31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Leveraging telemedicine for management of veterans with heart failure during COVID-19.

BackgroundTelemedicine and telemonitoring have become invaluable tools in managing chronic diseases, such as heart failure (HF). With the recent pandemic, telemedicine has become the preferred method of providing consultative care.Local problemThis rapid paradigm shift from face-to-face (F2F) consultations to telemedicine required a collaborative approach for successful implementation while maintaining quality of care. The processes for conducting a telemedicine visit for HF patient are not well defined or outlined.MethodUsing a collaborative practice model and nurse practitioner led program, technology was leveraged to manage the high-risk HF population using virtual care (consultation via phone or video-to-home) with two aims: first to provide ongoing HF care using available telemedicine technologies or F2F care when necessary and, second, to evaluate and direct those needing urgent/emergent level of care to emergency department (ED).InterventionThe process was converted into an intuitive algorithm that describes essential elements and team roles necessary for execution of a successful HF consultation.ResultsFollowing the algorithm, nurse practitioners conducted 132 visits, yielding 100% success in the conversion of F2F appointments to telemedicine, with 3 patients referred to ED for care. The information obtained through telemedicine consultation accurately informed decision for ED evaluation with resultant admission.ConclusionCollaborative team-based approach delineated in the algorithm facilitated successful virtual consultations for HF patients and accurately informed decisions for higher level of care

Leveraging telemedicine for management of veterans with heart failure during COVID-19

BackgroundTelemedicine and telemonitoring have become invaluable tools in managing chronic diseases, such as heart failure (HF). With the recent pandemic, telemedicine has become the preferred method of providing consultative care.Local problemThis rapid paradigm shift from face-to-face (F2F) consultations to telemedicine required a collaborative approach for successful implementation while maintaining quality of care. The processes for conducting a telemedicine visit for HF patient are not well defined or outlined.MethodUsing a collaborative practice model and nurse practitioner led program, technology was leveraged to manage the high-risk HF population using virtual care (consultation via phone or video-to-home) with two aims: first to provide ongoing HF care using available telemedicine technologies or F2F care when necessary and, second, to evaluate and direct those needing urgent/emergent level of care to emergency department (ED).InterventionThe process was converted into an intuitive algorithm that describes essential elements and team roles necessary for execution of a successful HF consultation.ResultsFollowing the algorithm, nurse practitioners conducted 132 visits, yielding 100% success in the conversion of F2F appointments to telemedicine, with 3 patients referred to ED for care. The information obtained through telemedicine consultation accurately informed decision for ED evaluation with resultant admission.ConclusionCollaborative team-based approach delineated in the algorithm facilitated successful virtual consultations for HF patients and accurately informed decisions for higher level of care

Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma

International audienceExisting antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632-45. ©2016 AACR