Emerging Translational Opportunities in Comparative Oncology With Companion Canine Cancers: Radiation Oncology.

It is estimated that more than 6 million pet dogs are diagnosed with cancer annually in the USA. Both primary care and specialist veterinarians are frequently called upon to provide clinical care that improves the quality and/or quantity of life for affected animals. Because these cancers develop spontaneously in animals that often share the same environment as their owners, have intact immune systems and are of similar size to humans, and because the diagnostic tests and treatments for these cancers are similar to those used for management of human cancers, canine cancer provides an opportunity for research that simultaneously helps improve both canine and human health care. This is especially true in the field of radiation oncology, for which there is a rich and continually evolving history of learning from the careful study of pet dogs undergoing various forms of radiotherapy. The purpose of this review article is to inform readers of the potential utility and limitations of using dogs in that manner; the peer-reviewed literature will be critically reviewed, and current research efforts will be discussed. The article concludes with a look toward promising future directions and applications of this pet dog "model.

Canine salivary gland carcinoma treated with stereotactic body radiation therapy: a retrospective case series

ObjectiveThe aim of this study was to describe the therapeutic outcomes of dogs with locally advanced salivary gland carcinomas (SGC) following stereotactic body radiation therapy (SBRT).MethodsA single institution retrospective study was conducted of client-owned dogs with macroscopic SGC treated with SBRT. Patient signalment, clinical characteristics, and treatment parameters were recorded. Clinical benefit was determined based on follow-up physical examination and medical history. Progression-free interval (PFI), median survival time (MST), and disease-specific survival (DSS) were calculated using Kaplan–Meier analysis. Acute and late toxicity were recorded according to Veterinary Radiation Therapy Oncology Group (VRTOG) criteria.ResultsSix patients were included in the study. Tumor origins were mandibular (n = 3), parotid (n = 2), and zygomatic (n = 1) salivary glands. The SBRT prescription was 10 Gy × 3 daily or every other day. All patients (100%) experienced clinical benefit from treatment at a median time of 34 days (range 28–214). No local or regional nodal failure was reported following SBRT. Progressive pulmonary metastatic disease was documented in three dogs (50%). The median PFI was 260 days (range 43–1,014) and the MST was 397 days (range 185–1,014). Median DSS was 636 days (range 185–1,014). Four dogs (66.6%) died of confirmed or suspected metastatic SGC. The reported acute side effects included grade 2 mucositis (n = 1) and vision loss (n = 1). No late side effects were recorded.ConclusionThis study suggests that SBRT may provide durable local control for invasive SGC in dogs. Further investigation in a larger cohort of patients is warranted. The incidence of reported acute and late toxicity was low

Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis.

BACKGROUND: Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT. METHODS: We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse models DEREG and BATF3-/-, flow and time-of-flight cytometry, RNA-Seq, Treg adoptive transfer studies, and in vitro experiments were used to further evaluate the role of dendritic cells (DCs) and Tregs in these treatments. RESULTS: In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103+ DC activation in tumor-draining lymph nodes as characterized by increases in CD80+ and CCR7+ DCs, resulting in a CD8 T cell-dependent response. Simultaneously, Tregs are reprogrammed to an effector phenotype demonstrated by increases in interferonγ+, tumor necrosis factorα+, PI3K+, pAKT+ and Eomes+ populations as well as decreases in CTLA4+ and NRP-1+ populations. Tumor eradication is observed when RT is increased to an 8 Gy x 5 hypofractionated regimen and combined with anti-CD25+ anti-CD137 treatment. In a human gene set from oral squamous cell carcinoma tumors, high Treg number is associated with earlier recurrence. CONCLUSIONS: Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches

Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy

Stereotactic body radiotherapy (SBRT) is known to induce important immunologic changes within the tumor microenvironment (TME). However, little is known regarding the early immune responses within the TME in the first few weeks following SBRT. Therefore, we used the canine spontaneous tumor model to investigate TME responses to SBRT, and how local injection of immune modulatory antibodies to OX40 and TLR 3/9 agonists might modify those responses. Pet dogs with spontaneous cancers (melanoma, carcinoma, sarcoma, n = 6 per group) were randomized to treatment with either SBRT or SBRT combined with local immunotherapy. Serial tumor biopsies and serum samples were analyzed for immunologic responses. SBRT alone resulted at two weeks after treatment in increased tumor densities of CD3+ T cells, FoxP3+ Tregs, and CD204+ macrophages, and increased expression of genes associated with immunosuppression. The addition of OX40/TLR3/9 immunotherapy to SBRT resulted in local depletion of Tregs and tumor macrophages and reduced Treg-associated gene expression (FoxP3), suppressed macrophage-associated gene expression (IL-8), and suppressed exhausted T cell-associated gene expression (CTLA4). Increased concentrations of IL-7, IL-15, and IL-18 were observed in serum of animals treated with SBRT and immunotherapy, compared to animals treated with SBRT. A paradoxical decrease in the density of effector CD3+ T cells was observed in tumor tissues that received combined SBRT and immunotherapy as compared to animals treated with SBRT only. In summary, these results obtained in a spontaneous large animal cancer model indicate that addition of OX40/TLR immunotherapy to SBRT modifies important immunological effects both locally and systemically

Linking the history of radiation biology to the hallmarks of cancer

Hanahan and Weinberg recently updated their conceptual framework of the “Hallmarks of Cancer”. The original article, published in 2000, is among the most highly cited reviews in the field of oncology. The goal of this review is to highlight important discoveries in radiation biology that pertain to the Hallmarks. We identified early studies that exemplified how ionizing radiation affects the hallmarks or how radiation was used experimentally to advance the understanding of key hallmarks. A literature search was performed to obtain relevant primary research, and topics were assigned to a particular hallmark to allow an organized, chronological account of the radiobiological advancements. The hallmarks are reviewed in an order that flows from cellular to microenvironmental effects

Emerging Translational Opportunities in Comparative Oncology With Companion Canine Cancers: Radiation Oncology.

It is estimated that more than 6 million pet dogs are diagnosed with cancer annually in the USA. Both primary care and specialist veterinarians are frequently called upon to provide clinical care that improves the quality and/or quantity of life for affected animals. Because these cancers develop spontaneously in animals that often share the same environment as their owners, have intact immune systems and are of similar size to humans, and because the diagnostic tests and treatments for these cancers are similar to those used for management of human cancers, canine cancer provides an opportunity for research that simultaneously helps improve both canine and human health care. This is especially true in the field of radiation oncology, for which there is a rich and continually evolving history of learning from the careful study of pet dogs undergoing various forms of radiotherapy. The purpose of this review article is to inform readers of the potential utility and limitations of using dogs in that manner; the peer-reviewed literature will be critically reviewed, and current research efforts will be discussed. The article concludes with a look toward promising future directions and applications of this pet dog "model.

Carcinosarcomas: tumors in transition?

Carcinosarcomas are rare, biphasic tumors that are comprised of carcinomatous and sarcomatous elements. While the exact mechanism by which these two phenotypes arise within a single tumor remains unclear, molecular evidence indicates that the epitheliod and spindle-cell components share a clonal origin. We propose that the biphasic nature of these neoplasms may represent an extreme case of epithelial plasticity, in which an epithelial-like cell undergoes a transition to a more mesenchymal phenotype. The present review will discuss both the histological and molecular biological evidence of the involvement of epithelial plasticity in driving the mixed phenotypes observed in carcinosarcomas

Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis

Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects