BackgroundInflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC.MethodsTen IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2–0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry.ResultsTwo neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg+/CD8+ ratio and changes in CD8+Granzyme B+ T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3+ lymphocytes, decrease in FoxP3+/CD3+ ratio (p<0.04 for all comparisons), and no changes in CC-3+ immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy.ConclusionsNeoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients.

Canine inflammatory mammary cancer (IMC) is highly malignant, invasive and a therapeutic challenge, because effective medical treatment is still unavailable. This retrospective study compares the efficacy of an oral cyclooxygenase‐2 (COX‐2) inhibitor combined with toceranib phosphate and oral cyclophosphamide (multi‐drug therapy [MT]) with COX‐2 inhibitor therapy alone (single‐drug therapy [ST]) in dogs diagnosed with secondary IMC. Clinical response, adverse events, overall survival time (OST), disease‐free survival (DFS) and time to progression (TTP) were evaluated. Sixteen patients were included, eight received MT and eight receiving ST. Median OST was significantly higher in patients receiving MT (96.0 vs. 37.5 days; p = .046) and in patients with post‐surgical rather than non‐surgical IMC (86.5 vs. 41.5 days; p = .038). Additionally, median TTP was significantly higher in patients treated with MT (p = .010). In patients with non‐surgical IMC, the clinical benefit (CB) was reached in 100% (n = 3) of patients receiving MT and in 33% (n = 1) of those receiving ST; the response duration was significantly longer in MT cases (p = .026). The absence of disease progression at day 30 of treatment was significantly associated with longer OST, DFS and TTP (p = .018, p = .002 and p < .001, respectively). Adverse events occurred more frequently in patients treated with MT compared with ST (p = .026). The MT protocol produced primarily mild to moderate toxicities, which were resolved with supportive care; therefore, the combination of drugs was adequately tolerated by most of the patients. The combination of toceranib, a COX‐2 inhibitor and oral cyclophosphamide may be a protocol with potential therapeutic efficacy for dogs with IMC.

Background: Systemic hypertension (SH) is common in dogs and humans with hypercortisolism and can persist after treatment. Objectives: To evaluate changes in prevalence of SH and systolic blood pressure (SBP) in dogs with pituitary-dependent hyperadrenocorticism (PDH) during the first year of trilostane treatment, its relationship with disease control and selected laboratory variables, and their response to antihypertensive treatment. Animals: Fifty-one dogs with PDH treated with trilostane Q12h. Methods: Prospective case series study. Dogs were evaluated at diagnosis (T0) and 1, 3, 6, and 12 months (T12). Dogs were classified as nonhypertensive (SBP < 160 mm Hg) or hypertensive (SBP≥160 mm Hg) and subclassified according to target organ damage (TOD) risk. Hypertensive dogs were treated with benazepril and, if control of SH was not achieved, amlodipine was added. Results: Prevalence of SH decreased from T0 (36/51) to T12 (17/37; P = .01). Changes in SBP during the study were influenced by the risk of TOD at T0. In severely hypertensive (SBP ≥ 180 mm Hg) dogs, the decrease in SBP was more pronounced whereas in normotensive (SBP < 140 mm Hg) dogs SBP increased slightly (P = .00). Blood pressure was not associated with disease control. Antihypertensive treatment was needed in 31/51 dogs, and in 13/31 dogs additional SH control with amlodipine was required. One third of nonhypertensive dogs at T0 required treatment with benazepril because SH developed during follow-up. Conclusions and Clinical Importance: In dogs with PDH, SBP should be measured at every visit, regardless of disease control or SBP at diagnosis. More than 1 drug may be necessary to manage SH in affected dogs.

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Background Twice daily low trilostane doses have proven to be effective to manage canine Cushing's syndrome. However, survival and prognostic factors in dogs treated with this protocol have not been evaluated. The aim of the study was to evaluate survival and prognostic factors, including systolic blood pressure (SBP) at diagnosis, in dogs with pituitary‐dependent hypercortisolism (PDH) treated with low trilostane doses. Methods Medical records of 91 dogs newly diagnosed with PDH initially treated with 0.2–1.1 mg/kg of trilostane twice daily were retrospectively included. Survival times were calculated using the Kaplan–Meier estimator. Univariable and multivariable analysis were performed using the Cox proportional hazard regression analysis. Results Overall, median survival was 998 days (range 26–1832 days, 95% confidence interval = 755–1241 days). In the multivariable analysis, age (hazard ratio [HR] = 1.337, p < 0.001), presence of calcinosis cutis (HR = 5.271, p < 0.001), body condition score (BCS) ≤3/9 (HR = 8.100, p < 0.001) and higher platelet count (HR = 1.002, p = 0.022) were negatively correlated with survival. SBP was not associated with survival. Conclusions Low‐dose trilostane treatment twice daily provides slightly longer survival than previously reported for dogs with PDH treated once or twice daily at higher doses. Older age, presence of calcinosis cutis, low BCS and higher platelet count, but not systemic hypertension, are predictive of poorer prognosis in dogs with PDH.

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Inflammatory breast cancer (IBC) is highly metastatic at the onset of the disease with no IBC-specific treatments, resulting in dismal patient survival. IBC treatment is a clear unmet clinical need. This commentary highlights findings from a recent seminal approach in which pembrolizumab, a checkpoint inhibitor against programmed cell death protein 1 (PD-1), was provided to a triple-negative IBC patient as a neoadjuvant immune therapy combined with anthracycline–taxane-based chemotherapy. We highlight the findings of the case report and offer a perspective on taking a proactive approach to deploy approved immune checkpoint inhibitors. On the basis of our recently published research study, we propose in situ vaccination with direct injection of immunostimulatory agents into the tumor as an option to improve outcomes safely, effectively, and economically for IBC patients.

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