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

<h4>Rationale</h4>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...

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Autores principales:	Kara Magee, Ian R Marsh, Michelle M Turek, Joseph Grudzinski, Eduardo Aluicio-Sarduy, Jonathan W Engle, Ilene D Kurzman, Cindy L Zuleger, Elizabeth A Oseid, Christine Jaskowiak, Mark R Albertini, Karla Esbona, Bryan Bednarz, Paul M Sondel, Jamey P Weichert, Zachary S Morris, Reinier Hernandez, David M Vail
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/614577853cda400990756e8aa63b13c4
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spelling	oai:doaj.org-article:614577853cda400990756e8aa63b13c42021-12-02T20:18:19ZSafety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.1932-620310.1371/journal.pone.0255798https://doaj.org/article/614577853cda400990756e8aa63b13c42021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255798https://doaj.org/toc/1932-6203<h4>Rationale</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Kara MageeIan R MarshMichelle M TurekJoseph GrudzinskiEduardo Aluicio-SarduyJonathan W EngleIlene D KurzmanCindy L ZulegerElizabeth A OseidChristine JaskowiakMark R AlbertiniKarla EsbonaBryan BednarzPaul M SondelJamey P WeichertZachary S MorrisReinier HernandezDavid M VailPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0255798 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kara Magee Ian R Marsh Michelle M Turek Joseph Grudzinski Eduardo Aluicio-Sarduy Jonathan W Engle Ilene D Kurzman Cindy L Zuleger Elizabeth A Oseid Christine Jaskowiak Mark R Albertini Karla Esbona Bryan Bednarz Paul M Sondel Jamey P Weichert Zachary S Morris Reinier Hernandez David M Vail Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
description	<h4>Rationale</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
format	article
author	Kara Magee Ian R Marsh Michelle M Turek Joseph Grudzinski Eduardo Aluicio-Sarduy Jonathan W Engle Ilene D Kurzman Cindy L Zuleger Elizabeth A Oseid Christine Jaskowiak Mark R Albertini Karla Esbona Bryan Bednarz Paul M Sondel Jamey P Weichert Zachary S Morris Reinier Hernandez David M Vail
author_facet	Kara Magee Ian R Marsh Michelle M Turek Joseph Grudzinski Eduardo Aluicio-Sarduy Jonathan W Engle Ilene D Kurzman Cindy L Zuleger Elizabeth A Oseid Christine Jaskowiak Mark R Albertini Karla Esbona Bryan Bednarz Paul M Sondel Jamey P Weichert Zachary S Morris Reinier Hernandez David M Vail
author_sort	Kara Magee
title	Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
title_short	Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
title_full	Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
title_fullStr	Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
title_full_unstemmed	Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
title_sort	safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/614577853cda400990756e8aa63b13c4
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Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.

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