c-FLIP Degradation Mediates Sensitization of Pancreatic Cancer Cells to TRAIL-Induced Apoptosis by the Histone Deacetylase Inhibitor LBH589

Great efforts have been made to develop novel and efficacious therapeutics against pancreatic cancer to improve the treatment outcomes. Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) is such a therapeutic cytokine with selective killing effect toward malignant cells. However, some human pancreatic cancers are intrinsically resistant to TRAIL-mediated apoptosis or therapy. In this study, we have shown that the histone deacetylase inhibitor LBH589 can synergize with TRAIL to augment apoptosis even in TRAIL-resistant cells. LBH589 decreased c-FLIP levels in every tested cell line and survivin levels in some of the tested cell lines. Enforced expression of ectopic c-FLIP, but not survivin, abolished the cooperative induction of apoptosis by the combination of LBH589 and TRAIL, indicating that c-FLIP downregulation plays a critical role in LBH589 sensitization of pancreatic cancer cells to TRAIL. Moreover, LBH589 decreased c-FLIP stability and the presence of the proteasome inhibitor MG132 prevented c-FLIP from reduction by LBH589. Correspondingly, we detected increased levels of ubiqutinated c-FLIP in LBH589-treated cells. These data thus indicate that LBH589 promotes ubiqutin/proteasome-mediated degradation of c-FLIP, leading to downregulation of c-FLIP. Collectively, LBH589 induces c-FLIP degradation and accordingly sensitizes pancreatic cancer cells to TRAIL-induced apoptosis, highlighting a novel therapeutic regimen against pancreatic cancer

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

Examining racial disparities in colorectal cancer care.

African Americans are disproportionately burdened with colorectal cancer. Although incidence and mortality rates have declined in the past two decades, the disparity in health outcomes has progressively increased. This comprehensive review examines the existing literature regarding racial disparities in colorectal cancer screening, stage at diagnosis, and treatment to determine if differences exist in the quality of care delivered to African Americans. A comprehensive review of relevant literature was performed. Two databases (EBSCOHOST Academic Search Premier and Scopus) were searched from 2000 to 2007. Articles that assessed racial disparities in colorectal cancer screening, stage of disease at diagnosis, and treatment were selected. The majority of studies identified examined colorectal cancer screening outcomes. Although racial disparities in screening have diminished in recent years, African American men and women continue to have higher colorectal cancer incidence and mortality rates and are diagnosed at more advanced stages. Several studies regarding stage of disease at diagnosis identified socioeconomic status (SES) and health insurance status as major determinants of disparity. However, some studies found significant racial disparities even after controlling for these factors. Racial disparities in treatment were also found at various diagnostic stages. Many factors affecting disparities between African Americans and Whites in colorectal cancer incidence and mortality remain unexplained. Although the importance of tumor biology, genetics, and lifestyle risk factors have been established, prime sociodemographic factors need further examination to understand variances in the care of African Americans diagnosed with colorectal cancer

Phase 1, multicenter, open-label study of single-agent bispecific antibody T-cell engager GBR 1342 in relapsed/refractory multiple myeloma

TPS81 Background: Available therapies have improved outcomes in multiple myeloma but patients eventually relapse, requiring treatment with agents that are active in refractory disease. CD38, a transmembrane glycoprotein, is upregulated on myeloma cells and is a validated disease target, evidenced by the anti-myeloma activity of daratumumab, an anti-CD38 human IgG1κ monoclonal antibody. GBR 1342 is a CD3xCD38 bispecific antibody engineered (using Glenmark’s BEAT ® platform) to direct T-cells to CD38-expressing myeloma cells. In preclinical studies, GBR 1342 redirected the cytotoxic potential of T-cells to human myeloma cell lines in vitro and in mouse xenograft models. This ongoing, 2-part, first-in-human study aims to: (1) evaluate the safety profile and maximum tolerable dose (MTD) of GBR 1342 monotherapy in subjects with relapsed/refractory multiple myeloma ( > 3 prior therapies); and (2) further elucidate the safety, tolerability, and preliminary clinical activity of GBR 1342 at the MTD. The study is also evaluating the mechanisms by which GBR 1342 redirects T-cells to tumor and enhances cytolytic activity of cytotoxic T-cells. Methods: In Part 1, intravenous GBR 1342 is administered on Day 1 and Day 15 in 28-day treatment cycles at escalating dose levels (Table). The first 4 cohorts consist of a single subject. Subsequent cohorts will enroll using a 3+3 design. In Part 2, 65 evaluable subjects will be treated at the MTD identified in Part 1 until disease progression or unacceptable toxicity occurs. Primary endpoints include frequency and severity of AEs, number of dose-limiting toxicities during Cycle 1 (Part 1 only), and objective response to GBR 1342 (Part 2 only). Secondary endpoints include pharmacokinetics and anti-tumor activity of GBR 1342 (objective response, progression-free and overall survival). [Table: see text

Fractional Flow Reserve Derived from Coronary Computed Tomography Angiography Safely Defers Invasive Coronary Angiography in Patients with Stable Coronary Artery Disease

Objectives: In the United States, the real-world feasibility and outcome of using fractional flow reserve from coronary computed tomography angiography (FFRCT) is unknown. We sought to determine whether a strategy that combined coronary computed tomography angiography (CTA) and FFRCT could safely reduce the need for invasive coronary angiography (ICA), as compared to coronary CTA alone. Methods: The study included 387 consecutive patients with suspected CAD referred for coronary CTA with selective FFRCT and 44 control patients who underwent CTA alone. Lesions with 30–90% diameter stenoses were considered of indeterminate hemodynamic significance and underwent FFRCT. Nadir FFRCT ≤ 0.80 was positive. The rate of patients having ICA, revascularization and major adverse cardiac events were recorded. Results: Using coronary CTA and selective FFRCT, 121 patients (32%) had at least one vessel with ≥50% diameter stenosis; 67/121 (55%) patients had at least one vessel with FFRCT ≤ 0.80; 55/121 (45%) underwent ICA; and 34 were revascularized. The proportion of ICA patients undergoing revascularization was 62% (34 of 55). The number of patients with vessels with 30–50% diameter of stenosis was 90 (23%); 28/90 (31%) patients had at least one vessel with FFRCT ≤ 0.80; 8/90 (9%) underwent ICA; and five were revascularized. In our institutional practice, compared to coronary CTA alone, coronary CTA with selective FFRCT reduced the rates of ICA (45% vs. 80%) for those with obstructive CAD. Using coronary CTA with selective FFRCT, no major adverse cardiac events occurred over a mean follow-up of 440 days. Conclusion: FFRCT safely deferred ICA in patients with CAD of indeterminate hemodynamic significance. A high proportion of those who underwent ICA were revascularized.Medicine, Faculty ofOther UBCNon UBCRadiology, Department ofReviewedFacult