Abstract
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.
Highlights
Metastatic cancer currently implies incurability for many patients and carries a guarded prognosis in humans and dogs alike, despite progress in available therapies
We have successfully used the theranostic pairing of 86Y-NM600 and 90Y-NM600 in mice to deliver tumor microenvironment (TME) modulating radiation therapy (~ 2–5 Gy) to second tumors, abrogating concomitant immune tolerance (CIT) [27, 28, 31]. This tri-modality immuno-radiotherapy approach theoretically could modulate the collective TME in a manner that promotes the propagation of an antitumor immune response to multifocal metastatic disease, as we have demonstrated by delivering external beam radiation therapy (EBRT) to both primary and secondary tumor sites in murine models [28]
All procedures and treatments performed on laboratory and client-owned companion dogs were approved by the Institutional Animal Care and Use Committees of the University of Wisconsin-Madison School of Veterinary Medicine (Approvals V006037 and V006123)
Summary
Metastatic cancer currently implies incurability for many patients and carries a guarded prognosis in humans and dogs alike, despite progress in available therapies. The immunologic effects of radiation on tumor cells and the tumor microenvironment (TME) are current areas of intense investigation. Inflammatory cytokine signaling and immune cell recruitment following irradiation can create a temporary immunostimulatory environment, [12,13,14], with increased presentation of tumor-antigens that may serve as an in situ vaccine for immune recognition. These local immunomodulating effects can result in abscopal responses that are immune mediated [15,16,17]. Sub-ablative external beam radiation therapy (EBRT) and systemic and local immunotherapeutic strategies have been shown in some
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