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

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.

Chronic adrenergic stress and generation of myeloid‐derived suppressor cells: Implications for cancer immunotherapy in dogs

“…New tools and approaches including targeted immunotherapies are being developed for dogs with cancer, and dogs are now widely recognised as an important spontaneous large animal model for investigating new approaches to treating cancer in humans. [65][66][67][68] The value of dogs as an immune cancer model stems in part from their 'educated' immune system, sculpted by prior vaccines, infections and age, much like the human immune system. In addition, the tumour biological behaviour in dogs more closely resembles human cancer responses, especially with respect to tumour metastatic processes.…”

Leading the pack: Best practices in comparative canine cancer genomics to inform human oncology

“…More recently, high intensity focused ultrasound (HIFU) was used to treat pet dogs with solid tumours and nCounter analysis of biopsy samples demonstrated differential expression of 28 genes associated with T‐cell activation following treatment 103 . Several other groups have published gene expression data generated from canine samples using the nCounter platform, and a multitude of studies are ongoing using this tool as part of the PRECINCT consortium 104–106 . It is worth noting that custom panels can be designed to facilitate targeted interrogation.…”

“…103 Several other groups have published gene expression data generated from canine samples using the nCounter platform, and a multitude of studies are ongoing using this tool as part of the PRECINCT consortium. [104][105][106] It is worth noting that custom panels can be designed to facilitate targeted interrogation. This approach was recently employed to support validation of an antibody panel designed to distinguish lymphoid versus myeloid lineage leukaemias, demonstrating 100% concordance between flow cytometry and gene expression for the lymphoid leukaemias and 80% concordance for myeloid leukaemias.…”

Canine Melanoma Immunology and Immunotherapy: Relevance of Translational Research

“…The combination of immunotherapy with local radiotherapy and/or chemotherapy that can induce immunogenic cell death is likewise a favorable way to prompt a more effective systemic anti-tumor immune response (100)(101)(102).…”

“…As an example, combinatorial approaches encompassing the use of cytokines, STING agonist and/or vaccines have indeed demonstrated enhanced efficacy when combined to radiotherapy in both pre-clinical and clinical studies, achieving improved therapeutic effects on melanoma-derived metastasis (103,104). Recently the combination of trimodal radiotherapy and intratumoral immunocytokine vaccination has been tested in advanced stage tumor-bearing dogs, including melanoma cases, and has preliminarily showed to induce positive immunomodulatory effects within the primary tumor (100). All these studies provide the proofs of principle of FIGURE 1 | B7-H3 expression and targeting in OMM.…”