We have shown, for the first time that NDV, like other oncolytic viruses, is a potent mediator of acute vascular shutdown and that preventing this through vascular normalization can promote regression in a preclinical model of advanced stage ovarian cancer. This challenges the current focus on induction of intravascular thrombosis as a requisite for successful oncolytic virotherapy.

The incidence of thyroid cancers has been steadily increasing worldwide over the past few decades. Although five-year survival rates for differentiated thyroid cancers are upwards of 90%, clinical outcomes for patients with undifferentiated, recurrent and/or metastatic disease are often dismal despite conventional interventions. As such, there is a demand for novel treatment options. Cancer immunotherapy represents the ultimate form of personalized medicine by leveraging the specificity and potency of a patient's immune system to kill their tumor. The thyroid cancer microenvironment is rich in immunological cells, making it a reasonable candidate for immunotherapy. This review maps out the immunological features of thyroid cancers and how these can be modulated. There are surprising immunological consequences of conventional therapies that demand attention. Also, hormonal modulation of the immune system is highlighted as a unique and confounding feature of thyroid cancers. A variety of cuttingedge immune-based therapies are discussed, with an emphasis placed on how these can be integrated with the current standard of care. Several high priority areas in need of research are also highlighted.

For a vaccine to be effective it must induce a sufficiently robust and specific immune response. Multi-site injection protocols can increase the titers of rabies virus-neutralizing antibodies. Hypothetically, spreading a vaccine dose across multiple lymphatic drainage regions could also potentiate T cell responses. We used a replication-deficient adenovirus serotype 5-vectored cancer vaccine targeting the melanoma-associated antigen dopachrome tautomerase. Clinically, high numbers of tumor-infiltrating CD8+ T cells are a positive prognostic indicator. As such, there is interest in maximizing tumor-specific T cell responses. Our findings confirm a positive correlation between the number of tumor-specific T cells and survival. More importantly, we show for the first time that using multiple injection sites could increase the number of vaccine-induced CD8+ T cells specific for a self-tumor antigen. Further, the number of tumor antigen-specific antibodies, as well CD8+ T cells specific for a foreign antigen could also be enhanced. Our results show that multi-site vaccination induces higher magnitude immune responses than a single-bolus injection. This provides a very simple and almost cost-free strategy to potentially improve the efficacy of any current and future vaccine. Broader clinical adoption of multi-site vaccination protocols for the treatment of cancers and infectious diseases should be given serious consideration.

<p>Supplementary Figure 1 Supplementary Data, Figure 1. Combination therapy results in decreased ascites fluid volume. At euthanasia, ascites fluid was aspirated from the abdomen of control and treated mice and the volume was quantified. Combined treatment with 3TSR and NDV(F3aa) resulted in a significant reduction in ascites volume compared to controls or other treatment groups. Means+/- SEM are shown. Data represents results from N=12 animals per experimental group. Data were analyzed by one-way analysis of variance with Tukey's multiple comparison test; *P<0.05.</p>

<p>Supplementary Data Figure 2 Supplementary Data, Figure 2. ID8, CAOV-3 and NOSE cells were infected or mock infected (1x PBS) at an MOI of 0.1. Infected and uninfected cells were collected 24 hours later and stained for Annexin V a marker for early apoptosis and 7-Aminoactinomycin D (7AAD) a marker for dead cells (N=3). A, The cytogram of the four quadrants was used to distinguish normal (Annexin Vâ^'/7AAD+), early apoptotic (Annexin V+/7AADâ^'), late apoptotic (Annexin V+/7AAD+), and necrotic cells (Annexin Vâ^'/7AAD+). B, The sum of early and late apoptosis was presented as total apoptosis. Means +/- SEM are shown. Data were analyzed by 2way analysis of variance with Sidak's multiple comparison test; **,P<0.01 (N=3).</p>