocytes, Tumor-Infiltrating - cytology Lymphocytes, Tumor-Infiltrating - metabolism Male Melanoma Melanoma - immunology Melanoma - pathology Melanoma - therapy Melanoma - veterinary Metastases Metastasis Methods Osteosarcoma Osteosarcoma - immunology Osteosarcoma - therapy Osteosarcoma - veterinary Patient outcomes Physics Positron emission Positron Emission Tomography Computed Tomography Public health Radiation therapy Radioisotopes Radiopharmaceuticals - adverse effects Radiopharmaceuticals - chemistry Radiopharmaceuticals - therapeutic use Radiotherapy Safety Software Tomography Translational research Tumor microenvironment Tumors Vaccination Vaccines Veterinary colleges Veterinary medicine Yttrium isotopes Yttrium Radioisotopes - chemistry
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Summary:	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. 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. 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. 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.
ISSN:	1932-6203 1932-6203